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1. Successful treatment of JAK1-associated inflammatory disease

Author

Fayand, Antoine, Hentgen, Véronique, Posseme, Céline, Lacout, Carole, Picard, Capucine, Moguelet, Philippe, Cescato, Margaux, Sbeih, Nabiha, Moreau, Thomas R.J., Zhu, Yixiang Y.J., Charuel, Jean-Luc, Corneau, Aurélien, Deibener-Kaminsky, Joelle, Dupuy, Stéphanie, Fusaro, Mathieu, Hoareau, Benedicte, Hovnanian, Alain, Langlois, Vincent, Le Corre, Laurent, Maciel, Thiago T., Miskinyte, Snaigune, Miyara, Makoto, Moulinet, Thomas, Perret, Magali, Schuhmacher, Marie Hélène, Rignault-Bricard, Rachel, Viel, Sébastien, Vinit, Angélique, Soria, Angèle, Duffy, Darragh, Launay, Jean-Marie, Callebert, Jacques, Herbeuval, Jean Philippe, Rodero, Mathieu P., and Georgin-Lavialle, Sophie

Published
2023
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6. Variability of Primary Sjögren's Syndrome Is Driven by Interferon α and Interferon α Blood Levels Are Associated With the Class II HLA–DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Hélène, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana‐Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, Gottenberg, Jacques Eric, Dernis, Emmanuelle, Devauchelle‐Pensec, Valerie, Dieude, Philippe, Dubost, Jean‐Jacques, Fauchais, Anne‐Laure, Goeb, Vincent, Hachulla, Eric, Hatron, Pierre Yves, Larroche, Claire, Le Guern, Véronique, Morel, Jacques, Perdriger, Aleth, Salliot, Carinne, Rist, Stephanie, Saraux, Alain, Vittecoq, Olivier, Nocturne, Gaétane, Ravaud, Philippe, Seror, Raphaèle, Abel, Laurent, Alcover, Andres, Aschard, Hugues, Astrom, Kalla, Bousso, Philippe, Bruhns, Pierre, Cumano, Ana, Demangel, Caroline, Deriano, Ludovic, Di Santo, James, Dromer, Françoise, Eberl, Gérard, Enninga, Jost, Gelpi, Odile, GompertsBoneca, Ivo, Hasan, Milena, Hercberg, Serge, Lantz, Olivier, Leclerc, Claude, Mouquet, Hugo, Pellegrini, Sandra, Pol, Stanislas, Rausell, Antonio, Rogge, Lars, Sakuntabhai, Anavaj, Schwartz, Olivier, Shorte, Spencer, Soumelis, Vassili, Tangy, Frédéric, Tartour, Eric, Toubert, Antoine, Touvier, Mathilde, Ungeheuer, Marie‐Noëlle, Albert, Matthew L., Biomédecine computationelle des systèmes / Computational systems biomedicine, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Service de Rhumatologie [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Projet NECESSITY (PN), Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS)-Immunologie des maladies virales, auto-immunes, hématologiques et bactériennes (IMVA-HB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Immunologie Translationnelle - Translational Immunology lab, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), Lausanne University Hospital, University of Bergen (UiB), Oklahoma Medical Research Foundation (OMRF), University of Oklahoma Health Sciences Center (OUHSC), Université de Strasbourg (UNISTRA), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Newcastle University [Newcastle], Newcastle Upon Tyne Hospitals NHS Foundation Trust, 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 Paris Cité (UPCité), Immunologie, Immunopathologie et Chimie Thérapeutique (I2CT), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biogen Inc. [Cambridge, MA, USA], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Supported by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (grant 806975). The JU receives support from the European Union’s Horizon 2020 research and innovation program and the European Unionand the European Federation of Pharmaceutical Industries and Associations. This work was also supported by the National Institutes of Health (National Institute of Arthritis and Musculoskeletal Skin Disease grant R01-AR-065953). The Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome(ASSESS) national multicenter prospective cohort was formed in 2006 with aFrench Ministry of Health grant (Programme Hospitalier de Recherche Clinique 2005 P060228). The ASSESS cohort is promoted by the French Society of Rheumatology and receives research grants from the French Society of Rheumatology. Dr. Gottenberg’s work was supported by Bristol Myers Squibbfor transcriptomic analysis of the ASSESS and Norwegian cohorts and by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögrenet des syndromes secs). Drs. Trutschel’s and Schwikowski’s work was supported by Geneviève Garnier (Association Française du Syndrome de Gougerot-Sjögren et des syndromes secs)., Milieu Intérieur Consortium, ASSESS study investigators, and NECESSITY Consortium: Emmanuelle Dernis, Valerie Devauchelle-Pensec, Philippe Dieude, Jean-Jacques Dubost, Anne-Laure Fauchais, Vincent Goeb, Eric Hachulla, Pierre Yves Hatron, Claire Larroche, Véronique Le Guern, Jacques Morel, Aleth Perdriger, Carinne Salliot, Stephanie Rist, Alain Saraux, Jean Sibilia, Olivier Vittecoq, Gaétane Nocturne, Philippe Ravaud, Raphaèle Seror, Laurent Abel, Andres Alcover, Hugues Aschard, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Odile Gelpi, Ivo GompertsBoneca, Milena Hasan, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Antonio Rausell, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Mathilde Touvier, Marie-Noëlle Ungeheuer, Matthew L Albert, Darragh Duffy, Lluis Quintana-Murci., European Project: 806975,NECESSITY, Clauss, Isabelle, and NEw Clinical Endpoints in primary Sjögren’s Syndrome: an Interventional Trial based on stratifYing patients - NECESSITY - 0000-00-00 - 0000-00-00 - 806975 - VALID

Subjects
Proteomics, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Sjogren's Syndrome, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, HLA-DQ Antigens, Immunology, Humans, Interferon-alpha, Immunology and Allergy, Prospective Studies
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa). Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA–DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., Arthritis & Rheumatology, 74 (12), ISSN:2326-5191, ISSN:2326-5205

Published
2022
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8. Early IFNβ Secretion Determines Variable Downstream IL-12p70 Responses Upon TLR4 Activation

Author

Posseme, Celine, primary, Llibre, Alba, additional, Charbit, Bruno, additional, Bondet, Vincent, additional, Rouilly, Vincent, additional, Saint André, Violaine, additional, Boussier, Jeremy, additional, Bergstedt, Jacob, additional, Smith, Nikaia, additional, Townsend, Liam, additional, Sugrue, Jamie A., additional, Cheallaigh, Clíona Ní, additional, Conlon, Niall, additional, Rotival, Maxime, additional, Kobor, Michael, additional, Mottez, Estelle, additional, Pol, Stanislas, additional, Patin, Etienne, additional, Albert, Matthew L., additional, Quintana-Murci, Lluis, additional, Duffy, Darragh, additional, and Consortium, Milieu Intérieur, additional

Published
2021
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9. Novel DSP Spectrin 6 Region Variant Causes Neonatal Erythroderma, Failure to Thrive, Severe Herpes Simplex Infections and Brain Lesions.

Author

VAKKILAINEN, Svetlana, PUHAKKA, Laura, KLEMETTI, Paula, HEISKANEN, Kaarina, SEPPÄNEN, Mikko, MUONA, Mikko, POSSEME, Celine, DUFFY, Darragh, VÄISÄNEN, Timo, ELOMAA, Outi, PALOMÄKI, Maarit, SAXÉN, Harri, RANKI, Annamari, and HANNULA-JOUPPI, Katariina

Subjects
PALMOPLANTAR keratoderma, HERPES simplex, BRAIN damage, SPECTRIN, IMMUNOGLOBULIN E, HERPES simplex virus
Abstract

Desmoplakin (DSP) and Desmoglein 1 (DSG1) variants result in skin barrier defects leading to erythroderma, palmoplantar keratoderma and variable other features. Some DSG1 variant carriers present with SAM syndrome (Severe dermatitis, multiple Allergies, Metabolic wasting) and a SAM-like phenotype has been reported in 4 subjects with different heterozygous DSP variants. We report here a patient with a novel DSP spectrin region (SR) 6 variant c.1756C>T, p.(His586Tyr), novel features of brain lesions and severe recurrent mucocutaneous herpes simplex virus infections, with a favourable response to ustekinumab. Through a review of reported cases of heterozygous variants in DSP SR6 (n = 15) and homozygous or compound heterozygous variants in DSG1 (n = 12) and SAM-like phenotype, we highlight phenotypic variability. Woolly hair, nail abnormalities and cardiomyopathy characterize patients with DSP variants, while elevated immunoglobulin E and food allergies are frequent in patients with DSG1 variants. Clinicians should be aware of the diverse manifestations of desmosomopathies. [ABSTRACT FROM AUTHOR]

Published
2019
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10. Early IFNβ secretion determines variable downstream IL-12p70 responses upon TLR4 activation.

Author

Posseme, Celine, Llibre, Alba, Charbit, Bruno, Bondet, Vincent, Rouilly, Vincent, Saint-André, Violaine, Boussier, Jeremy, Bergstedt, Jacob, Smith, Nikaïa, Townsend, Liam, Sugrue, Jamie A., Ní Cheallaigh, Clíona, Conlon, Niall, Rotival, Maxime, Kobor, Michael S., Mottez, Estelle, Pol, Stanislas, Patin, Etienne, Albert, Matthew L., and Quintana-Murci, Lluis

Abstract

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. [Display omitted] • High variability is observed in IL-12p70 after bacterial stimulation of whole blood • Upstream IFNβ secretion by monocytes is key to the regulation of LPS-induced IL-12p70 • Systems immunology reveals cellular, genetic, and epigenetic regulators of IL-12p70 • IFNβ/IL-12p70 pathway is perturbed in acute SARS-CoV-2 and chronic HCV infection Posseme et al. show a quarter of individuals secrete low levels of IL-12p70 after bacterial infection. Using 1,000 healthy donors, they show IL-12p70 is dependent upon upstream IFNβ, different cellular populations, and genetic changes. Levels of IFNβ and IL-12p70 are also altered in acute SARS-CoV-2 and chronic HCV infection. [ABSTRACT FROM AUTHOR]

Published
2022
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11. Defects in mucosal immunity and nasopharyngeal dysbiosis in HSC-transplanted SCID patients with IL2RG/JAK3 deficiency

Author

Goncalves, Pedro, Doisne, Jean-Marc, Eri, Toshiki, Charbit, Bruno, Bondet, Vincent, Posseme, Celine, Llibre, Alba, The Milieu Interieur, Consortium, Casrouge, Armanda, Lenoir, Christelle, Neven, Bénédicte, Duffy, Darragh, Fischer, Alain, Di Santo, James, Institut Pasteur [Paris] (IP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This study was supported by grants from the Institut Pasteur, INSERM, ANR (15-CE15-000-ILC3_MEMORY) and ERC (695467-ILC_REACTIVITY). P. Gonçalves was supported in part by the Labex Milieu Intérieur (ANR 10-LBX-69 MI). The Biomics Platform is supported by France Génomique (ANR-10-INBS-09-09) and IBISA, We thank Sean Kennedy and Laurence Motreff (Biomics Platform) for 16S rRNA sequencing, Amine Ghozlane and Emna Achouri (HUB) for assistance with sequencing data analysis and the Di Santo laboratory for discussions., ANR-15-CE15-0004,ILC3_MEMORY,Les cellules lymphoïdes innées et la mémoire immunologique(2015), 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), European Project: 695467,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ILC_REACTIVITY(2016), Di Santo, James, Les cellules lymphoïdes innées et la mémoire immunologique - - ILC3_MEMORY2015 - ANR-15-CE15-0004 - AAPG2015 - VALID, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, and Biological Determinants of ILC Reactivity for Immune Responses in Health and Disease - ILC_REACTIVITY - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-08-01 - 2021-07-31 - 695467 - VALID

Subjects
[SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Janus Kinase 3, Cell Biology, Hematology, Biochemistry, Immunity, Innate, Immunoglobulin A, Dysbiosis, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, Severe Combined Immunodeficiency, Lymphocytes, Immunity, Mucosal, Interleukin Receptor Common gamma Subunit
Abstract

Both innate and adaptive lymphocytes have critical roles in mucosal defense that contain commensal microbial communities and protect against pathogen invasion. Here we characterize mucosal immunity in patients with severe combined immunodeficiency (SCID) receiving hematopoietic stem cell transplantation (HSCT) with or without myeloablation. We confirmed that pretransplant conditioning had an impact on innate (natural killer and innate lymphoid cells) and adaptive (B and T cells) lymphocyte reconstitution in these patients with SCID and now show that this further extends to generation of T helper 2 and type 2 cytotoxic T cells. Using an integrated approach to assess nasopharyngeal immunity, we identified a local mucosal defect in type 2 cytokines, mucus production, and a selective local immunoglobulin A (IgA) deficiency in HSCT-treated SCID patients with genetic defects in IL2RG/GC or JAK3. These patients have a reduction in IgA-coated nasopharyngeal bacteria and exhibit microbial dysbiosis with increased pathobiont carriage. Interestingly, intravenous immunoglobulin replacement therapy can partially normalize nasopharyngeal immunoglobulin profiles and restore microbial communities in GC/JAK3 patients. Together, our results suggest a potential nonredundant role for type 2 immunity and/or of local IgA antibody production in the maintenance of nasopharyngeal microbial homeostasis and mucosal barrier function.

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12. Systems Biology in 874 Patients with Primary Sjogren's Syndrome Indicates the Predominant Role of Interferon Alpha Compared to Interferon Gamma, Its Association with Systemic Complications, and a New Aspect of the Genetic Contribution of HLA

Author

Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian, Jonsson, Roland, Lessard, Chris, Felten, Renaud, Ng, Fai, Silvis, K., Chatenoud, Lucienne, Dumortier, Helene, Jacques Fellay, Brostadt, Karl A., Appel, Silke, Tarn, Jessica R., Quintana-Murci, Lluis, Minguenau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, and Gottenberg, Jacques-Eric

13. Variability of Primary Sjogren's Syndrome Is Driven by Interferon alpha and Interferon alpha Blood Levels Are Associated With the Class II HLA-DQ Locus

Author

Trutschel, Diana, Bost, Pierre, Mariette, Xavier, Bondet, Vincent, Llibre, Alba, Posseme, Celine, Charbit, Bruno, Thorball, Christian W., Jonsson, Roland, Lessard, Christopher J., Felten, Renaud, Ng, Wan Fai, Chatenoud, Lucienne, Dumortier, Helene, Sibilia, Jean, Fellay, Jacques, Brokstad, Karl A., Appel, Silke, Tarn, Jessica R., Quintana-Murci, Lluis, Mingueneau, Michael, Meyer, Nicolas, Duffy, Darragh, Schwikowski, Benno, and Gottenberg, Jacques Eric

Subjects
disease-activity, signatures, pathways, innate, cells, autoantibody production, clinical phenotypes
Abstract

Objective Primary Sjogren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS. Methods We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-alpha (IFN alpha) and IFN gamma protein concentrations using digital single molecular arrays (Simoa). Results Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFN alpha and not by IFN gamma protein levels. IFN alpha protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFN alpha protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells. Conclusion We identified the predominance of IFN alpha as a driver of primary SS variability, with IFN alpha demonstrating an association with HLA gene polymorphisms.

14. Cytokine Autoantibodies Alter Gene Expression Profiles of Healthy Donors.

Author

von Stemann JH, Dubois F, Saint-André V, Bondet V, Posseme C, Charbit B, Quintana-Murci L, Hansen MB, Ostrowski SR, and Duffy D

Abstract

Autoantibodies against cytokines (c-aAb) have been implicated in the pathophysiology of autoimmune diseases, and a variety of infections. In addition, several independent studies have detected elevated titers of c-aAb in the circulation of healthy individuals. To further understand their impact on immune responses, we measured c-aAb against IFN-α, IFN-γ, CSF2, IL-1α, IL-6, and IL-10 in the plasma of 1000 healthy individuals of the Milieu Intérieur (MI) cohort. Focusing on donors above a defined positive cut-off we observed significant age effects for c-aAb against IL-1α, but no major environmental or lifestyle associated factors were identified. Using TruCulture stimulation data from the MI cohort, we observed a strong association between induced IL-1α and c-aAb levels after LPS stimulation. For several other stimuli, c-aAb against IL-1α and IL-10 were associated with decreased or increased proinflammatory gene expression, respectively. Finally, TruCulture assays supplemented with plasma containing high-titer c-aAb showed a strong influence of anti-IFN-α and anti-IL-6 c-aAb on both baseline and induced gene expression. In summary, this study shows a widespread prevalence of anti-cytokine autoantibodies in healthy donors with impacts on diverse immune responses, suggesting a significant contribution of c-aAb to interindividual immune heterogeneity., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Published
2024
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15. Variability of Primary Sjögren's Syndrome Is Driven by Interferon-α and Interferon-α Blood Levels Are Associated With the Class II HLA-DQ Locus.

Author

Trutschel D, Bost P, Mariette X, Bondet V, Llibre A, Posseme C, Charbit B, Thorball CW, Jonsson R, Lessard CJ, Felten R, Ng WF, Chatenoud L, Dumortier H, Sibilia J, Fellay J, Brokstad KA, Appel S, Tarn JR, Quintana-Murci L, Mingueneau M, Meyer N, Duffy D, Schwikowski B, and Gottenberg JE

Subjects
Humans, Interferon-alpha, Proteomics, Prospective Studies, HLA-DQ Antigens genetics, Sjogren's Syndrome
Abstract

Objective: Primary Sjögren's syndrome (SS) is the second most frequent systemic autoimmune disease, affecting 0.1% of the general population. To characterize the molecular and clinical variabilities among patients with primary SS, we integrated transcriptomic, proteomic, cellular, and genetic data with clinical phenotypes in a cohort of 351 patients with primary SS., Methods: We analyzed blood transcriptomes and genotypes of 351 patients with primary SS who were participants in a multicenter prospective clinical cohort. We replicated the transcriptome analysis in 3 independent cohorts (n = 462 patients). We determined circulating interferon-α (IFNα) and IFNγ protein concentrations using digital single molecular arrays (Simoa)., Results: Transcriptome analysis of the prospective cohort showed a strong IFN gene signature in more than half of the patients; this finding was replicated in the 3 independent cohorts. Because gene expression analysis did not discriminate between type I IFN and type II IFN, we used Simoa to demonstrate that the IFN transcriptomic signature was driven by circulating IFNα and not by IFNγ protein levels. IFNα protein levels, detectable in 75% of patients, were significantly associated with clinical and immunologic features of primary SS disease activity at enrollment and with increased frequency of systemic complications over the 5-year follow-up. Genetic analysis revealed a significant association between IFNα protein levels, a major histocompatibility (MHC) class II haplotype, and anti-SSA antibody. Additional cellular analysis revealed that an MHC class II HLA-DQ locus acts through up-regulation of HLA class II molecules on conventional dendritic cells., Conclusion: We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Published
2022
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