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1. Defective activation and regulation of type I interferon immunity is associated with increasing COVID-19 severity

Author: Nikaïa Smith, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, Bruno Charbit, Vincent Rouilly, Violaine Saint-André, Tom Dott, Andre Rodriguez Pozo, Nader Yatim, Olivier Schwartz, Minerva Cervantes-Gonzalez, Jade Ghosn, Paul Bastard, Jean Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O’Farrelly, Clíona Ní Cheallaigh, Nollaig M. Bourke, and Darragh Duffy
Subjects: Science
Abstract: The interferon response has been shown to be linked to severity of SARS-CoV-2 infection and is an essential component of the immune response to COVID-19. Here the authors stratify patients according to COVID-19 severity and asses the interferon response showing defective responses in severe infection and highlight the importance of assay variables and confounding factors that impact the detection of interferon.
Published: 2022
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2. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author: Alba Llibre, Nikaïa Smith, Vincent Rouilly, Munyaradzi Musvosvi, Elisa Nemes, Céline Posseme, Simbarashe Mabwe, Bruno Charbit, Stanley Kimbung Mbandi, Elizabeth Filander, Hadn Africa, Violaine Saint-André, Vincent Bondet, Pierre Bost, Humphrey Mulenga, Nicole Bilek, Matthew L. Albert, Thomas J. Scriba, and Darragh Duffy
Subjects: tuberculosis, IL-1ra, IL-1, immunometabolism, systems immunology, Immunologic diseases. Allergy, RC581-607
Abstract: Tuberculosis (TB) remains a major public health problem and we lack a comprehensive understanding of how Mycobacterium tuberculosis (M. tb) infection impacts host immune responses. We compared the induced immune response to TB antigen, BCG and IL-1β stimulation between latently M. tb infected individuals (LTBI) and active TB patients. This revealed distinct responses between TB/LTBI at transcriptomic, proteomic and metabolomic levels. At baseline, we identified a novel immune-metabolic association between pregnane steroids, the PPARγ pathway and elevated plasma IL-1ra in TB. We observed dysregulated IL-1 responses after BCG stimulation in TB patients, with elevated IL-1ra responses being explained by upstream TNF differences. Additionally, distinct secretion of IL-1α/IL-1β in LTBI/TB after BCG stimulation was associated with downstream differences in granzyme mediated cleavage. Finally, IL-1β driven signalling was dramatically perturbed in TB disease but was completely restored after successful treatment. This study improves our knowledge of how immune responses are altered during TB disease, and may support the design of improved preventive and therapeutic tools, including host-directed strategies.
Published: 2022
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3. Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients

Author: Alice Courties, Jeremy Boussier, Jérôme Hadjadj, Nader Yatim, Laura Barnabei, Hélène Péré, David Veyer, Solen Kernéis, Nicolas Carlier, Frédéric Pène, Frédéric Rieux-Laucat, Bruno Charbit, Vincent Bondet, Darragh Duffy, Francis Berenbaum, Benjamin Terrier, and Jérémie Sellam
Subjects: Medicine, Science
Abstract: Abstract The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9–11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.
Published: 2021
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4. Activation of NLRP3 Inflammasome in the Skin of Patients with Systemic and Cutaneous Lupus Erythematosus

Author: Katariina Mähönen, Annika Hau, Vincent Bondet, Darragh Duffy, Kari K. Eklund, Jaana Panelius, and Annamari Ranki
Subjects: cutaneous lupus erythematosus, inflammasomes, IL-1 beta, type I interferon, Dermatology, RL1-803
Abstract: NLRP3 inflammasome is suggested to contribute to the complex pathogenesis of systemic lupus erythematosus, but its role in cutaneous lupus erythematosus has not been addressed. This study investigated the expression of NLRP3 inflammasome components and levels of type I interferons in the skin of 20 patients with cutaneous lupus erythematosus. Expression of NLRP1/3, adaptor protein ASC (apoptosis-associated speck-like protein), caspase-1, interferon-α (IFN-α), myxovirus resistance protein (MxA), and interferon-induced proteins 1 and 2 (IFIT 1/2) in the skin was assessed using reverse transcription quantitative real-time PCR (RT-qPCR), western blotting and immunohistochemistry. Serum interferon-α protein levels from 12 patients were measured using digital enzyme-linked immunoassay (ELISA). Interleukin-1β expression was significantly upregulated in the lesional skin of patients with cutaneous lupus erythematosus compared with their uninvolved skin. However, NLRP1/3, ASC and caspase-1 were not significantly upregulated compared with the skin of control persons. IFN-α and IFN-induced proteins MxA and IFIT1/2 were strongly expressed in cutaneous lupus erythematosus skin. Variability in the expression of NLRP3 inflammasome components among patients suggests heterogeneity of pathological pathways in cutaneous lupus erythematosus.
Published: 2022
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5. Primary immune responses are negatively impacted by persistent herpesvirus infections in older people: results from an observational study on healthy subjects and a vaccination trial on subjects aged more than 70 years old

Author: Francesco Nicoli, Emmanuel Clave, Kerstin Wanke, Amrei von Braun, Vincent Bondet, Cécile Alanio, Corinne Douay, Margaux Baque, Claire Lependu, Peggy Marconi, Karin Stiasny, Franz X. Heinz, Margot Muetsch, Darragh Duffy, Jacques Boddaert, Delphine Sauce, Antoine Toubert, Urs Karrer, and Victor Appay
Subjects: Naive T lymphocytes, Thymus, Elderly, T-cell responses, Vaccines, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood. We aimed here at establishing the influence of persistent viral infections on the naive T-cell compartment and primary immune responsiveness in older adults. Methods: We assessed immunological parameters, related to CD8+ and CD4+ T-cell responsiveness, according to the serological status for common latent herpesviruses in two independent cohorts: 1) healthy individuals aged 19y to 95y (n = 150) and 2) individuals above 70y old enrolled in a primo-vaccination clinical trial (n = 137). Findings: We demonstrate a prevalent effect of age and CMV infection on CD8+ and CD4+ naive T cells, respectively. CMV seropositivity was associated with blunted CD4+ T-cell and antibody responses to primary vaccination. Interpretation: These data provide insights on the changes in adaptive immunity over time and the associated decline in vaccine efficacy with ageing. This knowledge is important for the management of emerging infectious diseases in elderly populations.
Published: 2022
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6. Constitutive IFNα Protein Production in Bats

Author: Vincent Bondet, Maxime Le Baut, Sophie Le Poder, Alexis Lécu, Thierry Petit, Rudy Wedlarski, Darragh Duffy, and Delphine Le Roux
Subjects: Chiroptera, bats, type I IFN, Simoa digital ELISA, protein levels, antiviral immunity, Immunologic diseases. Allergy, RC581-607
Abstract: Bats are the only mammals with self-powered flight and account for 20% of all extant mammalian diversity. In addition, they harbor many emerging and reemerging viruses, including multiple coronaviruses, several of which are highly pathogenic in other mammals, but cause no disease in bats. How this symbiotic relationship between bats and viruses exists is not yet fully understood. Existing evidence supports a specific role for the innate immune system, in particular type I interferon (IFN) responses, a major component of antiviral immunity. Previous studies in bats have shown that components of the IFN pathway are constitutively activated at the transcriptional level. In this study, we tested the hypothesis that the type I IFN response in bats is also constitutively activated at the protein level. For this, we utilized highly sensitive Single Molecule (Simoa) digital ELISA assays, previously developed for humans that we adapted to bat samples. We prospectively sampled four non-native chiroptera species from French zoos. We identified a constitutive expression of IFNα protein in the circulation of healthy bats, and concentrations that are physiologically active in humans. Expression levels differed according to the species examined, but were not associated with age, sex, or health status suggesting constitutive IFNα protein expression independent of disease. These results confirm a unique IFN response in bat species that may explain their ability to coexist with multiple viruses in the absence of pathology. These results may help to manage potential zoonotic viral reservoirs and potentially identify new anti-viral strategies.
Published: 2021
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7. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

Author: Priyanka Devi-Marulkar, Carolina Moraes-Cabe, Pascal Campagne, Béatrice Corre, Aida Meghraoui-Kheddar, Vincent Bondet, Alba Llibre, Darragh Duffy, Elisabeth Maillart, Caroline Papeix, Sandra Pellegrini, and Frédérique Michel
Subjects: multiple sclerosis, type I interferon, T cells, interferon-stimulated genes, HLA class II genes, immune phenotypes, Immunologic diseases. Allergy, RC581-607
Abstract: BackgroundInterferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients.AimTo determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach.MethodsThe immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors.ResultsClinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
Published: 2021
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8. Type I interferon in patients with systemic autoimmune rheumatic disease is associated with haematological abnormalities and specific autoantibody profiles

Author: John A. Reynolds, Tracy A. Briggs, Gillian I. Rice, Sathya Darmalinggam, Vincent Bondet, Ellen Bruce, Mumtaz Khan, Sahena Haque, Hector Chinoy, Ariane L. Herrick, Eoghan M. McCarthy, Leo Zeef, Andrew Hayes, Darragh Duffy, Ben Parker, and Ian N. Bruce
Subjects: Systemic autoimmune rheumatic disease, Interferon alpha, Autoantibodies, Diseases of the musculoskeletal system, RC925-935
Abstract: Abstract Objectives To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. Methods We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. Results Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p
Published: 2019
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9. First description of agonist and antagonist IP-10 in urine of patients with active TB

Author: Linda Petrone, Vincent Bondet, Valentina Vanini, Gilda Cuzzi, Fabrizio Palmieri, Ivana Palucci, Giovanni Delogu, Fabiola Ciccosanti, Gian Maria Fimia, Thomas Blauenfeldt, Morten Ruhwald, Darragh Duffy, and Delia Goletti
Subjects: Infectious and parasitic diseases, RC109-216
Abstract: Objectives: Biomarkers for tuberculosis (TB) diagnosis and clinical management are needed to defeat TB. In chronic hepatitis, patients not responding to interferon/ribavirin treatment had high levels of an antagonist form of IP-10. Recently, antagonist IP-10 has been shown to be involved also in TB pathogenesis. Here, we investigated IP-10 agonist/antagonist forms as potential inflammatory biomarkers to support TB diagnosis and monitoring. Methods: Total IP-10 and its agonist/antagonist forms were measured by SIMOA digital ELISA in urine obtained from patients with active TB at baseline and after treatment. Healthy donors (HD) and patients with pneumonia were enrolled as controls. Results: Patients with active TB had significantly higher levels of total and agonist IP-10 at baseline compared to HD; conversely, no differences were observed between IP-10 levels in active TB vs pneumonia. Moreover, in active TB a decline of total urine IP-10 was observed at therapy completion; agonist/antagonist forms reflected this decline although their differences were not statistically significant. Conclusions: We showed for the first time that agonist/antagonist IP-10 forms are measurable in urine. IP-10 levels associate with TB and pneumonia disease, suggesting their association with acute inflammation. Further studies are needed to assess their role to monitor TB treatment efficacy. Keywords: Tuberculosis, Biomarker, IP-10 antagonism, Urine, Treatment monitoring
Published: 2019
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10. CXCR3 Expression Pattern on CD4+ T Cells and IP-10 Levels with Regard to the HIV-1 Reservoir in the Gut-Associated Lymphatic Tissue

Author: Max Augustin, Carola Horn, Meryem Seda Ercanoglu, Ute Sandaradura de Silva, Vincent Bondet, Isabelle Suarez, Seung-Hun Chon, Dirk Nierhoff, Elena Knops, Eva Heger, Carlo Vivaldi, Hartmut Schäfer, Mark Oette, Gerd Fätkenheuer, Florian Klein, Darragh Duffy, Michaela Müller-Trutwin, and Clara Lehmann
Subjects: HIV reservoir, GALT, cART, CXCR3, IP-10, immune activation, Medicine
Abstract: (1) Background: The gut-associated lymphatic tissue (GALT) represents the largest lymphoid organ, and is considered to be the largest HIV reservoir. The exact size of the GALT reservoir remains unclear. Several markers, such as the chemokine receptor CXCR3 and its pro-inflammatory ligand IP-10, have been proposed to define the size of HIV reservoirs in the peripheral blood (PB). However, little is known about the role of CXCR3 and IP-10 within the GALT. (2) Methods: We compared the CXCR3 expression, IP-10 levels, and cell-associated HIV DNA of distinct memory CD4+ T cell subsets from the terminal ileum (TI), PB and rectum (RE) of 18 HIV+ patients with antiretroviral therapy (ART), 6 HIV+ treatment-naive patients and 16 healthy controls. (3) Results: While the relative distributions of CD4+ T cell subsets were similar in PB, TI and RE, HIV DNA and CXCR3 expression were markedly increased and IP-10 levels were decreased in TI when compared to PB. No significant correlation was found between the CXCR3 expression and memory CD4+ T cell subsets, IP-10 levels and the HIV DNA amounts measured in PB, TI or RE. (4) Conclusions: During a chronic HIV-1 infection, neither CXCR3 nor IP-10 are indicative of the size of the viral reservoir in the GALT (TI and RE).
Published: 2022
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11. Decreased Type I Interferon Production by Plasmacytoid Dendritic Cells Contributes to Severe Dengue

Author: Vinit Upasani, Carolina Scagnolari, Federica Frasca, Nikaïa Smith, Vincent Bondet, Axelle Vanderlinden, Sokchea Lay, Heidi Auerswald, Sothy Heng, Denis Laurent, Sowath Ly, Veasna Duong, Guido Antonelli, Philippe Dussart, Darragh Duffy, and Tineke Cantaert
Subjects: dengue virus, plasmacytoid dendritic cell, myloid dendritic cells, interferon stimulated genes, simoa immunoassay, type I interferon, Immunologic diseases. Allergy, RC581-607
Abstract: The clinical presentation of dengue virus (DENV) infection is variable. Severe complications mainly result from exacerbated immune responses. Type I interferons (IFN-I) are important in antiviral responses and form a crucial link between innate and adaptive immunity. Their contribution to host defense during DENV infection remains under-studied, as direct quantification of IFN-I is challenging. We combined ultra-sensitive single-molecule array (Simoa) digital ELISA with IFN-I gene expression to elucidate the role of IFN-I in a well-characterized cohort of hospitalized Cambodian children undergoing acute DENV infection. Higher concentrations of type I IFN proteins were observed in blood of DENV patients, compared to healthy donors, and correlated with viral load. Stratifying patients for disease severity, we found a decreased expression of IFN-I in patients with a more severe clinical outcome, such as dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). This was seen in parallel to a correlation between low IFNα protein concentrations and decreased platelet counts. Type I IFNs concentrations were correlated to frequencies of plasmacytoid DCs, not DENV-infected myloid DCs and correlated inversely with neutralizing anti-DENV antibody titers. Hence, type I IFN produced in the acute phase of infection is associated with less severe outcome of dengue disease.
Published: 2020
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12. Dysregulation of tryptophan catabolism at the host-skin microbiota interface in hidradenitis suppurativa

Author: Laure Guenin-Macé, Jean-David Morel, Jean-Marc Doisne, Angèle Schiavo, Lysiane Boulet, Véronique Mayau, Pedro Goncalves, Sabine Duchatelet, Alain Hovnanian, Vincent Bondet, Darragh Duffy, Marie-Noëlle Ungeheuer, Maïa Delage, Aude Nassif, James P. Di Santo, and Caroline Demangel
Subjects: Dermatology, Inflammation, Medicine
Abstract: Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin.
Published: 2020
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13. The proteome of neutrophils in sickle cell disease reveals an unexpected activation of interferon alpha signaling pathway

Author: Patricia Hermand, Slim Azouzi, Emilie-Fleur Gautier, François Guillonneau, Vincent Bondet, Darragh Duffy, Sebastien Dechavanne, Pierre-Louis Tharaux, Patrick Mayeux, Caroline Le Van Kim, and Berengere Koehl
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2020
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14. Type I interferon-mediated autoinflammation due to DNase II deficiency

Author: Mathieu P. Rodero, Alessandra Tesser, Eva Bartok, Gillian I. Rice, Erika Della Mina, Marine Depp, Benoit Beitz, Vincent Bondet, Nicolas Cagnard, Darragh Duffy, Michael Dussiot, Marie-Louise Frémond, Marco Gattorno, Flavia Guillem, Naoki Kitabayashi, Fabrice Porcheray, Frederic Rieux-Laucat, Luis Seabra, Carolina Uggenti, Stefano Volpi, Leo A H. Zeef, Marie-Alexandra Alyanakian, Jacques Beltrand, Anna Monica Bianco, Nathalie Boddaert, Chantal Brouzes, Sophie Candon, Roberta Caorsi, Marina Charbit, Monique Fabre, Flavio Faletra, Muriel Girard, Annie Harroche, Evelyn Hartmann, Dominique Lasne, Annalisa Marcuzzi, Bénédicte Neven, Patrick Nitschke, Tiffany Pascreau, Serena Pastore, Capucine Picard, Paolo Picco, Elisa Piscianz, Michel Polak, Pierre Quartier, Marion Rabant, Gabriele Stocco, Andrea Taddio, Florence Uettwiller, Erica Valencic, Diego Vozzi, Gunther Hartmann, Winfried Barchet, Olivier Hermine, Brigitte Bader-Meunier, Alberto Tommasini, and Yanick J. Crow
Subjects: Science
Abstract: Nucleic acid sensing is important to ensure that an innate immune response is only mounted against microbial nucleic acid. Here, the authors identify loss-of-function mutations in the DNASE2 gene that cause type I interferon-mediated autoinflammation due to enhanced systemic interferon signaling.
Published: 2017
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15. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one

Author: F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild
Subjects: Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published: 2017
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16. Plasma Type I IFN Protein Concentrations in Human Tuberculosis

Author: Alba Llibre, Nicole Bilek, Vincent Bondet, Fatoumatta Darboe, Stanley Kimbung Mbandi, Adam Penn-Nicholson, Mark Hatherill, Flore Rozenberg, Thomas J. Scriba, and Darragh Duffy
Subjects: tuberculosis, interferon, protein biomarker, Cytokines, IFNa, IFNb, Microbiology, QR1-502
Abstract: Tuberculosis (TB) remains one of the leading causes of mortality worldwide, and a lack of understanding of basic disease pathogenesis is hampering development of new vaccines and treatments. Multiple studies have previously established a role for type I interferon (IFN) in TB disease. Type I IFNs are critical immune mediators for host responses to viral infection, yet their specific influence in bacterial infection remains unclear. As IFN-stimulated genes (ISGs) can have both stimulatory and inhibitory effects on immune function, clarifying the role of type I interferon in TB remains an important question. The quantification of interferon proteins in the circulation of patients has been restricted until the recent development of digital ELISA. To test the hypothesis that patients with active TB disease have elevated circulating type I IFN we quantified plasma IFNα and β proteins with Simoa digital ELISA in patients with active disease and asymptomatic M. tuberculosis infection. Strikingly no differences were observed between these two groups, while plasma from acute influenza infection revealed significantly higher plasma levels of both IFNα and IFNβ proteins. These results suggest a discordance between ISG mRNA expression by blood leukocytes and circulating type I IFN in TB.
Published: 2019
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17. Interplay of DDP4 and IP-10 as a Potential Mechanism for Cell Recruitment to Tuberculosis Lesions

Author: Thomas Blauenfeldt, Linda Petrone, Franca del Nonno, Andrea Baiocchini, Laura Falasca, Teresa Chiacchio, Vincent Bondet, Valentina Vanini, Fabrizio Palmieri, Gianni Galluccio, Armanda Casrouge, Jesper Eugen-Olsen, Matthew L. Albert, Delia Goletti, Darragh Duffy, and Morten Ruhwald
Subjects: tuberculosis, pulmonary, CXCL10, DPP4/CD26, bronchoalveolar lavage fluid, cytokines, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionMycobacterium tuberculosis is one of the world’s most successful pathogens equipped to establish itself within the human host as a subclinical infection without overt disease. Unable to eradicate the bacteria, the immune system contains the infection in a granuloma structure. Th1 cells that are essential for infection control are recruited to the site of infection directed by chemokines, predominantly CXCL10. It has previously been shown that CXCL10 in the plasma of patients chronically infected with hepatitis C virus is present primarily in an antagonist form. This is due to N-terminal truncation by the enzyme DPP4, which results in the antagonist form that is capable of binding its receptor CXCR3, but does not induce signaling. We aimed to explore whether such CXCL10 antagonism may have an impact on the pathogenesis of tuberculosis (TB).ResultsWe measured plasma levels of agonist and antagonist CXCL10 by Simoa digital ELISA, as well as DPP4 enzyme activity in the plasma of 20 patients with active TB infection, 10 patients with pneumonia infection, and a group of 10 healthy controls. We found higher levels of total and antagonist CXCL10 and reduced DPP4 enzyme activity in the plasma of TB patients compared to controls. We traced the source of CXCL10 secretion using immunohistochemical and confocal analysis to multinucleated giant cells in the TB lesions, and variable expression by macrophages. Interestingly, these cells were associated with DPP4-positive T cells. Moreover, the analysis of lymphocytes at the site of TB infection (bronchoalveolar lavage) showed a reduced frequency of CXCR3+ T cells.InterpretationOur data suggests that CXCL10 antagonism may be an important regulatory mechanism occurring at the site of TB pathology. CXCL10 can be inactivated shortly after secretion by membrane bound DPP4 (CD26), therefore, reducing its chemotactic potential. Given the importance of Th1 cell functions and IFN-γ-mediated effects in TB, our data suggest a possible unappreciated regulatory role of DPP4 in TB.PerspectivesDPP4 is the target for a class of enzyme inhibitors used in the treatment of diabetes, and the results from this study suggest that these drugs could be repurposed as an adjunct immunotherapy of patients with TB and MDR-TB.
Published: 2018
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18. JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study

Author: Marie-Louise Frémond, Marie Hully, Benjamin Fournier, Rémi Barrois, Romain Lévy, Mélodie Aubart, Martin Castelle, Delphine Chabalier, Clarisse Gins, Eugénie Sarda, Buthaina Al Adba, Sophie Couderc, Céline D’ Almeida, Claire-Marine Berat, Chloé Durrleman, Caroline Espil, Laetitia Lambert, Cécile Méni, Maximilien Périvier, Pascal Pillet, Laura Polivka, Manuel Schiff, Calina Todosi, Florence Uettwiller, Alice Lepelley, Gillian I. Rice, Luis Seabra, Sylvia Sanquer, Anne Hulin, Claire Pressiat, Lauriane Goldwirt, Vincent Bondet, Darragh Duffy, Despina Moshous, Brigitte Bader-Meunier, Christine Bodemer, Florence Robin-Renaldo, Nathalie Boddaert, Stéphane Blanche, Isabelle Desguerre, Yanick J. Crow, Bénédicte Neven, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Neurogénétique et neuroinflammation = Neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sidra Medicine [Doha, Qatar], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Centre Hospitalier Intercommunal Castres-Mazamet (CHIC-CM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester [Manchester], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Edinburgh, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), M.-L. F. received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. C. is supported by a UK Medical Research Council Human Genetics Unit core grant (MRC, U127580972). Y. J. C. and D. D. acknowledge the ANR (grant CE17001002). D. D. thanks ImmunoQure AG for the provision of antibodies for the Simoa assay. The project was supported by MSDAVENIR (Devo-Decode Project)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018)
Subjects: JAK inhibitors, [SDV]Life Sciences [q-bio], Aicardi-Goutières syndrome (AGS), Immunology, Immunology and Allergy, interferon
Abstract: The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
Published: 2023

19. Central role of macrophages and nucleic acid release in Myasthenia Gravis thymus

Author: Cloé A. Payet, Axel You, Odessa‐Maud Fayet, Edouard Hemery, Frederique Truffault, Vincent Bondet, Darragh Duffy, Frédérique Michel, Elie Fadel, Julien Guihaire, Sophie Demeret, Sonia Berrih‐Aknin, Rozen Le Panse, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Marie-Lannelongue, Université Paris-Sud - Paris 11 (UP11), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This work was supported by grants from the Association Française contre les Myopathies (AFM), the Agence Nationale de la Recherche (ANR grant number CE17001002), and Idex Sorbonne University (contract n° C19/1375)
Subjects: Neurology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neurology (clinical)
Abstract: International audience; Objective: Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-β. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investigated the chronic thymic IFN-I signature.Methods: Serum levels of IFN-β and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in PBMCs were analyzed. The contribution of endogenous nucleic acids in thymicexpression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68+ and CD163+ macrophages were analyzed in AChR-MG.To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody. Results: No IFN-I signature was observed in the periphery emphasizing that the IFN-I signature is restricted to the MG thymus. Molecules mimicking endogenous dsDNA signalization (Poly(dA:dT) and 2’3’-cGAMP), or dexamethasone-induced necrotic thymocytes increased IFN-β and α-AChR expression by thymic epithelial cells, and in the mouse thymus. A significant decrease in thymic macrophages was demonstrated in AChR-MG. In mice, a decrease in thymic macrophages led to an increase of necrotic thymocytes associated with IFN-β and α-AChR expression. Interpretation: These results suggest that the decrease of thymic macrophages in AChR-MG impairs the elimination of apoptotic thymocytes favoring the release of endogenous nucleic acids from necrotic thymocytes. In this inflammatory context, thymic epithelial cells may overexpress IFN-β, which specifically induces α-AChR, resulting in self-sensitization and thymic changes leading to AChR-MG.
Published: 2023

20. Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Author: Yann Aquino, Aurélie Bisiaux, Zhi Li, Mary O’Neill, Javier Mendoza-Revilla, Sarah Hélène Merkling, Gaspard Kerner, Milena Hasan, Valentina Libri, Vincent Bondet, Nikaïa Smith, Camille de Cevins, Mickaël Ménager, Francesca Luca, Roger Pique-Regi, Giovanna Barba-Spaeth, Stefano Pietropaoli, Olivier Schwartz, Geert Leroux-Roels, Cheuk-Kwong Lee, Kathy Leung, Joseph T.K. Wu, Malik Peiris, Roberto Bruzzone, Laurent Abel, Jean-Laurent Casanova, Sophie A. Valkenburg, Darragh Duffy, Etienne Patin, Maxime Rotival, Lluis Quintana-Murci, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Wayne State University [Detroit], University of Rome 'Tor Vergeta', Università degli Studi di Roma Tor Vergata [Roma], Virologie Structurale - Structural Virology, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Universiteit Gent = Ghent University (UGENT), Ghent University Hospital, Hong Kong Red Cross Blood Transfusion Service, Hospital Authority, The University of Hong Kong (HKU), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Howard Hughes Medical Institute (HHMI), University of Melbourne, Hong Kong Science and Technology Parks Corporation (HKSTP), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), The Human Evolutionary Genetics Laboratory is supported by the Institut Pasteur, the Collège de France, the Centre Nationale de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (ANR) grants COVID-19-POPCELL (ANR-21-CO14-0003-01), POPCELL-REG (ANR-22-CE12-0030-01) and COVIFERON (ANR-21-RHUS-0008), the EU HORIZON-HLTH-2021-DISEASE-04-07 grant UNDINE (no. 101057100), the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10- LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), the Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339214), the Fondation Allianz-Institut de France, and the Fondation de France (no. 00106080). K.L., J.T.K.W. and M.P. are supported by the Health and Medical Research Fund Commissioned Research on the Novel Coronavirus Disease, Hong Kong SAR (COVID190126), S.A.V by the Theme-based Research Scheme of the Research Grants Council of the Hong Kong SAR (T11-705/21-N, SAV: T11-712/19-N), and M.P., R.B. and D.D. by InnoHK, an initiative of the Innovation and Technology Commission, the Government of the Hong Kong SAR., ANR-21-CO14-0003,COVID-19-POPCELL,Facteurs génétiques et infectieux à l'origine de la variabilité populationnelle de la réponse immunitaire à l'infection par le SARS-CoV-2(2021), ANR-22-CE12-0030,popCell-REG,Variation populationnelle des profils d'accessibilité de la chromatine à l'échelle unicellulaire(2022), ANR-21-RHUS-0008,COVIFERON,Covid-19 and interferons: from discovery to therapy(2021), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: The RNA sequencing data generated and analyzed in this study have been deposited in the Institut Pasteur data repository, OWEY, which can be accessed via the following link: https://doi.org/XXXX. The genome-wide genotyping data generated or used in this study have been deposited in OWEY and can be accessed at the following URL: https://doi.org/XXXX. Data access and use is restricted to academic research related to the variability of the human immune response.; Humans display vast clinical variability upon SARS-CoV-2 infection 1–3 , partly due to genetic and immunological factors 4 . However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk.
Published: 2023

21. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author: Nicole Bilek, Violaine Saint-André, Elisa Nemes, Stanley Kimbung Mbandi, Elizabeth Filander, Munyaradzi Musvosvi, Humphrey Mulenga, Matthew L. Albert, Alba Llibre, Vincent Rouilly, Hadn Africa, Céline Posseme, Simba Mabwe, Nikaïa Smith, Vincent Bondet, Thomas J. Scriba, Pierre Bost, Darragh Duffy, Bruno Charbit, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Datactix, University of Cape Town, Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département de Biologie Computationnelle - Department of Computational Biology, Insitro [San Francisco], This study was funded by the Bill and Melinda Gates Foundation (OPP1114368 and OPP1204624), with additional support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. AL was supported by the Fondation Recherche Médicale (SPF20170938617) and the European Commision (H2020-MSCA-IF 2018, 841729). NS was supported by an Institut Pasteur Roux Cantarini fellowship., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Nanostring analysis. DD thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFN-α assay. We are grateful to the study participants and the SATVI clinical and laboratory teams., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Tuberculosis, Immunology, Disease, Mycobacterium tuberculosis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, Interleukin 1 (IL-1), Medicine, Immunology and Allergy, Interleukin 1 Receptor antagonist (IL-1ra), 030304 developmental biology, Systems immunology, 0303 health sciences, Immunometabolism, biology, business.industry, biology.organism_classification, medicine.disease, 3. Good health, Granzyme, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, 030215 immunology
Abstract: SUMMARYTuberculosis (TB) remains a major public health problem with host-directed therapeutics offering potential as novel treatment strategies. However, their successful development still requires a comprehensive understanding of howMycobacterium tuberculosis(M.tb) infection impacts immune responses. To address this challenge, we applied standardised immunomonitoring tools to compare TB antigen, BCG and IL-1β induced immune responses between individuals with latentM.tbinfection (LTBI) and active TB disease, at diagnosis and after cure. This revealed distinct responses between TB and LTBI groups at transcriptomic, proteomic and metabolomic levels. At baseline, we identified pregnane steroids and the PPARγ pathway as new immune-metabolic drivers of elevated plasma IL-1ra in TB. We also observed dysregulated induced IL-1 responses after BCG stimulation in TB patients. Elevated IL-1 antagonist responses were explained by upstream differences in TNF responses, while for IL-1 agonists it was due to downstream differences in granzyme mediated cleavage. Finally, the immune response to IL-1β driven signalling was also dramatically perturbed in TB disease but was completely restored after successful antibiotic treatment. This systems immunology approach improves our knowledge of how immune responses are altered during TB disease, and may support design of improved diagnostic, prophylactic and therapeutic tools.
Published: 2022

22. Defective type I interferon immunity is associated with increasing COVID-19 severity

Author: Darragh Duffy, Nikaïa SMITH, Céline Possémé, Vincent Bondet, Jamie Sugrue, Liam Townsend, Bruno Charbit, Vincent Rouilly, Violaine Saint-André, Tom Dott, Andre Rodriguez Pozo, Nader Yatim, Olivier Schwartz, Minerva Cervantes-Gonzales, Jade Ghosn, Paul Bastard, Jean-Laurent Casanova, Tali-Anne Szwebel, Benjamin Terrier, Niall Conlon, Cliona O'Farrelly, Cliona Ni Cheallaigh, Nollaig Bourke, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Trinity College Dublin, Datactix, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], St James' Hospital, This study was supported by the 'URGENCE COVID-19' fundraising campaign the Institut Pasteur (CoVarImm and Steroid Response), from the Agence Nationale de la Recherche (ANR-flash COVID-19), by the Laboratoire d’Excellence ‘Milieu Intérieur’ (grant no. ANR-10-LABX-69-01), the Fonds IMMUNOV for Innovation in Immunopathology, and Science Foundation Ireland. We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource which supported collection of patient samples. NS is a recipient of the Pasteur-Roux-Cantarini Fellowship. COF, NC and CNC are part-funded by a Science Foundation Ireland (SFI) grant, Grant Code 20/SPP/3685. LT is supported by the Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland. N.B. is funded under the Science Foundation Ireland Phase 2 COVID-19 Rapid Response Call (20/COV/8487) and the Health Research Board COVID-19 Rapid Response Call (COV19e2020e053). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), ANR AABIFNCOV (ANR-20-CO11-0001) and ANR GenMISC (ANR-21-COVR-0039) projects, the European Union’s Horizon 2020 research and innovation programme under grant agreement No 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, The French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM and the University of Paris. PB was supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller)., We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Nanostring analysis. We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Hopital Cochin, Hopital Bichat, and St James’s Hospital Dublin., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Institut Pasteur [Paris]-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)
Subjects: [SDV]Life Sciences [q-bio]
Abstract: Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported that reduced blood type I interferon (IFN-I) in severe COVID-19 patients preceded clinical worsening. These results were supported by studies which identified genetic mutations in loci of the TLR3- or TLR7-dependent IFN-I pathways, or autoantibodies neutralizing IFNα or IFNω, as major risk factors for development of severe and critical COVID-19 pneumonia. Here, we analyzed a range of IFN-I associated responses in patient cohorts with different severities of COVID-19, showing that baseline plasma IFNα measures differed significantly according to the immunoassay used, as well as timing of sampling, the IFNα subtype measured, and the presence of autoantibodies. We then compared immune responses induced by ex vivo stimulation between non-hospitalized moderate cases (n=27) and hospitalized (n=17) adult patients that required oxygen supplementation. This showed a consistently reduced induction of IFN-I proteins in hospitalized COVID-19 patients upon stimulation, that was not associated with detectable neutralizing autoantibodies against IFNα or IFNω. We confirmed the poor induction of IFN-I in an independent patient cohort (n=33), and showed it was more pronounced with severe disease. Intracellular proteomic analysis showed that while monocyte numbers were increased in hospitalized COVID-19 patients, they did not secrete IFN-I in response to stimulation. This was further confirmed by ex vivo whole blood stimulation with IFN-I which induced a transcriptomic response associated with inflammation in hospitalized COVID-19 patients, that was not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to IFN-I based treatments in late stage COVID-19, despite the critical importance of IFN-I in early acute infection. An improved understanding of such variable responses to treatment may help to identify potential alternative therapeutic strategies.
Published: 2022

23. Juvenile Neuropsychiatric Systemic Lupus Erythematosus: Identification of Novel Central Neuroinflammation Biomarkers

Author: Mathilde Labouret, Stefania Costi, Vincent Bondet, Vincent Trebossen, Enora Le Roux, Alexandra Ntorkou, Sophie Bartoli, Stéphane Auvin, Brigitte Bader-Meunier, Véronique Baudouin, Olivier Corseri, Glory Dingulu, Camille Ducrocq, Cécile Dumaine, Monique Elmaleh, Nicole Fabien, Albert Faye, Isabelle Hau, Véronique Hentgen, Théresa Kwon, Ulrich Meinzer, Naim Ouldali, Cyrielle Parmentier, Marie Pouletty, Florence Renaldo, Isabelle Savioz, Flore Rozenberg, Marie-Louise Frémond, Alice Lepelley, Gillian I. Rice, Luis Seabra, Jean-François Benoist, Darragh Duffy, Yanick J. Crow, Pierre Ellul, Isabelle Melki, Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID, Elaboration of the type I interferonopathies - E-T1IFNs - - ERC-2017-ADG2018-11-01 - 2023-10-31 - 786142 - VALID, AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Università degli Studi di Milano = University of Milan (UNIMI), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Centre d'Investigation Clinique 1426 (CIC 1426), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital universitaire Robert-Debré [Paris], Epidémiologie Clinique et Evaluation Economique Appliquées aux Populations Vulnérables (ECEVE (U1123 / UMR_S_1123)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), CHU Necker - Enfants Malades [AP-HP], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier Sud Francilien, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), CHI Créteil, Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), GHU AP-HP Centre Université de Paris, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), University of Manchester [Manchester], Université Paris-Saclay, University of Edinburgh, Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], YJC acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ program bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). YJC and DD acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018), UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.IMM] Life Sciences [q-bio]/Immunology, Central nervous system, Immunology, Immunology and Allergy, Interferon-alpha, [SDV.IMM]Life Sciences [q-bio]/Immunology, Neuropsychiatric, Biomarker, Juvenile systemic lupus erythematosus, Neopterin
Abstract: Introduction Juvenile systemic lupus erythematosus (j-SLE) is a rare chronic autoimmune disease affecting multiple organs. Ranging from minor features, such as headache or mild cognitive impairment, to serious and life-threatening presentations, j-neuropsychiatric SLE (j-NPSLE) is a therapeutic challenge. Thus, the diagnosis of NPSLE remains difficult, especially in pediatrics, with no specific biomarker of the disease yet validated. Objectives To identify central nervous system (CNS) disease biomarkers of j-NPSLE. Methods A 5-year retrospective tertiary reference monocentric j-SLE study. A combination of standardized diagnostic criteria and multidisciplinary pediatric clinical expertise was combined to attribute NP involvement in the context of j-SLE. Neopterin and interferon-alpha (IFN-α) protein levels in cerebrospinal fluid (CSF) were assessed, together with routine biological and radiological investigations. Results Among 51 patients with j-SLE included, 39% presented with j-NPSLE. J-NPSLE was diagnosed at onset of j-SLE in 65% of patients. No specific routine biological or radiological marker of j-NPSLE was identified. However, CSF neopterin levels were significantly higher in active j-NPSLE with CNS involvement than in j-SLE alone (p = 0.0008). Neopterin and IFN-α protein levels in CSF were significantly higher at diagnosis of j-NPSLE with CNS involvement than after resolution of NP features (respectively p = 0.0015 and p = 0.0010) upon immunosuppressive treatment in all patients tested (n = 10). Both biomarkers correlated strongly with each other (Rs = 0.832, p n = 23 paired samples). Conclusion CSF IFN-α and neopterin constitute promising biomarkers useful in the diagnosis and monitoring of activity in j-NPSLE.
Published: 2022

24. Inactive disease in patients with lupus is linked to autoantibodies to type I interferons that normalize blood IFNα and B cell subsets

Author: Hannah F. Bradford, Liis Haljasmägi, Madhvi Menon, Thomas C.R. McDonnell, Karita Särekannu, Martti Vanker, Pärt Peterson, Chris Wincup, Rym Abida, Raquel Fernandez Gonzalez, Vincent Bondet, Darragh Duffy, David A. Isenberg, Kai Kisand, and Claudia Mauri
Subjects: General Biochemistry, Genetics and Molecular Biology
Published: 2023

25. Enhanced TLR3 Responsiveness in Hepatitis C Virus Resistant Women From the Irish Anti-D Cohort

Author: Jamie A. Sugrue, Céline Posseme, Ziyang Tan, Christian Pou, Bruno Charbit, Vincent Bondet, Nollaig M. Bourke, Petter Brodin, Darragh Duffy, Cliona O’Farrelly, Trinity College Dublin, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Karolinska Institutet [Stockholm], Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), The VirScan data handling was enabled by resources in project sens2018511 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. The authors acknowledge colleagues at the Irish Blood Transfusion Service for their help in matching donors to their batch numbers. This study was funded through a Science Foundation Ireland grant to C.O.F. (12/IA/1667) and benefitted from an Irish Research Council – Campus France Ulysses award., and The authors are grateful to the many blood donors who contributed to this study. The authors acknowledge Margaret Needham for help processing samples and the administrative support in organizing the blood donations.
Subjects: [SDV.IMM]Life Sciences [q-bio]/Immunology, Humans, Female, Hepacivirus, Hepatitis C, Antiviral Agents, General Biochemistry, Genetics and Molecular Biology, Toll-Like Receptor 3
Abstract: Cytokine data presented in this manuscript is available at https://dx.doi.org/10.17632/m65wh4vc9z.1. NanoString data is available at https://data.mendeley.com/datasets/z4nr7p7ry7. Additional data reported in this paper will be shared by the lead contact upon request.; International audience; Natural resistance to infection is an overlooked outcome after hepatitis C virus (HCV) exposure. Between 1977 and 1979, 1,200 Rhesus D-negative Irish women were exposed to HCV-contaminated anti-D immunoglobulin. Here, we investigate why some individuals appear to resist infection despite exposure (exposed seronegative [ESN]). We screen HCV-resistant and -susceptible donors for anti-HCV adaptive immune responses using ELISpots and VirScan to profile antibodies against all know human viruses. We perform standardized ex vivo whole blood stimulation (TruCulture) assays with antiviral ligands and assess antiviral responses using NanoString transcriptomics and Luminex proteomics. We describe an enhanced TLR3-type I interferon response in ESNs compared with seropositive women. We also identify increased inflammatory cytokine production in response to polyIC in ESNs compared with seropositive women. These enhanced responses may have contributed to innate immune protection against HCV infection in our cohort.
Published: 2022

26. Variability in primary Sjögren’s syndrome is driven by interferon alpha, and genetically associated with the class II HLA DQ locus

Author: Diana Trutschel, Pierre Bost, Xavier Mariette, Vincent Bondet, Alba Llibre, et al, Milieu Interieur, ASSESS investigators, and NECESSITY consortium
Published: 2022
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27. Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

Author: Anne Sophie Rebillat, Marie Goulet, Darawan Rinchai, Tanwir Habib, Vincent Bondet, Martine Conte, Anne Puel, Clotilde Mircher, Xiao-Fei Kong, Luyan Liu, Puthen V. Jithesh, Arnold Munnich, Laurent Abel, Damien Chaussabel, Stanislas Lyonnet, Jean-Laurent Casanova, Mohammed Elanbari, Emilie Nonnotte, Jacinta Bustamante, Mélanie Migaud, Nicolas Gürtler, Lisa Worley, Stuart G. Tangye, Aimé Ravel, Cindy S. Ma, Darragh Duffy, Stéphanie Boisson-Dupuis, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Columbia University Irving Medical Center (CUIMC), Garvan Institute of Medical Research [Darlinghurst, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Sidra Medical and Research Center [Doha, Qatar], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jérôme Lejeune, University Hospital Basel [Basel], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Embryology and genetics of human malformation (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Fédération de Génétique, Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Service d'immuno-hématologie pédiatrique [CHU Necker], X-F.K was supported by the Jerome Lejeune Foundation and Alexander’s Angels Inc. X-F.K is currently a gastroenterology fellow in CUIMC supported by NIH grant T32 DK083256. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number UL1TR001866 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grants 5R01AI127564 and 5R37AI095983), grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), ANR-IFNGPHOX (ANR-13-ISV3-0001-01) and ANR-GENMSMD (ANR-16-CE17-0005-01), LTh-MSMD-CMCD (ANR-18-CE93-0008-01), HGDIFD (ANR-14-CE15-0006-01), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, and The Rockefeller University and the Helmut Horten Foundation., We thank Yanick Crow, Barry Coller, Charlie Rice, James Krueger, and Timothy Wang for helpful discussions and critical reading. We thank Y. Nemirovskaya, T. Kochetkov, M. Romanick, L. Amar, C. Patissier, C. Desvallées, M. Woollett, A. Gall, and J. Gonzalez for technical and secretarial assistance and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-13-ISV3-0001,IFNGPHOX,L'immunité anti-tuberculeuse dépendante de l'IFN-gamma chez l'homme opère via la NADPH oxydase phagocytaire(2013), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-18-CE93-0008,LTh-MSMD-CMCD,Différenciation des lymphocytes T-helper (Th) dans les défauts génétiques de l'immunité contre Mycobacterium et/ou Candida species.(2018), ANR-14-CE15-0006,HGDIFD,Déterminisme génétique des infections fongiques invasives chez l'homme(2014), Garvan Institute of medical research, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Embryology and genetics of human malformation, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Male, 0301 basic medicine, Down syndrome, Gene Dosage, Monocytes, JAK-STAT, 0302 clinical medicine, T-Lymphocyte Subsets, Interferon, Immunology and Allergy, Medicine, STAT1, Child, Receptors, Interferon, B-Lymphocytes, biology, interferonopathy, Chromosome Mapping, JAK-STAT signaling pathway, Middle Aged, Penetrance, interferon receptors, 3. Good health, STAT1 Transcription Factor, Child, Preschool, Interferon Type I, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, medicine.drug, Adult, Adolescent, Immunology, Article, Young Adult, 03 medical and health sciences, Downregulation and upregulation, Humans, Genetic Predisposition to Disease, business.industry, Gene Expression Profiling, medicine.disease, 030104 developmental biology, Genetic Loci, biology.protein, Transcriptome, business, Chromosome 21, CD8, 030215 immunology
Abstract: International audience; Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8+ T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.
Published: 2020

28. Use of ruxolitinib in COPA syndrome manifesting as life-threatening alveolar haemorrhage

Author: Yanick J. Crow, Hugues Begueret, Serge Amselem, Hubert Ducou Le Pointe, Michael Fayon, Marie-Louise Frémond, Gillian I. Rice, Nadia Nathan, Darragh Duffy, Emilie Filhol-Blin, Laura Berdah, Nicolas Richard, Vincent Bondet, Chiara Sileo, Annick Clement, Marie Legendre, Aurore Coulomb, Bénédicte Neven, Sylvie Roullaud, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier d'Angoulême (CH Angoulême), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Edinburgh, Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des maladies génétiques d'expression pédiatrique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier d'Angoulême, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service de Pneumologie Pédiatrique [CHU Trousseau], Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: Lung Diseases, massive haemoptysis, Pulmonary and Respiratory Medicine, Ruxolitinib, Hemosiderosis, paediatric interstitial lung disease, Arthritis, Hemorrhage, Disease, 03 medical and health sciences, 0302 clinical medicine, Interferon, Nitriles, medicine, Humans, 030212 general & internal medicine, Child, rare lung diseases, business.industry, Interstitial lung disease, medicine.disease, 3. Good health, systemic disease and lungs, Pyrimidines, 030228 respiratory system, Pulmonary haemosiderosis, Coatomer, Mutation (genetic algorithm), Immunology, Pyrazoles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, paediatric lung disaese, business, medicine.drug
Abstract: COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA. Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy COPA screening. Functional tests can help to personalise patient therapy.
Published: 2019

29. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation

Author: Celine Posseme, Alba Llibre, Bruno Charbit, Vincent Bondet, Vincent Rouilly, Violaine Saint-André, Jeremy Boussier, Jacob Bergstedt, Nikaïa Smith, Liam Townsend, Jamie A. Sugrue, Clíona Ní Cheallaigh, Niall Conlon, Maxime Rotival, Michael S. Kobor, Estelle Mottez, Stanislas Pol, Etienne Patin, Matthew L. Albert, Lluis Quintana-Murci, Darragh Duffy, Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, null Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A. Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Sandra Pellegrini, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université Paris Cité (UPCité)-Université Paris sciences et lettres (PSL), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), St James’s Hospital [Dublin, Ireland], Trinity College Dublin, University of British Columbia [Vancouver], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HIBIO [South San Francisco], Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), This study was funded with support from the French Governments Investissement dAvenir Program, Laboratoire Excellence Milieu Interieur Grant ANR-10-LABX-69-01 and by an Agence National de Recherche foundation grant (CE17001002)., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke (Trinity College Dublin), Petter Brodin (Karolinska Institutet), Pierre Bruhns, Nadine Cerf-Bensussan (INSERM UMR 1163 – Institut Imagine), Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes (Institut Roche), Gunilla Karlsson Hedestam (Karolinska Institutet), Serge Hercberg (Université Paris 13), Molly Ingersoll, Rose Anne Kenny (Trinity College Dublin), Olivier Lantz (Institut Curie), Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly (Trinity College Dublin), Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 – Institut Imagine), Frédéric Rieux-Laucat (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert (In Sitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-CE17-0010,ELECTRO,Inhibition de l'Exchange Protein directly activated by cAMP -1 pour traiter la Fibrillation Atrial(2020), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute-University of British Columbia (UBC), University of Cape Town, Département d'hépatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Insitro [San Francisco], St James's University Hospital, Leeds Teaching Hospitals NHS Trust, University of British Columbia (UBC), This study was funded with support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' grant ANR-10-LABX-69-01, and by an Agence National de Recherche Foundation grant (CE17001002). We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting data generation, Pierre-Henri Commere for help with flow cytometry sorting, Aurelie Bisiaux for flow cytometry advice, and Dr. Molly Ingersoll for scientific advice and critical reading of the manuscript. D.D. thanks Immunoqure for provision of the mAbs under an MTA for the Simoa IFNα assay. We thank the STTAR-Bioresource of TCD-SJH-TUH COVID-19 bioresource, which supported collection of COVID-19 patient samples, and the 'URGENCE COVID-19' fundraising campaign of the Institut Pasteur (CoVarImm and Steroid Response) for supporting data generation of COVID-19 samples. N.S. is a recipient of the Pasteur-Roux-Cantarini Fellowship. N.C. and C.N.C. are part funded by a Science Foundation Ireland (SFI) grant, grant code 20/SPP/3685. L.T. is supported by the Irish Clinical Academic Training (ICAT) Program, supported by the Wellcome Trust and the Health Research Board (grant number 203930/B/16/Z), the Health Service Executive, National Doctors Training and Planning, and the Health and Social Care, Research and Development Division, Northern Ireland., Milieu Intérieur Consortium: Laurent Abel, Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke, Petter Brodin, Pierre Bruhns, Nadine Cerf-Bensussan, Ana Cumano, Caroline Demangel, Christophe d'Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes, Gunilla Karlsson Hedestam, Serge Hercberg, Molly A Ingersoll, Rose Anne Kenny, Olivier Lantz, Mickael Ménager, Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly, Etienne Patin, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Frédéric Rieux-Laucat, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci, and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)
Subjects: Lipopolysaccharides, Proteomics, History, Polymers and Plastics, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Disease, systems immunology, Biology, General Biochemistry, Genetics and Molecular Biology, Industrial and Manufacturing Engineering, Immune system, medicine, Humans, Secretion, Epigenetics, Business and International Management, Epigenomics, TLR4 immune responses, Systems immunology, SARS-CoV-2, COVID-19, CP: Immunology, Interferon-beta, Interleukin-12, Toll-Like Receptor 4, Cytokine, IL-12p70, type I interferons, Immunology, TLR4, Cytokine variability, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines
Abstract: International audience; The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection.
Published: 2021

30. Constitutive IFNα protein production in bats

Author: S. Le Poder, R. Wedlarski, Darragh Duffy, Vincent Bondet, D. Le Roux, Thierry Petit, Alexis Lécu, M. Le Baut, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), Virologie UMR1161 (VIRO), École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Muséum national d'Histoire naturelle (MNHN), Parc Zoologique de La Palmyre, Bioparc de Doué-la-Fontaine, Partenaires INRAE, Biologie moléculaire et immunologie parasitaires et fongiques (BIPAR), École nationale vétérinaire d'Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This work was funded by the Agence Nationale pour la Recherche (ANR), grant number CE17001002, We thank the ProteoGenix company (Schiltigheim, France) for the production of the bIFNα ELISA assay calibrator, Marielle Cochet for technical help, Florence Va, Dr Vitomir Djokic and Isabelle Badreau for helping in RT-qPCR datas analysis, the technical staff of the zoos and the Association Française des Vétérinaires de Parcs Zoologiques. We thank the CBUTechS platform of the Institut Pasteur for access to the Simoa instrument., Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris]-Université Paris Cité (UPC), and École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé
Subjects: Transcription, Genetic, [SDV]Life Sciences [q-bio], Immunology, bats, Enzyme-Linked Immunosorbent Assay, Disease, Biology, Cell Line, 03 medical and health sciences, Antiviral immunity, Extant taxon, Species Specificity, Interferon, Chiroptera, Protein biosynthesis, medicine, Immunology and Allergy, Animals, Simoa digital ELISA, Symbiosis, 030304 developmental biology, Original Research, Genetics, 0303 health sciences, Chiroptera species, Innate immune system, Ifn response, 030306 microbiology, Interferon-alpha, Immunity, Innate, antiviral immunity, Gene Expression Regulation, protein levels, Host-Pathogen Interactions, Viruses, type I IFN, medicine.drug
Abstract: Posté sur bioRxiv le 22 juin 2021.; International audience; Bats are the only mammals with self-powered flight and account for 20% of all extant mammalian diversity. In addition, they harbor many emerging and reemerging viruses, including multiple coronaviruses, several of which are highly pathogenic in other mammals, but cause no disease in bats. How this relationship between bats and viruses exists is not yet fully understood. Existing evidence supports a specific role for the innate immune system, in particular type I interferon (IFN) responses, a major component of antiviral immunity. Previous studies in bats have shown that components of the IFN pathway are constitutively activated at the transcriptional level. In this study, we tested the hypothesis that the type I IFN response in bats is also constitutively activated at the protein level. For this we utilized highly sensitive Single Molecule (Simoa) digital ELISA assays, previously developed for humans that we adapted to bat samples. We prospectively sampled four non-native chiroptera species from French zoos. We identified a constitutive expression of IFNα protein in the circulation of healthy bats, and concentrations that are physiologically active in humans. Expression levels differed according to the species examined, but was not associated with age, sex, or health status suggesting constitutive IFNα protein expression independent of disease. These results confirm a unique IFN response in bat species that may explain their ability to coexist with multiple viruses in the absence of pathology. These results may help to manage potential zoonotic viral reservoirs and potentially identify new anti-viral strategies.
Published: 2021

31. Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients

Author: Vincent Bondet, Eric Savier, Olivier Scatton, Clémence Hollande, Matthew L. Albert, Jeremy Boussier, Stanislas Pol, Alba Llibre, Vincent Mallet, Estelle Mottez, Tan Phuc Buivan, Bruno Charbit, Frédéric Charlotte, Darragh Duffy, Université Paris Cité (UPCité), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatologie médicale [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anatomie et cytologie pathologiques = Service de Pathologie [CHU Pitié-Salpêtrière] (ACP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique [CHU Pitié-Salpétrière], Fondation ARC pour la Recherche sur le Cancer, BONDET, Vincent, Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et cytologie pathologiques [CHU Pitié-Salpêtrière] (ACP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, Pharmaceutical Science, Chronic liver disease, Gastroenterology, sitagliptin, 03 medical and health sciences, 0302 clinical medicine, dipeptidyl peptidase 4, Internal medicine, medicine, Pharmacology (medical), neoadjuvant therapy, education, Adverse effect, Neoadjuvant therapy, Dipeptidyl peptidase-4, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, hepatocellular carcinoma, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Complementary and alternative medicine, 030220 oncology & carcinogenesis, Sitagliptin, Hepatocellular carcinoma, business, Adjuvant, leucocyte trafficking, medicine.drug
Abstract: International audience; Background & Aims : Systemic therapies for hepatocellular carcinoma (HCC) treatment have limited efficacy and poor safety. Dipeptidyl peptidase-4 inhibitors were initially developed and approved as treatment for type 2 diabetes, yet oral administration of sitagliptin has recently been shown to improve naturally occurring tumour immunity in animal models of HCC.Methods : We conducted a phase Ib clinical trial to evaluate the impact of a pre-operative 3-week DPP4 inhibitor (sitagliptin) treatment in HCC patients undergoing liver resection. The primary objective was to evaluate the safety of a sitagliptin treatment in each of the three groups of patients, according to an escalating dosage of sitagliptin (100, 200 and 600 mg/d). Secondary objectives included the assessment of DPP4 activity, cytokine expression in plasma samples and circulating immune populations.Results : Fourteen patients were included and analysed. In all three dose groups, no severe adverse event related to sitagliptin was reported. A significant inhibition of DPP4 activity was observed upon sitagliptin treatment, which prevented the N-terminal truncation of CXCL10, leading to a mobilization of circulating CD8+ T cells and eosinophils. Immunochemistry analysis showed a lymphoid infiltration in all tumour samples with the presence of a population of CXCR3+ T cells in all but one of the tumours. Positivity for CXCL10 (IP10) and CCR3 in tumour and/or stroma cells was found in all resection pieces.Conclusion : In summary, sitagliptin can be used safely in patients with chronic liver disease and HCC, and could be tested in phase 2 trial, as an adjuvant in combination with others drugs, for the treatment of HCC patients.
Published: 2021

32. Regulation of the acetylcholine/α7nAChR anti-inflammatory pathway in COVID-19 patients

Author: Jeremy Boussier, Frédéric Rieux-Laucat, Hélène Péré, Laura Barnabei, Vincent Bondet, Alice Courties, Benjamin Terrier, David Veyer, Jérémie Sellam, Darragh Duffy, Solen Kernéis, Francis Berenbaum, Nicolas Carlier, Nader Yatim, Frédéric Pène, Jérôme Hadjadj, Bruno Charbit, Service de rhumatologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Gestionnaire, HAL Sorbonne Université 5, Institut Pasteur [Paris] (IP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), and ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017)
Subjects: Adult, Male, medicine.medical_specialty, alpha7 Nicotinic Acetylcholine Receptor, Science, Down-Regulation, Inflammation, Article, Nicotine, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Internal medicine, Humans, Medicine, Acute inflammation, Aged, 030304 developmental biology, Whole blood, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Multidisciplinary, SARS-CoV-2, business.industry, COVID-19, Middle Aged, Choline acetyltransferase, Acetylcholine, 3. Good health, Nicotinic agonist, Endocrinology, Viral infection, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, Tumor necrosis factor alpha, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: International audience; The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine. Coronavirus disease 19 (COVID-19) is characterized by clinical heterogeneity, with severity ranging from asymptomatic patients to critical and life-threatening disease 1. Severe and critical COVID-19 are characterized by an acute respiratory distress syndrome (ARDS) driven by an exacerbated inflammatory response that can lead to multi-organ failure and death 2. This hypercytokinemia, initially named "cytokine storm", is associated with high levels of circulating tumor necrosis factor (TNF) and interleukin-6 (IL-6), profound peripheral blood lymphopenia and chemoattraction of mononuclear cells within the lungs 3-5. Overall, this imbalanced inflammatory response is responsible for tissue damage and disease severity.
Published: 2021

33. Inactive disease in lupus patients is linked to autoantibodies to type-I interferons that normalize blood IFNα and B cell subsets

Author: Martti Vanker, David A. Isenberg, Madhvi Menon, Kai Kisand, Darragh Duffy, Rym Abida, Vincent Bondet, Chris Wincup, Liis Haljasmägi, Pärt Peterson, Hannah F Bradford, Raquel Fernandez Gonzalez, Claudia Mauri, University of Manchester [Manchester], University College of London [London] (UCL), University of Tartu, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], This work is funded by Versus Arthritis UK program grant (21140) and Research Award (21786) to C.M., by the European Regional Development Fund (Project No 2014- 2020.4.01.15-0012 and the Centre of Excellence in Genomics (EXCEGEN) framework) (LH, PP, KK), the Estonian Research Council grants PRG1117 (KK) and PRG377 (PP). H.F.B. is funded by a UCB BIOPHARMA SPRL/BBSRC PhD Studentship (BB/P504725/1). We thank Immunoqure for provision of mAbs for the pan-IFNa assay under an MTA to D.D. D.D. acknowledges support from the ANR (CE17001002)., ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Institut Pasteur [Paris] (IP), and We thank Immunoqure for the provision of monoclonal Abs (mAbs) for the pan-IFNα assay under an MTA to D.D. D.D. acknowledges support from the ANR (CE17001002). We thank Drs. Diego Catalan and Christopher Piper for critically reviewing the manuscript. The graphical abstract was created with BioRender.com
Subjects: B cells, 0303 health sciences, Systemic lupus erythematosus, business.industry, autoimmunity, SLE, Autoantibody, Disease, medicine.disease, Phenotype, In vitro, 3. Good health, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Interferon, Immunology, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, B cell, 030304 developmental biology, 030215 immunology, medicine.drug
Abstract: Posté sur medRxiv le 07/04/2021Referred to byAntibodies against type I IFN: The bad guys self-restrain in systemic lupus erythematosusCell Reports Medicine, Volume 4, Issue 1, 17 January 2023, Pages 100903Simon Fillatreau; International audience; Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNα protein levels, inhibition of IFN-I downstream gene signatures, and inactive global disease score. Hallmarks of SLE pathogenesis, including increased immature, double-negative plasmablast B cell populations and reduction in regulatory B cell (Breg) frequencies, were normalized in patients with neutralizing anti-IFN-Abs compared with other patient groups. Immunoglobulin G (IgG) purified from sera of patients with SLE with neutralizing anti-IFN-Abs impedes CpGC-driven IFNα-dependent differentiation of B cells into immature B cells and plasmablasts, thus recapitulating the neutralizing effect of anti-IFN-Abs on B cell differentiation in vitro. Our findings highlight a role for neutralizing anti-IFN-Abs in controlling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutralizing-anti-IFN-Abs.
Published: 2021

34. Distinct systemic and mucosal immune responses to SARS-CoV-2

Author: Ludivine Grzelak, Bruno Charbit, Vincent Bondet, Hélène Péré, Hugo Mouquet, Cyril Planchais, Darragh Duffy, Benjamin Terrier, Vincent Rouilly, Sarah H. Merkling, Nader Yatim, Pedro Gonçalves, Maxime Beretta, Timothée Bruel, Frederic Rieux-Leucat, Nikaïa Smith, Solen Kernéis, Jérôme Hadjadj, James P. Di Santo, Olivier Schwartz, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunité Innée - Innate Immunity, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Immunologie humorale - Humoral Immunology, Datactix, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Assistance Publique Hôpitaux de Paris-Centre (APHP-CUP), Université de Paris, Paris, France, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), This study was supported by an Institut Pasteur Covid-19 research grant and by a grant (CoVarImm) from the Agence National de la Recherche (ANR-flash Covid19) awarded to DD and JPD, and by the Laboratoire d’Excellence ‘‘Milieu Intérieur' (grant no. ANR-10-LABX-69-01) and the Fonds IMMUNOV, for Innovation in Immunopathology. NS is a recipient of the Pasteur-Roux-Cantarini Fellowship. We thank the UTechS CB of the Center for Translational Research, Institut Pasteur for supporting Luminex and Simoa analysis. We thank Laurence Motreff and Laurence Ma, Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09), IBISA and the Illumina COVID-19 Projects’ offer for microbial sequencing., ANR-20-COVI-0053,CoVarImm,Variation de la réponse immune systémique et muqueuse pendant l'infection par le SRAS-CoV-2 et la convalescence(2020), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Subjects: systemic immunity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Proinflammatory cytokine, 03 medical and health sciences, 0302 clinical medicine, Immune system, Interferon, medicine, Microbiome, 030304 developmental biology, 0303 health sciences, biology, business.industry, Compartmentalization (psychology), cytokines, 3. Good health, Immunology, biology.protein, mucosal immunity, [SDV.IMM]Life Sciences [q-bio]/Immunology, Antibody, business, Covid-19, Viral load, 030217 neurology & neurosurgery, medicine.drug
Abstract: SummaryCoordinated local mucosal and systemic immune responses following SARS-CoV-2 infection protect against COVID-19 pathologies or fail leading to severe clinical outcomes. To understand this process, we performed an integrated analysis of SARS-CoV-2 spike-specific antibodies, cytokines, viral load and 16S bacterial communities in paired nasopharyngeal swabs and plasma samples from a cohort of clinically distinct COVID-19 patients during acute infection. Plasma viral load was associated with systemic inflammatory cytokines that were elevated in severe COVID-19, and also with spike-specific neutralizing antibodies. In contrast, nasopharyngeal viral load correlated with SARS-CoV-2 humoral responses but inversely with interferon responses, the latter associating with protective microbial communities. Potential pathogenic microrganisms, often implicated in secondary respiratory infections, were associated with mucosal inflammation and elevated in severe COVID-19. Our results demonstrate distinct tissue compartmentalization of SARS-CoV-2 immune responses and highlight a role for the nasopharyngeal microbiome in regulating local and systemic immunity that determines COVID-19 clinical outcomes.
Published: 2021

35. Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

Author: Sofie E. Jørgensen, Pärt Peterson, Lili Milani, E. Graham Davies, Vincent Bondet, Mario Saare, Darragh Duffy, Epp Kaleviste, Sascha Sauer, Timothy Ronan Leahy, Helke Nurm, Trine H. Mogensen, Ann-Christine Syvänen, Kai Kisand, Winnie Ip, University of Tartu, Our Lady's Children's Hospital Crumlin (OLCHC), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Aarhus University [Aarhus], Aarhus University Hospital, Tallinn Children's Hospital [Tallinn, Estonia], Great Ormond Street Hospital for Children [London] (GOSH), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Uppsala University, The research was funded by the European Union through the European Regional Development Fund (Project No 2014–2020.4.01.15‐0012), by Estonian Research Council (grants PUT1367 for KK, IUT 2‐2 for PP), and by [FP7/2007‐2013] under grant agreement number n° 262055 (ESGI). D. Duffy acknowledges support from the ANR (CE17001002) and Immunoqure for provision of mAbs for Simoa., European Project: 262055,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2010-1,ESGI(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: STAT3 Transcription Factor, 0301 basic medicine, Immunology, chronic mucocutaneous candidiasis, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Interferon, STAT1 gain-of-function mutation, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Epigenetics, Phosphorylation, epigenetics, Janus kinase 1, Chromatin binding, autoimmunity, Candidiasis, Chronic Mucocutaneous, 3. Good health, Chromatin, Intracellular signal transduction, STAT1 Transcription Factor, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Gain of Function Mutation, Cancer research, type I interferon, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chromatin Immunoprecipitation Sequencing, H3K4me3, Interferons, Chromatin immunoprecipitation, Protein Binding, Signal Transduction, 030215 immunology, medicine.drug
Abstract: International audience; STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.
Published: 2019

36. Differential levels of IFNα subtypes in autoimmunity and viral infection

Author: Nassima Bekaddour, Ian N. Bruce, Tracy A Briggs, Stanislas Pol, David Hunt, Liis Haljasmägi, David A. Isenberg, Darragh Duffy, Kai Kisand, Jérémie Decalf, Mathieu P Rodero, Claudia Mauri, John A. Reynolds, Jean-Philippe Herbeuval, Madhvi Menon, Benno Schwikowski, Pierre Bost, Céline Posseme, J Eric Gottenberg, Vincent Bondet, Tineke Cantaert, Gillian I. Rice, Flore Rozenberg, Vinit Upasani, and Xavier Mariette
Subjects: Immunology, medicine, Alpha (ethology), Stimulation, Biological activity, Disease, Biology, medicine.disease_cause, Receptor, Viral infection, Phenotype, Autoimmunity
Abstract: Type I interferons are essential for host response to viral infections, while dysregulation of their response can result in autoinflammation or autoimmunity. Among IFNα (alpha) responses, 13 subtypes exist that signal through the same receptor, but have been reported to have different effector functions. However, the lack of available tools for discriminating these closely related subtypes, in particular at the protein level, has restricted the study of their differential roles in disease. We developed a digital ELISA with specificity and high sensitivity for the IFNα2 subtype. Application of this assay, in parallel with our previously described pan-IFNα assay, allowed us to study different IFNα protein responses following cellular stimulation and in diverse patient cohorts. We observed different ratios of IFNα protein responses between viral infection and autoimmune patients. This analysis also revealed a small percentage of autoimmune patients with high IFNα2 protein measurements but low pan-IFNα measurements. Correlation with an ISG score and functional activity showed that in this small sub group of patients, IFNα2 protein measurements did not reflect its biological activity. This unusual phenotype was partly explained by the presence of anti-IFNα auto-antibodies in a subset of autoimmune patients. This study reports ultrasensitive assays for the study of IFNα proteins in patient samples and highlights the insights that can be obtained from the use of multiple phenotypic readouts in translational and clinical studies.
Published: 2021

37. JAK inhibitors are effective in a subset of patients with juvenile dermatomyositis: a monocentric retrospective study

Author: Christine Bodemer, Arnaud Isapof, Cyril Gitiaux, Mathieu P Rodero, Jean-Philippe Herbeuval, Florence Aeschlimann, Brigitte Bader-Meunier, Marie-Louise Frémond, Isabelle Melki, Jean-Luc Charuel, François-Jérôme Authier, Vincent Bondet, Pierre Quartier, Darragh Duffy, Tom Le Voyer, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Université Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de dermatologie [CHU Necker], Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), AP-HP Hôpital universitaire Robert-Debré [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Institut Pasteur [Paris] (IP)
Subjects: Male, Ruxolitinib, medicine.medical_specialty, Adolescent, Disease, Gastroenterology, Dermatomyositis, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Refractory, Internal medicine, Nitriles, Medicine, Humans, Janus Kinase Inhibitors, Pharmacology (medical), Immunoadsorption, Child, Juvenile dermatomyositis, Janus kinase inhibitor, Autoantibodies, Janus Kinases, Retrospective Studies, 030203 arthritis & rheumatology, Sulfonamides, Muscle biopsy, medicine.diagnostic_test, business.industry, juvenile dermatomyositis, Interferon-alpha, type 1 interferon, Retrospective cohort study, medicine.disease, 3. Good health, Pyrimidines, Treatment Outcome, Janus-kinase inhibitor, Purines, Child, Preschool, Azetidines, Pyrazoles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, business, 030217 neurology & neurosurgery, Biomarkers, medicine.drug
Abstract: Objective To evaluate the efficacy and safety of Janus kinase inhibitors (JAKis) in JDM. Methods We conducted a single-centre retrospective study of patients with JDM treated by JAKi with a follow-up of at least 6 months. Proportion of clinically inactive disease (CID) within 6 months of JAKi initiation was evaluated using PRINTO criteria and skin Disease Activity Score. Serum IFN-α concentration was measured by Simoa assay. Results Nine refractory and one new-onset patients with JDM treated with ruxolitinib (n = 7) or baricitinib (n = 3) were included. The main indications for treatment were refractory muscle involvement (n = 8) and ulcerative skin disease (n = 2). CID was achieved in 5/10 patients (two/two anti-MDA5, three/four anti-NXP2, zero/three anti-TIF1γ-positive patients) within 6 months of JAKi introduction. All responders could withdraw plasmatic exchange, immunoadsorption and other immunosuppressive drugs. The mean daily steroid dose decreased from 1.1 mg/kg (range 0.35–2 mg/kg/d) to 0.1 (range, 0–0.3, P = 0.008) in patients achieving CID, and was stopped in two. Serum IFN-α concentrations were elevated in all patients at the time of treatment initiation and normalized in both responder and non-responder. A muscle biopsy repeated in one patient 26 months after the initiation of JAKi, showed a complete restoration of muscle endomysial microvascular bed. Herpes zoster and skin abscesses developed in three and two patients, respectively. Conclusion JAKis resulted in a CID in a subset of new-onset or refractory patients with JDM and may dramatically reverse severe muscle vasculopathy. Overall tolerance was good except for a high rate of herpes zoster infection.
Published: 2021

38. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Author: Olivier Brocq, Pere Soler-Palacín, Jérôme Sirvente, Brigitte Bader-Meunier, Rawane Dagher, Naoki Kitabayashi, Laureline Berteloot, Sophie Willcocks, Nadia Jeremiah, Laura Barnabei, Stefano Volpi, Eline Van Aerde, Sylvain Breton, Damien Chan, Alice Hadchouel, Vincent Bondet, Eric Jeziorski, Despina Moshous, Antonella Insalaco, Jean-Christophe Dubus, Thierry Jo Molina, Isabelle Melki, Nathalie Stremler-Le Bel, Stéphane Blanche, Marie-Anne Morren, Alain Fischer, Mireia Lopez-Corbeto, Gillian I. Rice, Marie-Louise Frémond, Carine Wouters, Yanick J. Crow, Séverine Feuillet-Soummer, Jacques G. Rivière, Françoise Mazingue, Violaine Bresson, Bénédicte Neven, Alexandre Belot, Mathieu Fusaro, Guillaume Thouvenin, Darragh Duffy, Frédéric Rieux-Laucat, Caroline Thumerelle, Luis Seabra, Marco Gattorno, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie Allergologie [CHU Necker], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de radiologie pédiatrique [CHU Necker], AP-HP Hôpital universitaire Robert-Debré [Paris], Urgences pédiatriques [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Immunologie Translationnelle - Translational Immunology lab, Hôpital Princesse Grace [Monaco], Women’s and Children’s Hospital [Adelaide], CHU Notre Dame des Secours [Jbeil], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre chirurgical Marie Lannelongue, CHU Necker - Enfants Malades [AP-HP], IRCCS Istituto Giannina Gaslini [Genoa, Italy], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospitals Leuven [Leuven], Lausanne University Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Queensland Children's Hospital, Partenaires INRAE, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service de pathologie [CHU Necker], Collège de France (CdF (institution)), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. Crow and D. Duffy acknowledge the National Research Agency (France) (grant CE17001002)., The authors wish to thank the patients and their families for their cooperation in this study. The authors are grateful to Elvira Duchesne (NP) and Samira Plassart (PhD) for their very helpful technical assistance. They thank Thomas Blauwblomme (MD, PhD, Neurosurgery Unit, Necker Hospital, Paris, France) for providing CSF from children with idiopathic hydrocephalus., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre Chirurgical Marie Lannelongue (CCML), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Adolescent, Late onset, Interstitial lung disease, Vasculopathy, Systemic inflammation, Gastroenterology, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Lymphopenia, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Vascular Diseases, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Child, Type I interferonopathy, Immunodeficiency, Inflammation, STING1, JAK inhibitors, business.industry, Infant, Membrane Proteins, medicine.disease, 3. Good health, Polyarthritis, 030228 respiratory system, Failure to thrive, Mutation, Aicardi–Goutières syndrome, medicine.symptom, Stimulator of interferon genes, business, Lung Diseases, Interstitial
Abstract: BACKGROUND: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).OBJECTIVE: To describe a cohort of patients with SAVI.METHODS: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.CONCLUSION: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
Published: 2021

39. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Author: Alice Hadchouel, Odile Boespflug-Tanguy, Eric Jeziorski, Thomas Blauwblomme, Buthaina Al Adba, Alice Lepelley, Isabelle Desguerre, Gillian I. Rice, Edwin Carter, Véronique Hentgen, Christine Bodemer, Lorenzo Lodi, Sandrine Passemard, Yanick J. Crow, Marie Hully, Fanny Mochel, Camille Ducrocq, Magalie Barth, Jay Shetty, Brigitte Bader-Meunier, Isabelle Melki, Florence Renaldo, Vincent Bondet, Miguel Hie, Marie Pouletty, Russell C. Dale, Romain Lévy, Pierre Ellul, Simona Orcesi, Bénédicte Neven, Cécile Dumaine, Luis Seabra, Darragh Duffy, Fabienne Dulieu, Marie-Louise Frémond, Stéphane Blanche, Rainer Seidl, Maria José Martin-Niclos, Pierre Quartier, Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Azienda Ospedaliero Universitaria A. Meyer [Firenze, Italy], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), University of Manchester [Manchester], University of Edinburgh, Sidra Medicine [Doha, Qatar], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Service de dermatologie [CHU Necker], The University of Sydney, Service de neurologie pédiatrique [CHU Necker], Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Pneumologie Allergologie [CHU Necker], Centre Hospitalier de Versailles André Mignot (CHV), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département Pédiatrie [CHRU Montpellier], Pôle Femme Mère Enfant [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Pavia = University of Pavia (UNIPV), CHU Trousseau [APHP], Medizinische Universität Wien = Medical University of Vienna, Royal Hospital for Sick Children [Edinburgh], Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre National de Référence du Lupus Systémique, Syndrome des Anticorps Anti-phospholipides et Maladies Auto-immunes Systémiques Rares [CHU Pitié Salpêtrière], Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut E3M [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF Neurométabolique Bioclinique et Génétique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Pavia, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Immunology, Central nervous system, Alpha interferon, Aicardi-Goutières syndrome, cerebrospinal fluid, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, Medical microbiology, Downregulation and upregulation, systemic lupus erythematosus, Interferon, Humans, Immunology and Allergy, Medicine, Child, Retrospective Studies, business.industry, Infant, Interferon-alpha, medicine.disease, 3. Good health, Hydrocephalus, Phenotype, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, Organ Specificity, Case-Control Studies, Child, Preschool, Interferon Type I, Mutation, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, STING-associated vasculopathy with onset in infancy, business, 030215 immunology, medicine.drug
Abstract: International audience; Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.
Published: 2021

40. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Author: Isabelle Meyts, Xin Mu, Emmanuelle Jouanguy, Daxing Gao, Aurélie Cobat, Lazaro Lorenzo, Mary Hasek, Damien Chaussabel, Luigi D. Notarangelo, Darragh Duffy, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Lorenz Studer, Gregory A. Smith, Sun Hur, Jie Chen, Peng Zhang, Michael J. Ciancanelli, Jessica L. McAlpine, Gabriele Ciceri, Shen-Ying Zhang, Oliver Harschnitz, Yuval Itan, Michael S. Diamond, Benedetta Bigio, Vincent Bondet, Esperanza Anguiano, Laurent Abel, Rockefeller University [New York], University of Science and Technology of China [Hefei] (USTC), Turnstone Biologics [New York], Memorial Sloane Kettering Cancer Center [New York], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Imperial College London, Baylor Institute for Immunology Research (BIIR), Benaroya Research Institute [Seattle] (BRI), Sidra Medicine [Doha, Qatar], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Feinberg School of Medicine, Northwestern University [Evanston], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1TR001866), NIH (R01NS072381, R01AI088364, and R21AI151663), the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), and grants ANR-14-CE14-0008-01 and ANR-18-CE15-0020-02, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. DG is supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and the National Natural Science Foundation of China (grant 31970855). IM is supported by KU Leuven C1 grant C16/18/007 and Fonds Wetenschappelijk Onderzoek Vlaanderen grant G0C8517N., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), Institut Pasteur [Paris] (IP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: 0301 basic medicine, viruses, NF-KAPPA-B, Herpesvirus 1, Human, Research & Experimental Medicine, RIG-I, Mice, 0302 clinical medicine, ADAPTER PROTEIN, Induced pluripotent stem cell, GENE-EXPRESSION, Cerebral Cortex, Mice, Knockout, Neurons, Innate immunity, Infectious disease, biology, virus diseases, VESICULAR STOMATITIS-VIRUS, General Medicine, 3. Good health, Cell biology, INTERFERON-ALPHA/BETA, Medicine, Research & Experimental, Vesicular stomatitis virus, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESSENGER-RNA, Life Sciences & Biomedicine, Research Article, HERPES-SIMPLEX ENCEPHALITIS, Immunology, chemical and pharmacologic phenomena, DOUBLE-STRANDED-RNA, Cell Line, 03 medical and health sciences, Immunity, Animals, Humans, Secretion, Messenger RNA, Science & Technology, Innate immune system, TOLL-LIKE RECEPTOR-3, Interferon-beta, Vesiculovirus, Fibroblasts, biology.organism_classification, Embryonic stem cell, Toll-Like Receptor 3, 030104 developmental biology, TLR3
Abstract: Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:1 ispartof: location:United States status: published
Published: 2021

41. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation in health and disease

Author: Vincent Rouilly, Matthew L. Albert, Michael S. Kobor, Jeremy Boussier, Lluis Quintana-Murci, Maxime Rotival, Jacob Bergstedt, Stanislas Pol, Etienne Patin, Estelle Mottez, Alba Llibre, Violaine Saint-André, Nikaïa Smith, Darragh Duffy, Vincent Bondet, Bruno Charbit, Celine Posseme, Thomas J. Scriba, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Ecole Doctorale Frontiere de l’Innovation en Recherche et Education (ED 474 FIRE), Université de Paris (UP)-Université Paris sciences et lettres (PSL), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Datactix, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute-University of British Columbia (UBC), University of Cape Town, Département d'hépatologie [CHU Cochin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Insitro [San Francisco], Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), This study was funded with support from the French Governments Investissement dAvenir Program, Laboratoire Excellence Milieu Interieur Grant ANR-10-LABX-69-01 and by an Agence National de Recherche foundation grant (CE17001002)., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Philippe Bousso, Nollaig Bourke (Trinity College Dublin), Petter Brodin (Karolinska Institutet), Pierre Bruhns, Nadine Cerf-Bensussan (INSERM UMR 1163 – Institut Imagine), Ana Cumano, Caroline Demangel, Christophe d’Enfert, Ludovic Deriano, Marie-Agnès Dillies, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne), Ivo Gomperts-Boneca, Milena Hasan, Magnus Fontes (Institut Roche), Gunilla Karlsson Hedestam (Karolinska Institutet), Serge Hercberg (Université Paris 13), Molly Ingersoll, Rose Anne Kenny (Trinity College Dublin), Olivier Lantz (Institut Curie), Frédérique Michel, Hugo Mouquet, Cliona O'Farrelly (Trinity College Dublin), Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 – Institut Imagine), Frédéric Rieux-Laucat (INSERM UMR 1163 – Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Frédéric Tangy, Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Christophe Zimmer, Matthew L. Albert (In Sitro), Darragh Duffy, Lluis Quintana-Murci, ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), and ANR-20-CE17-0010,ELECTRO,Inhibition de l'Exchange Protein directly activated by cAMP -1 pour traiter la Fibrillation Atrial(2020)
Subjects: Systems immunology, 0303 health sciences, Hepatitis C virus, Disease, Biology, medicine.disease_cause, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, 030220 oncology & carcinogenesis, Immunology, medicine, TLR4, [SDV.IMM]Life Sciences [q-bio]/Immunology, Secretion, Epigenetics, 030304 developmental biology, Epigenomics
Abstract: SummaryThe IL-12 family of cytokines comprises the only heterodimeric cytokines mediating diverse functional effects. We previously observed a bi-modal IL-12p70 response to LPS in healthy donors of the Milieu Interieur cohort. Herein, we demonstrate that IFNβ expression serves as an upstream determinant of variable IL-12p70 production. Integrative modelling of proteomic, genetic, epigenomic and cellular data confirmed IFNβ as key for regulation of LPS induced IL12A and IL-12p70 variability. The clinical relevance was supported by reduced and variable IL-12p70 responses in individuals infected with the hepatitis C virus (HCV), and findings that IFN-based therapy for HCV is more likely to fail in those patients with dysregulated pre-treatment IL-12p70 responses. In sum, our systems immunology approach has defined a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection in health and disease.
Published: 2020

42. Heterozygous RELA mutations cause early-onset systemic lupus erythematosus by hijacking the NF-κB pathway towards transcriptional activation of type-I Interferon genes

Author: Marie-Claude Stolzenberg, Christine Bodemer, Sven Kracker, Marion Rabant, Olivier Pellé, Vincent Bondet, Brigitte Bader-Meunier, Sidonie Jacques, Rémi Salomon, Miguel Hie, Mathieu Castela, Matthieu Moncan, Frédéric Rieux-Laucat, Loic Chentout, Marina Cavazzana, Sajedeh Mirshavalad, Capucine Picard, Marc Bras, Mélanie Parisot, Jonathan J. Miner, Amine Bouafia, Alexandre Belot, Carolina Uggenti, Darragh Duffy, Nadia Jeremiah, Aude Magérus, Laura Barnabei, Hicham Lamrini, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, [SDV]Life Sciences [q-bio], Mutant, Autoantibody, NF-κB, Biology, 3. Good health, Proinflammatory cytokine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Interferon, Cancer research, Consensus sequence, medicine, skin and connective tissue diseases, Gene, Exome sequencing, 030304 developmental biology, 030215 immunology, medicine.drug
Abstract: Systemic Lupus Erythematosus (SLE) is an autoimmune and inflammatory disease characterized by uncontrolled production of autoantibodies and inflammatory cytokines such as the type-I interferons. Due to the lack of precise pathophysiological mechanisms, treatments are based on broad unspecific immunossupression. To identify genetic factors associated with SLE we performed whole exome sequencing and identified two RELA heterozygous activating mutations in 3 early-onset and familial SLE cases. The corresponding RELA/p65 mutant were abundant in the nucleus but poorly activate transcription of genes controlled by NF-κB consensus sequences. The co-expression of the mutant and wild-type RELA/p65 strongly activated the expression of genes controlled by the IFNα-consensus sequences. These molecular mechanisms lead to the overproduction of type-I IFN in the patients’ cells. Our findings highlight a novel mechanism of autoimmunity where these new RELA mutants are transactivating the type-I IFN genes and are thus promoting type-I interferon production and early-onset SLE, thereby paving the way to the identification of new and specific therapeutic targets.SummaryHeterozygous RELA mutations are associated with Systemic Lupus Erythematosus, with increased expression of genes controlled by the IFNα-consensus sequences.
Published: 2020

43. Altered Immune Phenotypes and

Author: Priyanka, Devi-Marulkar, Carolina, Moraes-Cabe, Pascal, Campagne, Béatrice, Corre, Aida, Meghraoui-Kheddar, Vincent, Bondet, Alba, Llibre, Darragh, Duffy, Elisabeth, Maillart, Caroline, Papeix, Sandra, Pellegrini, and Frédérique, Michel
Subjects: Adult, CD4-Positive T-Lymphocytes, Male, Immunology, T cells, Genetic Variation, blood biomarkers, Middle Aged, multiple sclerosis, immune phenotypes, HLA class II genes, Young Adult, Multiple Sclerosis, Relapsing-Remitting, Phenotype, interferon-stimulated genes, Case-Control Studies, Interferon Regulatory Factors, HLA-DQ beta-Chains, Humans, Immunologic Factors, type I interferon, Female, Treatment Failure, Interferon beta-1a, Original Research
Abstract: Background Interferon beta (IFNβ) has been prescribed as a first-line disease-modifying therapy for relapsing-remitting multiple sclerosis (RRMS) for nearly three decades. However, there is still a lack of treatment response markers that correlate with the clinical outcome of patients. Aim To determine a combination of cellular and molecular blood signatures associated with the efficacy of IFNβ treatment using an integrated approach. Methods The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFNβ1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4+ T cells and naïve/memory T cell subsets, by measurement of circulating IFNα/β proteins with digital ELISA (Simoa) and analysis of ~600 immune related genes including 159 interferon-stimulated genes (ISGs) with the Nanostring technology. The potential impact of HLA class II gene variation in treatment responsiveness was investigated by genotyping HLA-DRB1, -DRB3,4,5, -DQA1, and -DQB1, using as a control population the Milieu Interieur cohort of 1,000 French healthy donors. Results Clinical responders and non-responders displayed similar plasma levels of IFNβ and similar ISG profiles. However, non-responders mainly differed from other subject groups with reduced circulating naïve regulatory T cells, enhanced terminally differentiated effector memory CD4+ TEMRA cells, and altered expression of at least six genes with immunoregulatory function. Moreover, non-responders were enriched for HLA-DQB1 genotypes encoding DQ8 and DQ2 serotypes. Interestingly, these two serotypes are associated with type 1 diabetes and celiac disease. Overall, the immune signatures of non-responders suggest an active disease that is resistant to therapeutic IFNβ, and in which CD4+ T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities.
Published: 2020

44. Absence of Neuronal Autoantibodies in Neuropsychiatric Systemic Lupus Erythematosus

Author: Vincent Bondet, Patrick Waters, Michael S. Zandi, Eleanor Grant, Magnus Andersson, Antonio Berretta, James Varley, Sarosh R. Irani, Fredrik Piehl, David Hunt, Darragh Duffy, Nuffield Department of Clinical Neurosciences [Oxford], University of Oxford [Oxford], John Radcliffe Hospital [Oxford University Hospital], Karolinska Institutet [Stockholm], National Hospital for Neurology and Neurosurgery, Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Center for Clinical Brain Sciences (CCBS), University of Edinburgh, J.V. was supported by the Association of British Neurologists and the Guarantors of Brain. S.R.I. is supported by the Wellcome Trust (104079/Z/14/Z), The UCB‐Oxford University Alliance, BMA Research Grants – 2013 Vera Down grant and 2017 Margaret Temple, Epilepsy Research UK (P1201), and by the Fulbright UK‐US commission (MS‐Research Society Award). P.W. is supported by the UK NMO commissioning group. The work is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). D.D. acknowledges support from the ANR (CE17001002)., D.D. thanks Immunoqure for provision of mAbs for the SIMOA assay., Vougny, Marie-Christine, University of Oxford, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)
Subjects: Adult, Male, 0301 basic medicine, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, Peptide, Hippocampal formation, Hippocampus, Receptors, N-Methyl-D-Aspartate, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Cerebrospinal fluid, immune system diseases, Extracellular, Humans, Medicine, Receptor, skin and connective tissue diseases, Cells, Cultured, Aged, Autoantibodies, Neurons, chemistry.chemical_classification, biology, business.industry, Lupus Vasculitis, Central Nervous System, Autoantibody, Interferon-alpha, Middle Aged, 3. Good health, Neuropsychiatric systemic lupus erythematosus, 030104 developmental biology, Neurology, chemistry, Case-Control Studies, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Neurology (clinical), Antibody, business, 030217 neurology & neurosurgery
Abstract: International audience; This study aimed to characterise both neuronal autoantibodies and levels of interferon α, two proposed causative agents in neuropsychiatric systemic lupus erythematosus (NPSLE). Cerebrospinal fluid (CSF) and plasma from 35 patients with systemic lupus erythematosus (SLE; 15 with NPSLE) showed no antibodies against natively expressed N-methyl-D-aspartate receptors (NMDARs), or the surface of live hippocampal neurons. By comparison to controls (n = 104), patients with SLE had antibodies that bound to a peptide representing the extracellular domain of NMDARs (p
Published: 2020

45. Dysregulation of tryptophan catabolism at the host-skin microbiota interface in Hidradenitis Suppurativa

Author: Jean-Marc Doisne, Pedro Gonçalves, Lysiane Boulet, Marie-Noëlle Ungeheuer, Laure Guenin-Macé, Sabine Duchatelet, Vincent Bondet, James P. Di Santo, Alain Hovnanian, Aude Nassif, Darragh Duffy, Maïa Delage, Angèle Schiavo, Véronique Mayau, J Morel, Caroline Demangel, Immunobiologie de l'Infection - Immunobiology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), École normale supérieure de Lyon (ENS de Lyon), Immunité Innée - Innate Immunity, Biochimie Hormonale et Nutritionnelle, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunobiologie des Cellules dendritiques, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP), Centre Médical de l'Institut Pasteur (CMIP), This study was supported by Institut Pasteur (to CD and JPDS) via the Center for Translational Science, INSERM (U1221, to CD, U1223, to JPDS), and 'Société Française de Dermatologie' (to AN). The Biomics Platform, C2RT, Institut Pasteur is supported by France Génomique (ANR-10-INBS-09-09) and IBISA., We thank Armanda Casrouge for assistance in performing the immunostaining of skin biopsies, Olivier Join-Lambert for fruitful discussions on the skin microbiota of patients with HS, and Harry Sokol for his critical reading of this manuscript. We also thank Valérie Briolat and Laurence Motreff of the Biomics Wet-Lab Platform for 16S rRNA sequencing and the Image Analysis Hub for immunofluorescence data processing., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], École normale supérieure - Lyon (ENS Lyon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Centre Médical de l'Institut Pasteur, Vougny, Marie-Christine, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Kynurenine pathway, chemistry.chemical_compound, 030207 dermatology & venereal diseases, 0302 clinical medicine, Hidradenitis suppurativa, Immune homeostasis, Kynurenine, Skin, 0303 health sciences, integumentary system, biology, Tryptophan, General Medicine, Middle Aged, Hidradenitis Suppurativa, 3. Good health, 030220 oncology & carcinogenesis, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.symptom, Research Article, Adult, [SDV.IMM] Life Sciences [q-bio]/Immunology, Inflammation, Dermatology, Amino acid metabolism, Tryptophan catabolism, 03 medical and health sciences, medicine, Humans, 030304 developmental biology, Host Microbial Interactions, business.industry, Cellular immune response, Fibroblasts, medicine.disease, Aryl hydrocarbon receptor, Metabolism, 030104 developmental biology, Receptors, Aryl Hydrocarbon, chemistry, Axilla, Immunology, biology.protein, business, Dysbiosis
Abstract: Hidradenitis suppurativa (HS) is a chronic skin disorder of unknown etiology that manifests as recurrent, painful lesions. Cutaneous dysbiosis and unresolved inflammation are hallmarks of active HS, but their origin and interplay remain unclear. Our metabolomic profiling of HS skin revealed an abnormal induction of the kynurenine pathway of tryptophan catabolism in dermal fibroblasts, correlating with the release of kynurenine pathway–inducing cytokines by inflammatory cell infiltrates. Notably, overactivation of the kynurenine pathway in lesional skin was associated with local and systemic depletion in tryptophan. Yet the skin microbiota normally degrades host tryptophan into indoles regulating tissue inflammation via engagement of the aryl hydrocarbon receptor (AHR). In HS skin lesions, we detected contextual defects in AHR activation coinciding with impaired production of bacteria-derived AHR agonists and decreased incidence of AHR ligand-producing bacteria in the resident flora. Dysregulation of tryptophan catabolism at the skin-microbiota interface thus provides a mechanism linking the immunological and microbiological features of HS lesions. In addition to revealing metabolic alterations in patients with HS, our study suggests that correcting AHR signaling would help restore immune homeostasis in HS skin., Loss of homeostasis of tryptophan metabolism at the host-microbiota interface may contribute to Hidradenitis Suppurativa.
Published: 2020

46. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author: Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract: Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.
Published: 2020

47. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling

Author: Nicolas Manel, Siham Boulisfane-El Khalifi, Mary Brennan, Darragh Duffy, Nadia Nathan, Serge Amselem, Kathryn J. McKenzie, Maria José Martin-Niclos, Jonny Hertzog, Carolina Uggenti, Marie Legendre, Stéphanie Chhun, Caroline Thumerelle, Luis Seabra, Marie-Louise Frémond, Vincent Bondet, Bénédicte Neven, Joseph A. Marsh, Marie Wislez, Catherine McDougall, Marine Depp, Jan Rehwinkel, Gillian I. Rice, Aurore Coulomb L'Hermine, Yanick J. Crow, Lucienne Chatenoud, Melvin Le Bihan, Thierry Jo Molina, Karen J. Mackenzie, Alice Lepelley, Edwin Carter, Jonathan Marey, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Radcliffe Department of Medicine [Oxford], University of Oxford [Oxford], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Royal Hospital for Sick Children [Edinburgh], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service de pathologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Royal Infirmary of Edinburgh, Département de Pathologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (000427993) and acknowledges La Fondation Square. Y.J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs), and a state subsidy managed by the Agence Nationale de la Recherche under the 'Investments for the Future' program (ANR-10-IAHU-01). Y.J. Crow and D. Duffy acknowledge the Agence Nationale de la Recherche (grant CE17001002). J.A. Marsh is supported by a Medical Research Council Career Development Award (MR/M02122X/1) and is a Lister Institute of Preventive Medicine Research Prize Fellow. N. Manel was supported by LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* and ANR-11-LABX-0043), ANR-17-CE15-0025-01, ANR-18-CE92-0022-01, Fondation BMS, Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ECTZ71745), Sidaction (VIH2016126002), and Ile-de-France Emergence. M. Le Bihan received a doctoral fellowship from Ile-de-France ARDoc. The project was supported by MSDAVENIR (Devo-Decode Project)., We thank Immunoqure AG for provision of antibodies for the Simoa assay., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-17-CE15-0025,STINGCHECK,Mécanismes des points de contrôle du senseur de l'immunité innée STING(2017), ANR-18-CE92-0022,cGAS-Vac,Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants(2018), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Oxford, Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Initiative d'excellence - Paris Sciences et Lettres - - PSL2010 - ANR-10-IDEX-0001 - IDEX - VALID, Mécanismes des points de contrôle du senseur de l'immunité innée STING - - STINGCHECK2017 - ANR-17-CE15-0025 - AAPG2017 - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Analyses fonctionnelles de la voie cGAS/STING au cours d'infections bactériennes et infections virales et implications pour le développement de vaccins innovants - - cGAS-Vac2018 - ANR-18-CE92-0022 - AAPG2018 - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Protein subunit, Immunology, Mutant, Biology, medicine.disease_cause, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Interferon, medicine, Immunology and Allergy, Gene silencing, Mutation, HEK 293 cells, Golgi apparatus, eye diseases, 3. Good health, Cell biology, Sting, 030104 developmental biology, 030220 oncology & carcinogenesis, symbols, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.drug
Abstract: International audience; Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.
Published: 2020

48. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Author: Aurélien Corneau, David Veyer, Tali Anne Szwebel, Nicolas Roche, Bruno Charbit, Darragh Duffy, Laura Barnabei, Hélène Péré, Flore Rozenberg, Nathalie Marin, Vincent Bondet, Benjamin Terrier, Pierre-Louis Tharaux, Solen Kernéis, Nader Yatim, Jeremy Boussier, Nikaïa Smith, Sarah H. Merkling, Alain Fischer, Nicolas Carlier, Frédéric Rieux-Laucat, Jean-Marc Treluyer, Camille Chenevier-Gobeaux, Paul Breillat, Rémy Gauzit, Luc Mouthon, Frédéric Pène, Jérôme Hadjadj, Caroline Morbieu, Catherine Blanc, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire de Virologie [Hôpital Européen Georges Pompidou - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Diagnostic biologique automatisé [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité Equipe mobile d'Infectiologie [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Unité de Soins Intensifs [CHU Cochin], Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Virologie [CHU Cochin], Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Institut Pasteur, by a government grant managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (ANR-10-IAHU-01 and the Laboratoire d’Excellence ‘‘Milieu Intérieur', grant no. ANR-10-LABX-69-01), and by a grant from the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). J.H. is a recipient of an Institut Imagine MD-PhD fellowship program supported by the Fondation Bettencourt Schueller. L.B. is supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) program of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program., We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Cochin Hospital, especially C. Azoulay L. Beaudeau, E. Canoui, P. Cohen, A. Contejean, B. Dunogué, D.Journois, P. Legendre, J. Marey and A. Régent. We thank Y. Gaudin for his advices on viral mechanism. We thank all the patients, supporters and our families for their confidence in our work., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Chaire Médecine expérimentale (A. Fischer)
Subjects: Male, 0302 clinical medicine, Interferon, T-Lymphocyte Subsets, 0303 health sciences, Multidisciplinary, biology, NF-kappa B, Interleukin, Middle Aged, Viral Load, 3. Good health, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, Female, medicine.symptom, Coronavirus Infections, Viral load, medicine.drug, Signal Transduction, Adult, Critical Illness, Pneumonia, Viral, Alpha interferon, Inflammation, Interferon alpha-2, 03 medical and health sciences, Betacoronavirus, Immune system, medicine, Humans, Interleukin 6, Pandemics, 030304 developmental biology, Aged, business.industry, Interleukin-6, SARS-CoV-2, Tumor Necrosis Factor-alpha, Gene Expression Profiling, COVID-19, Interferon-alpha, Interferon-beta, Immunity, Innate, Cross-Sectional Studies, Immunology, biology.protein, business
Abstract: Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626
Published: 2020

49. Cardiac valve involvement in ADAR -related type I interferonopathy

Author: Alessandro Giardini, Jacques Patrick Barbet, Gillian I. Rice, Shamima Rahman, Charlotte Boussard, Cyril Gitiaux, Vincent Bondet, Nathalie Dedieu, Marie Hully, Brigitte Bader-Meunier, Nandaki Keshavan, Yanick J. Crow, Geanina Bercu, Darragh Duffy, Luis Seabra, University of Edinburgh, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Great Ormond Street Hospital for Children [London] (GOSH), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Manchester [Manchester], Rheumatism and autoimmune diseases (RAISE), Mother and Children University Hospital, YJC acknowledges funding from the European Research Council (GA 309449), fellowship and a state subsidy managed by the National Research Agency (ANR, France) under the 'Investments for the Future' (ANR-10-IAHU-01). SR acknowledges funding from the Great Ormond Street Hospital Children’s Charity, the NIHR Great Ormond Street Hospital Biomedical Research Centre and the Lily Foundation., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Definition and characterization of type I interferonopathies - T1-IFN - - EC:FP7:ERC2013-03-01 - 2018-02-28 - 309449 - VALID
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Encephalopathy, Context (language use), Disease, 03 medical and health sciences, 0302 clinical medicine, Aortic valve replacement, Internal medicine, Genetics, Medicine, metabolic disorders, immunology (including allergy), Genetics (clinical), business.industry, medicine.disease, 3. Good health, Stenosis, 030104 developmental biology, cardiovascular medicine, Cardiology, Etiology, cardiovascular system, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Paraplegia, 030217 neurology & neurosurgery, clinical genetics, Calcification
Abstract: BackgroundAdenosine deaminases acting on RNA (ADAR) mutations cause a spectrum of neurological phenotypes ranging from severe encephalopathy (Aicardi-Goutières syndrome) to isolated spastic paraplegia and are associated with enhanced type I interferon signalling. In children, non-neurological involvement in the type I interferonopathies includes autoimmune and rheumatological phenomena, with calcifying cardiac valve disease only previously reported in the context of MDA5 gain-of-function.ResultsWe describe three patients with biallelic ADAR mutations who developed calcifying cardiac valvular disease in late childhood (9.5–14 years). Echocardiography revealed progressive calcification of the valvular leaflets resulting in valvular stenosis and incompetence. Two patients became symptomatic with biventricular failure after 5–6.5 years. In one case, disease progressed to severe cardiac failure despite maximal medical management, with death occurring at 17 years. Another child received mechanical mitral and aortic valve replacement at 16 years with good postoperative outcome. Histological examination of the affected valves showed fibrosis and calcification.ConclusionsType I interferonopathies of differing genetic aetiology demonstrate an overlapping phenotypic spectrum which includes calcifying cardiac valvular disease. Individuals with ADAR-related type I interferonopathy may develop childhood-onset multivalvular stenosis and incompetence which can progress insidiously to symptomatic, and ultimately fatal, cardiac failure. Regular surveillance echocardiograms are recommended to detect valvular disease early.
Published: 2020

50. Catatonia in a patient with Aicardi-Goutières syndrome efficiently treated with immunoadsorption

Author: Flore Rozenberg, Richard Delorme, Pierre Ellul, Odile Boespflug-Tanguy, Vincent Bondet, Yanick J. Crow, Theresa Kwon, Darragh Duffy, Isabelle Melki, Monique Elmaleh-Bergès, Séverine Drunat, Anaël Ayrolles, Florence Renaldo, Service Psychiatrie de l'Enfant et de l'Adolescent, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Génétique Humaine et Fonctions Cognitives, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare [AP-HP Hôpital Robert-Debré] (LEUKOFRANCE), Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de radiologie pédiatrique [AP-HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], We acknowledge the contribution of the General Paediatrics, Infectious Disease and Internal Medicine Department, the Child and Adolescent Psychiatry Department, the Child Neurology Department, the Pediatric Nephrology Department and the Genetics Department of Robert Debre Hospital. We thank the patient and his family members for allowing us to report the findings of his case., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: Pathology, medicine.medical_specialty, Catatonia, Alpha interferon, Interstitial lung disease, Aicardi-Goutières syndrome, Nervous System Malformations, 03 medical and health sciences, Autoimmune Diseases of the Nervous System, 0302 clinical medicine, medicine, Humans, Immunoadsorption, Biological Psychiatry, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, business.industry, Interferon-alpha, medicine.disease, 3. Good health, Psychiatry and Mental health, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Aicardi–Goutières syndrome, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], business, 030217 neurology & neurosurgery
Abstract: International audience; Letter to the Editor
Published: 2020

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