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45 results on '"Llibre, Alba"'

1. Machine Learning-Based Single Cell and Integrative Analysis Reveals That Baseline mDC Predisposition Correlates With Hepatitis B Vaccine Antibody Response

Author

Aevermann, Brian D, Shannon, Casey P, Novotny, Mark, Ben-Othman, Rym, Cai, Bing, Zhang, Yun, Ye, Jamie C, Kobor, Michael S, Gladish, Nicole, Lee, Amy Huei-Yi, Blimkie, Travis M, Hancock, Robert E, Llibre, Alba, Duffy, Darragh, Koff, Wayne C, Sadarangani, Manish, Tebbutt, Scott J, Kollmann, Tobias R, and Scheuermann, Richard H

Subjects
Immunization, Biotechnology, Digestive Diseases, Hepatitis, Liver Disease, Hepatitis - B, Vaccine Related, Infectious Diseases, Prevention, Prevention of disease and conditions, and promotion of well-being, 3.4 Vaccines, Good Health and Well Being, Adult, Aged, Canonical Correlation Analysis, Dendritic Cells, Female, Gene Expression Profiling, Hepatitis B, Hepatitis B Antibodies, Hepatitis B Vaccines, High-Throughput Nucleotide Sequencing, Host-Pathogen Interactions, Humans, Machine Learning, Male, Middle Aged, Single-Cell Analysis, Vaccination, Vaccine Efficacy, dendritic cells, endotypes, vaccines, machine learning, canonical correlation analysis, single cell RNA sequencing, baseline correlates, Immunology, Medical Microbiology
Abstract

Vaccination to prevent infectious disease is one of the most successful public health interventions ever developed. And yet, variability in individual vaccine effectiveness suggests that a better mechanistic understanding of vaccine-induced immune responses could improve vaccine design and efficacy. We have previously shown that protective antibody levels could be elicited in a subset of recipients with only a single dose of the hepatitis B virus (HBV) vaccine and that a wide range of antibody levels were elicited after three doses. The immune mechanisms responsible for this vaccine response variability is unclear. Using single cell RNA sequencing of sorted innate immune cell subsets, we identified two distinct myeloid dendritic cell subsets (NDRG1-expressing mDC2 and CDKN1C-expressing mDC4), the ratio of which at baseline (pre-vaccination) correlated with the immune response to a single dose of HBV vaccine. Our results suggest that the participants in our vaccine study were in one of two different dendritic cell dispositional states at baseline - an NDRG2-mDC2 state in which the vaccine elicited an antibody response after a single immunization or a CDKN1C-mDC4 state in which the vaccine required two or three doses for induction of antibody responses. To explore this correlation further, genes expressed in these mDC subsets were used for feature selection prior to the construction of predictive models using supervised canonical correlation machine learning. The resulting models showed an improved correlation with serum antibody titers in response to full vaccination. Taken together, these results suggest that the propensity of circulating dendritic cells toward either activation or suppression, their "dispositional endotype" at pre-vaccination baseline, could dictate response to vaccination.

Published
2021

3. Expression, regulation and function of lectin-like transcript 1 (LLT1)

Author

Llibre, Alba, Willberg, Christian B., Klenerman, Paul, and Phillips, Rodney E.

Subjects
572
Abstract

Receptor-ligand pairs of C-type lectin-like proteins have been shown to orchestrate and modulate immune responses within particular immune cell subsets or in distinct body locations. The function of CD161 and Lectin-Like Transcript 1 (LLT1) has not been extensively studied, partially due to the lack of validated anti-LLT1 antibodies. Here, I characterised two novel anti-LLT1 monoclonal antibodies (2H7 and 7G7). Using them for flow cytometric and immunohistological staining, I characterised the expression of LLT1 in different healthy human tissues and found that LLT1 levels were particularly high in immune-privileged sites. Germinal centres (GC) are microanatomical structures that are critical for the development of high-affinity antibodies and B cell memory. They are organised into two zones, light and dark, with coordinated roles controlled by local signalling. LLT1 protein is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. I found high expression of LLT1 on GC-associated B cells, early plasmablasts and GC- derived lymphomas. LLT1 expression was readily induced via BCR, CD40 and CpG stimulation on B cells. Ubiquitous expression of CD161 on Follicular Dendritic Cells (FDCs) was revealed, as well as on a subset of T follicular cells. Triggering of LLT1 supported B cell activation, CD83 upregulation and Chemokine (C-X-C Motif) Receptor 4 (CXCR4) downregulation, which is consistent with a role in drivingtransition from a dark to a light zone phenotype. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B cell maturation within the GC in humans. A deep understanding of the GC reaction and the process of B cell selection could provide invaluable knowledge into effective vaccine design, generation of auto-antibodies and malignant transformation.

Published
2016

6. Targeting the chemokine receptor CXCR4 with histamine analog to reduce inflammation in juvenile arthritis

Author

Bekaddour, Nassima, primary, Smith, Nikaïa, additional, Beitz, Benoit, additional, Llibre, Alba, additional, Dott, Tom, additional, Baudry, Anne, additional, Korganow, Anne-Sophie, additional, Nisole, Sébastien, additional, Mouy, Richard, additional, Breton, Sylvain, additional, Bader-Meunier, Brigitte, additional, Duffy, Darragh, additional, Terrier, Benjamin, additional, Schneider, Benoit, additional, Quartier, Pierre, additional, Rodero, Mathieu P., additional, and Herbeuval, Jean-Philippe, additional

Published
2023
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7. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author

Llibre, Alba, primary, Smith, Nikaïa, additional, Rouilly, Vincent, additional, Musvosvi, Munyaradzi, additional, Nemes, Elisa, additional, Posseme, Céline, additional, Mabwe, Simbarashe, additional, Charbit, Bruno, additional, Mbandi, Stanley Kimbung, additional, Filander, Elizabeth, additional, Africa, Hadn, additional, Saint-André, Violaine, additional, Bondet, Vincent, additional, Bost, Pierre, additional, Mulenga, Humphrey, additional, Bilek, Nicole, additional, Albert, Matthew L., additional, Scriba, Thomas J., additional, and Duffy, Darragh, additional

Published
2022
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9. 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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10. Machine Learning-Based Single Cell and Integrative Analysis Reveals That Baseline mDC Predisposition Correlates With Hepatitis B Vaccine Antibody Response

Author

Aevermann, Brian D., primary, Shannon, Casey P., additional, Novotny, Mark, additional, Ben-Othman, Rym, additional, Cai, Bing, additional, Zhang, Yun, additional, Ye, Jamie C., additional, Kobor, Michael S., additional, Gladish, Nicole, additional, Lee, Amy Huei-Yi, additional, Blimkie, Travis M., additional, Hancock, Robert E., additional, Llibre, Alba, additional, Duffy, Darragh, additional, Koff, Wayne C., additional, Sadarangani, Manish, additional, Tebbutt, Scott J., additional, Kollmann, Tobias R., additional, and Scheuermann, Richard H., additional

Published
2021
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11. Targeting the chemokine receptor CXCR4 with histamine analogue to reduce inflammation in juvenile arthritis: a proof of concept for COVID-19 therapeutic approach

Author

Bekaddour, Nassima, primary, Smith, Nikaïa, additional, Beitz, Benoit, additional, Llibre, Alba, additional, Dott, Tom, additional, Baudry, Anne, additional, Korganow, Anne-Sophie, additional, Nisole, Sébastien, additional, Mouy, Richard, additional, Breton, Sylvain, additional, Bader-Meunier, Brigitte, additional, Duffy, Darragh, additional, Terrier, Benjamin, additional, Schneider, Benoit, additional, Quartier, Pierre, additional, Rodero, Mathieu P, additional, and Herbeuval, Jean-Philippe, additional

Published
2021
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12. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment

Author

Devi-Marulkar, Priyanka, Moraes-Cabe, Carolina, Campagne, Pascal, Corre, Béatrice, Meghraoui-Kheddar, Aida, Bondet, Vincent, Llibre, Alba, Duffy, Darragh, Maillart, Elisabeth, Papeix, Caroline, Pellegrini, Sandra, Michel, Frédérique, Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was funded by the ARSEP (Aide à la Recherche sur la Sclérose En Plaques), FRM (Fondation pour la Recherche Médicale), INSERM, the Milieu Interieur ANR-10-LABX-69-01, and the Institut Pasteur, Paris., We thank the Milieu Interieur consortium and Etienne Patin for HLA class II typing data. We thank Prof. Bertrand Fontaine (Hospital Pitié-Salpêtrière, Paris) for advice in the initiation of the study. DD thanks ImmunoQure AG for sharing antibodies used in the IFNα assay. We acknowledge for support in conducting this study, the Technology Core of the Center for Translational Science, Estelle Mottez from the Clinical Core, the biobanking ICAReB core, Damien Mornico and Natalia Pietrosemoli from the Center of Bioinformatics, Biostatistics and Integrative biology, Institut Pasteur, Paris., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), BONDET, Vincent, and Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract

International audience; Background Interferon beta (IFN β ) 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 IFN β treatment using an integrated approach. Methods The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN β 1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4 + T cells and naïve/memory T cell subsets, by measurement of circulating IFN α / 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 IFN β 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 + T EMRA 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 IFN β , 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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15. Safety of sitagliptin in treatment of hepatocellular carcinoma in chronic liver disease patients

Author

Hollande, Clémence, primary, Boussier, Jeremy, additional, Mottez, Estelle, additional, Bondet, Vincent, additional, Buivan, Tan Phuc, additional, Charbit, Bruno, additional, Llibre, Alba, additional, Charlotte, Frédéric, additional, Savier, Eric, additional, Scatton, Olivier, additional, Duffy, Darragh, additional, Albert, Matthew, additional, Mallet, Vincent, additional, and Pol, Stanislas, additional

Published
2021
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16. Immune profiling enables stratification of patients with active TB disease or M. tuberculosis infection

Author

Duffy, Darragh, Nemes, Elisa, Llibre, Alba, Rouilly, Vincent, Musvosvi, Munyaradzi, Smith, Nikaïa, Filander, Elizabeth, Africa, Hadn, Mabwe, Simbarashe, Jaxa, Lungisa, Charbit, Bruno, Mulenga, Humphrey, Milieu Intérieur, Consortium, Tameris, Michele, Walzl, Gerhard, Malherbe, Stephanus, Thomas, Stephanie, Hatherill, Mark, Bilek, Nicole, Scriba, Thomas, Albert, Matthew, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cape Town, Datactix, Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Stellenbosch University, Insitro [San Francisco], We acknowledge the Bill and Melinda Gates Foundation (OPP1114368) for funding the study and additional support from the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence ' Milieu Intérieur' Grant ANR-10-LABX-69-01. For clinical collection of TB patient samples included in the replication cohort we acknowledge support from the Bill and Melinda Gates Foundation (OPP1155128), the European and Developing Countries Clinical Trials Partnership (96425), and the Intramural Research Program of the NIAID, NIH, and the National Institutes of Health (1U01AI115619-01). EN is an International Society for Advancement of Cytometry (ISAC) Marylou Ingram Scholar and AL was supported by the Fondation Recherche Médicale (SPF20170938617)., We acknowledge the UTechS CB and Icareb platforms of the Center for Translational Research, Institut Pasteur. We are grateful to the study participants and the SATVI clinical and laboratory teams., The Milieu Intérieur Consortium is composed of the following team leaders: Laurent Abel (Hôpital Necker), Andres Alcover, Hugues Aschard, Kalla Astrom (Lund University), Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay (EPFL, Lausanne) Odile Gelpi, Ivo Gomperts-Boneca, Milena Hasan, Serge Hercberg (Université Paris 13), Olivier Lantz (Institut Curie), Claude Leclerc, Hugo Mouquet, Etienne Patin, Sandra Pellegrini, Stanislas Pol (Hôpital Côchin), Antonio Rausell (INSERM UMR 1163 –Institut Imagine), Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis (Institut Curie), Frédéric Tangy, Eric Tartour (Hôpital Européen George Pompidou), Antoine Toubert (Hôpital Saint-Louis), Mathilde Touvier (Université Paris 13), Marie-Noëlle Ungeheuer, Matthew L. Albert (Insitro), 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), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]

Subjects
Patient stratification, Tuberculosis, biomarkers, [SDV.IMM]Life Sciences [q-bio]/Immunology, bacterial infections and mycoses, Immune profiling, cytokines
Abstract

International audience; BackgroundTuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection.MethodsWe hypothesized that TruCulture, an immunomonitoring method for whole blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from active TB patients and compared to LTBI donors. Mtb- specific antigens and live bacillus Calmette-Guerin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital ELISA, as well as Luminex.ResultsTruCulture showed discrimination of active TB cases from LTBI (p < 0.0001 AUC = 0.81) as compared to QFT (p = 0.45 AUC = 0.56), based on an IFNγ readout after Mtb antigen stimulation. This result was replicated in an independent cohort (AUC = 0.89). In exploratory analyses, TB stratification could be further improved by the Mtb Ag/BCG IFNγ ratio (p < 0.0001 AUC = 0.91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with TB patients, suggesting the possibility to identify sub-clinical disease.ConclusionsTruCulture offers a next-generation solution for whole blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection.

Published
2020
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17. Machine learning-based single cell and integrative analysis reveals that baseline mDC predisposition predicts protective Hepatitis B vaccine response

Author

Aevermann, Brian, primary, Shannon, Casey P., additional, Novotny, Mark, additional, Ben-Othman, Rym, additional, Cai, Bing, additional, Zhang, Yun, additional, Ye, Jamie C., additional, Kobor, Michael S., additional, Gladish, Nicole, additional, Lee, Amy, additional, Blimke, Travis M, additional, Hancock, Robert E., additional, Llibre, Alba, additional, Duffy, Darragh, additional, Koff, Wayne C., additional, Sadarangani, Manish, additional, Tebbutt, Scott J., additional, Kollmann, Tobias R., additional, and Scheuermann, Richard H., additional

Published
2021
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18. 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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19. Tuberculosis alters immune-metabolic pathways resulting in perturbed IL-1 responses

Author

Llibre, Alba, primary, Smith, Nikaïa, additional, Rouilly, Vincent, additional, Musvosvi, Munyaradzi, additional, Nemes, Elisa, additional, Posseme, Céline, additional, Mabwe, Simba, additional, Charbit, Bruno, additional, Mbandi, Stanley Kimbung, additional, Filander, Elizabeth, additional, Africa, Hadn, additional, Saint-André, Violaine, additional, Bondet, Vincent, additional, Bost, Pierre, additional, Mulenga, Humphrey, additional, Bilek, Nicole, additional, Albert, Matthew L, additional, Scriba, Thomas J, additional, and Duffy, Darragh, additional

Published
2020
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20. Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults

Author

Ben-Othman, Rym, primary, Cai, Bing, additional, Liu, Aaron C., additional, Varankovich, Natallia, additional, He, Daniel, additional, Blimkie, Travis M., additional, Lee, Amy H., additional, Gill, Erin E., additional, Novotny, Mark, additional, Aevermann, Brian, additional, Drissler, Sibyl, additional, Shannon, Casey P., additional, McCann, Sarah, additional, Marty, Kim, additional, Bjornson, Gordean, additional, Edgar, Rachel D., additional, Lin, David Tse Shen, additional, Gladish, Nicole, additional, Maclsaac, Julia, additional, Amenyogbe, Nelly, additional, Chan, Queenie, additional, Llibre, Alba, additional, Collin, Joyce, additional, Landais, Elise, additional, Le, Khoa, additional, Reiss, Samantha M., additional, Koff, Wayne C., additional, Havenar-Daughton, Colin, additional, Heran, Manraj, additional, Sangha, Bippan, additional, Walt, David, additional, Krajden, Mel, additional, Crotty, Shane, additional, Sok, Devin, additional, Briney, Bryan, additional, Burton, Dennis R., additional, Duffy, Darragh, additional, Foster, Leonard J., additional, Mohn, William W., additional, Kobor, Michael S., additional, Tebbutt, Scott J., additional, Brinkman, Ryan R., additional, Scheuermann, Richard H., additional, Hancock, Robert E. W., additional, Kollmann, Tobias R., additional, and Sadarangani, Manish, additional

Published
2020
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21. Ultrasensitive Interferons quantification in idiopathic inflammatory myopathies serve as biomarkers of activity in dermatomyositis and anti-synthetase syndrome

Author

Loïs, BOLKO, primary, Anquetil, Celine, additional, llibre, Alba, additional, Maillard, Solene, additional, Amelin, Damien, additional, Dorgham, Karim, additional, Bondet, Vincent, additional, Landon-Cardinal, Oceane, additional, Toquet, Segolene, additional, Mariampillai, Kuberaka, additional, Mahoudeau, Alexandrine, additional, Hervier, Baptiste, additional, Rodero, Mathieu, additional, Gorochov, Guy, additional, Duffy, Darragh, additional, Benveniste, Olivier, additional, and Allenbach, Yves, additional

Published
2020
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22. Immune Profiling Enables Stratification of Patients With Active Tuberculosis Disease or Mycobacterium tuberculosis Infection.

Author

Duffy, Darragh, Nemes, Elisa, Llibre, Alba, Rouilly, Vincent, Musvosvi, Munyaradzi, Smith, Nikaïa, Filander, Elizabeth, Africa, Hadn, Mabwe, Simbarashe, Jaxa, Lungisa, Charbit, Bruno, Mulenga, Humphrey, Tameris, Michele, Walzl, Gerhard, Malherbe, Stephanus, Thomas, Stephanie, Hatherill, Mark, Bilek, Nicole, Scriba, Thomas J, and Albert, Matthew L

Subjects
MYCOBACTERIAL disease diagnosis, ANTIGEN analysis, BLOOD testing, PROTEIN analysis, TUBERCULOSIS diagnosis, INTERFERON gamma release tests, CYTOKINES, BIOMARKERS, PREDICTIVE tests, BACILLUS (Bacteria), IMMUNOPHENOTYPING, ENZYME-linked immunosorbent assay
Abstract

Background Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) infection and is a major public health problem. Clinical challenges include the lack of a blood-based test for active disease. Current blood-based tests, such as QuantiFERON (QFT) do not distinguish active TB disease from asymptomatic Mtb infection. Methods We hypothesized that TruCulture, an immunomonitoring method for whole-blood stimulation, could discriminate active disease from latent Mtb infection (LTBI). We stimulated whole blood from patients with active TB and compared with LTBI donors. Mtb -specific antigens and live bacillus Calmette-Guérin (BCG) were used as stimuli, with direct comparison to QFT. Protein analyses were performed using conventional and digital enzyme-linked immunosorbent assay (ELISA), as well as Luminex. Results TruCulture showed discrimination of active TB cases from LTBI (P <.0001, AUC =.81) compared with QFT (P =.45, AUC =.56), based on an interferon γ (IFNγ) readout after Mtb antigen (Ag) stimulation. This result was replicated in an independent cohort (AUC =.89). In exploratory analyses, TB stratification could be further improved by the Mtb antigen to BCG IFNγ ratio (P <.0001, AUC =.91). Finally, the combination of digital ELISA and transcriptional analysis showed that LTBI donors with high IFNγ clustered with patients with TB, suggesting the possibility to identify subclinical disease. Conclusions TruCulture offers a next-generation solution for whole-blood stimulation and immunomonitoring with the possibility to discriminate active and latent infection. [ABSTRACT FROM AUTHOR]

Published
2021
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23. LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation

Author

Llibre, Alba, López-Macías, Constantino, Marafioti, Teresa, Mehta, Hema, Partridge, Amy, Kanzig, Carina, Rivellese, Felice, Galson, Jacob D., Walker, Lucy J., Milne, Paul, Phillips, Rodney E., Kelly, Dominic F., Freeman, Gordon J., El Shikh, Mohey Eldin, Klenerman, Paul, and Willberg, Christian B.

Subjects
B-Lymphocytes, Receptors, CXCR4, Down-Regulation, Receptors, Cell Surface, Cell Separation, Flow Cytometry, Germinal Center, Lymphocyte Activation, Real-Time Polymerase Chain Reaction, Immunohistochemistry, Humans, Clinical and Human Immunology, Lectins, C-Type, NK Cell Lectin-Like Receptor Subfamily B
Abstract

Germinal centers (GCs) are microanatomical structures critical for the development of high-affinity Abs and B cell memory. They are organized into two zones, light and dark, with coordinated roles, controlled by local signaling. The innate lectin-like transcript 1 (LLT1) is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. In this study, we report high expression of LLT1 on GC-associated B cells, early plasmablasts, and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40, and CpG stimulation on B cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on follicular dendritic cells. Triggering of LLT1 supported B cell activation, CD83 upregulation, and CXCR4 downregulation. Overall, these data suggest that LLT1–CD161 interactions play a novel and important role in B cell maturation within the GC in humans., The Journal of Immunology, 196 (5), ISSN:0022-1767, ISSN:1048-3233, ISSN:1047-7381, ISSN:1550-6606

Published
2016

24. Development and Validation of an Ultrasensitive Single Molecule Array Digital Enzyme-linked Immunosorbent Assay for Human Interferon-α

Author

Llibre, Alba, Bondet, Vincent, Rodéro, Mathieu, Hunt, David, Crow, Yanick, Duffy, Darragh, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Edinburgh, University of Manchester [Manchester], DD and YJC acknowledge support from the ANR (Project IFNX, no. CE17001002) and ImmunoQure AG for providing monoclonal antibodies. YJC acknowledges the European Research Council (GA 309449: Fellowship to YJC), 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., We thank Brigitte Bader-Meunier, Nathalia Bellon, Christine Bodemer, Alex Belot, Isabelle Melki, and Pierre Quartier for providing clinical samples., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Vougny, Marie-Christine, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]

Subjects
MESH: Humans, [SDV.IMM] Life Sciences [q-bio]/Immunology, MESH: Enzyme-Linked Immunosorbent Assay, Interferon-alpha, Reproducibility of Results, Enzyme-Linked Immunosorbent Assay, protein biomarkers, interferon, high sensitivity, cytokines, MESH: Reproducibility of Results, Digital ELISA, Issue 136, [SDV.IMM]Life Sciences [q-bio]/Immunology, Humans, antibodies, MESH: Interferon-alpha, Immunology and Infection
Abstract

International audience; The main aim of this protocol is to describe the development and validation of an interferon (IFN)-α single molecule array digital Enzyme-Linked ImmunoSorbent Assay (ELISA) assay. This system enables the quantification of human IFN-α protein with unprecedented sensitivity, and with no cross-reactivity for other species of IFN. The first key step of the protocol is the choice of the antibody pair, followed by the conjugation of the capture antibody to paramagnetic beads, and biotinylation of the detection antibody. Following this step, different parameters such as assay configuration, detector antibody concentration, and buffer composition can be modified until optimum sensitivity is achieved. Finally, specificity and reproducibility of the method are assessed to ensure confidence in the results. Here, we developed an IFN-α single molecule array assay with a limit of detection of 0.69 fg/mL using high-affinity autoantibodies isolated from patients with biallelic mutations in the autoimmune regulator (AIRE) protein causing autoimmune polyendocrinopathy syndrome type 1/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1/APECED). Importantly, these antibodies enabled detection of all 13 IFN-α subtypes. This new methodology allows the detection and quantification of IFN-α protein in human biological samples at attomolar concentrations for the first time. Such a tool will be highly useful in monitoring the levels of this cytokine in human health and disease states, most particularly infection, autoimmunity, and autoinflammation.

Published
2018
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25. Plasma Type I IFN Protein Concentrations in Human Tuberculosis

Author

Llibre, Alba, primary, Bilek, Nicole, additional, Bondet, Vincent, additional, Darboe, Fatoumatta, additional, Mbandi, Stanley Kimbung, additional, Penn-Nicholson, Adam, additional, Hatherill, Mark, additional, Rozenberg, Flore, additional, Scriba, Thomas J., additional, and Duffy, Darragh, additional

Published
2019
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26. Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

Author

Rice, Gillian I., primary, Meyzer, Candice, additional, Bouazza, Naïm, additional, Hully, Marie, additional, Boddaert, Nathalie, additional, Semeraro, Michaela, additional, Zeef, Leo A.H., additional, Rozenberg, Flore, additional, Bondet, Vincent, additional, Duffy, Darragh, additional, Llibre, Alba, additional, Baek, Jinmi, additional, Sambe, Mame N., additional, Henry, Elodie, additional, Jolaine, Valerie, additional, Barnerias, Christine, additional, Barth, Magalie, additional, Belot, Alexandre, additional, Cances, Claude, additional, Debray, François-Guillaume, additional, Doummar, Diane, additional, Frémond, Marie-Louise, additional, Kitabayashi, Naoki, additional, Lepelley, Alice, additional, Levrat, Virginie, additional, Melki, Isabelle, additional, Meyer, Pierre, additional, Nougues, Marie-Christine, additional, Renaldo, Florence, additional, Rodero, Mathieu P., additional, Rodriguez, Diana, additional, Roubertie, Agathe, additional, Seabra, Luis, additional, Uggenti, Carolina, additional, Abdoul, Hendy, additional, Treluyer, Jean-Marc, additional, Desguerre, Isabelle, additional, Blanche, Stéphane, additional, and Crow, Yanick J., additional

Published
2018
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28. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, primary, Shimakawa, Yusuke, additional, Mottez, Estelle, additional, Ainsworth, Shaun, additional, Buivan, Tan-Phuc, additional, Firth, Rick, additional, Harrison, Elliott, additional, Rosenberg, Arielle R, additional, Meritet, Jean-François, additional, Fontanet, Arnaud, additional, Castan, Pablo, additional, Madejón, Antonio, additional, Laverick, Mark, additional, Glass, Allison, additional, Viana, Raquel, additional, Pol, Stanislas, additional, McClure, C Patrick, additional, Irving, William Lucien, additional, Miele, Gino, additional, Albert, Matthew L, additional, and Duffy, Darragh, additional

Published
2018
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29. T-cell biomarkers for diagnosis of tuberculosis: candidate evaluation by a simple whole blood assay for clinical translation

Author

Musvosvi, Munyaradzi, primary, Duffy, Darragh, additional, Filander, Elizabeth, additional, Africa, Hadn, additional, Mabwe, Simbarashe, additional, Jaxa, Lungisa, additional, Bilek, Nicole, additional, Llibre, Alba, additional, Rouilly, Vincent, additional, Hatherill, Mark, additional, Albert, Matthew, additional, Scriba, Thomas J., additional, and Nemes, Elisa, additional

Published
2018
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32. 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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33. Expression of lectin-like transcript-1 in human tissues

Author

Llibre, Alba, Garner, Lucy, Partridge, Amy, Freeman, Gordon J., Klenerman, Paul, and Willberg, Chris B.

Subjects
Articles, Immune Response, Lectin-Like Transcript 1 (LLT1), C-type lectins, immune-privilege, human, distribution, natural killer cell
Abstract

Background: Receptor-ligand pairs of C-type lectin-like proteins have been shown to play an important role in cross talk between lymphocytes, as well as in immune responses within concrete tissues and structures, such as the skin or the germinal centres. The CD161-Lectin-like Transcript 1 (LLT1) pair has gained particular attention in recent years, yet a detailed analysis of LLT1 distribution in human tissue is lacking. One reason for this is the limited availability and poor characterisation of anti-LLT1 antibodies. Methods: We assessed the staining capabilities of a novel anti-LLT1 antibody clone (2H7), both by immunohistochemistry and flow cytometry, showing its efficiency at LLT1 recognition in both settings. We then analysed LLT1 expression in a wide variety of human tissues. Results: We found LLT1 expression in circulating B cells and monocytes, but not in lung and liver-resident macrophages. We found strikingly high LLT1 expression in immune-privileged sites, such as the brain, placenta and testes, and confirmed the ability of LLT1 to inhibit NK cell function. Conclusions: Overall, this study contributes to the development of efficient tools for the study of LLT1. Moreover, its expression in different healthy human tissues and, particularly, in immune-privileged sites, establishes LLT1 as a good candidate as a regulator of immune responses.

Published
2016
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35. 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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36. 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

37. 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.

38. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., Duffy, Darragh, Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., and Duffy, Darragh

Abstract

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

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39. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., Duffy, Darragh, Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., and Duffy, Darragh

Abstract

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

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40. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., Duffy, Darragh, Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., and Duffy, Darragh

Abstract

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

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41. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., Duffy, Darragh, Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., and Duffy, Darragh

Abstract

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

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42. Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus

Author

Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., Duffy, Darragh, Llibre, Alba, Shimakawa, Yusuke, Mottez, Estelle, Ainsworth, Shaun, Buivan, Tan-Phuc, Firth, Rick, Harrison, Elliott, Rosenberg, Arielle R., Meritet, Jean-Francois, Fontanet, Arnaud, Castan, Pablo, Madejon, Antonio, Laverick, Mark, Glass, Allison, Viana, Raquel, Pol, Stanislas, McClure, C. Patrick, Irving, William Lucien, Miele, Gino, Albert, Matthew L., and Duffy, Darragh

Abstract

Objective: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. Design: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case–control study comparing results with those obtained with the Abbott RealTime HCV test. Results: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource-limited country. Conclusion: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions.

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43. 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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44. Altered Immune Phenotypes and HLA-DQB1 Gene Variation in Multiple Sclerosis Patients Failing Interferon β Treatment.

Author

Devi-Marulkar P, Moraes-Cabe C, Campagne P, Corre B, Meghraoui-Kheddar A, Bondet V, Llibre A, Duffy D, Maillart E, Papeix C, Pellegrini S, and Michel F

Subjects
Adult, CD4-Positive T-Lymphocytes metabolism, Case-Control Studies, Female, HLA-DQ beta-Chains immunology, Humans, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting blood, Multiple Sclerosis, Relapsing-Remitting genetics, Multiple Sclerosis, Relapsing-Remitting immunology, Phenotype, Treatment Failure, Young Adult, CD4-Positive T-Lymphocytes immunology, Genetic Variation, HLA-DQ beta-Chains genetics, Immunologic Factors therapeutic use, Interferon beta-1a therapeutic use, Multiple Sclerosis, Relapsing-Remitting drug therapy
Abstract

Background: Interferon beta (IFN β ) 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 IFN β treatment using an integrated approach., Methods: The immune status of 40 RRMS patients, 15 of whom were untreated and 25 that received IFN β 1a treatment (15 responders, 10 non-responders), was investigated by phenotyping regulatory CD4 + T cells and naïve/memory T cell subsets, by measurement of circulating IFN α / 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 IFN β 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 + T EMRA 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 IFN β , and in which CD4 + T cells, likely restricted by DQ8 and/or DQ2, exert enhanced autoreactive and bystander inflammatory activities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Devi-Marulkar, Moraes-Cabe, Campagne, Corre, Meghraoui-Kheddar, Bondet, Llibre, Duffy, Maillart, Papeix, Pellegrini and Michel.)

Published
2021
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45. LLT1 and CD161 Expression in Human Germinal Centers Promotes B Cell Activation and CXCR4 Downregulation.

Author

Llibre A, López-Macías C, Marafioti T, Mehta H, Partridge A, Kanzig C, Rivellese F, Galson JD, Walker LJ, Milne P, Phillips RE, Kelly DF, Freeman GJ, El Shikh ME, Klenerman P, and Willberg CB

Subjects
B-Lymphocytes metabolism, Cell Separation, Down-Regulation, Flow Cytometry, Humans, Immunohistochemistry, Lectins, C-Type biosynthesis, NK Cell Lectin-Like Receptor Subfamily B biosynthesis, Real-Time Polymerase Chain Reaction, Receptors, CXCR4 biosynthesis, Receptors, Cell Surface biosynthesis, B-Lymphocytes immunology, Germinal Center immunology, Lectins, C-Type immunology, Lymphocyte Activation immunology, NK Cell Lectin-Like Receptor Subfamily B immunology, Receptors, CXCR4 immunology, Receptors, Cell Surface immunology
Abstract

Germinal centers (GCs) are microanatomical structures critical for the development of high-affinity Abs and B cell memory. They are organized into two zones, light and dark, with coordinated roles, controlled by local signaling. The innate lectin-like transcript 1 (LLT1) is known to be expressed on B cells, but its functional role in the GC reaction has not been explored. In this study, we report high expression of LLT1 on GC-associated B cells, early plasmablasts, and GC-derived lymphomas. LLT1 expression was readily induced via BCR, CD40, and CpG stimulation on B cells. Unexpectedly, we found high expression of the LLT1 ligand, CD161, on follicular dendritic cells. Triggering of LLT1 supported B cell activation, CD83 upregulation, and CXCR4 downregulation. Overall, these data suggest that LLT1-CD161 interactions play a novel and important role in B cell maturation within the GC in humans., (Copyright © 2016 The Authors.)

Published
2016
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