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5 results on '"Immunobiologie des Cellules Dendritiques"'

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

Author

Sofie E. Jørgensen, Pärt Peterson, Lili Milani, E. Graham Davies, Vincent Bondet, Mario Saare, Darragh Duffy, Epp Kaleviste, Sascha Sauer, Timothy Ronan Leahy, Helke Nurm, Trine H. Mogensen, Ann-Christine Syvänen, Kai Kisand, Winnie Ip, University of Tartu, Our Lady's Children's Hospital Crumlin (OLCHC), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Aarhus University [Aarhus], Aarhus University Hospital, Tallinn Children's Hospital [Tallinn, Estonia], Great Ormond Street Hospital for Children [London] (GOSH), Max Planck Institute for Molecular Genetics (MPIMG), Max-Planck-Gesellschaft, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Uppsala University, The research was funded by the European Union through the European Regional Development Fund (Project No 2014–2020.4.01.15‐0012), by Estonian Research Council (grants PUT1367 for KK, IUT 2‐2 for PP), and by [FP7/2007‐2013] under grant agreement number n° 262055 (ESGI). D. Duffy acknowledges support from the ANR (CE17001002) and Immunoqure for provision of mAbs for Simoa., European Project: 262055,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2010-1,ESGI(2011), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)

Subjects
STAT3 Transcription Factor, 0301 basic medicine, Immunology, chronic mucocutaneous candidiasis, Biology, Epigenesis, Genetic, 03 medical and health sciences, 0302 clinical medicine, Interferon, STAT1 gain-of-function mutation, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Epigenetics, Phosphorylation, epigenetics, Janus kinase 1, Chromatin binding, autoimmunity, Candidiasis, Chronic Mucocutaneous, 3. Good health, Chromatin, Intracellular signal transduction, STAT1 Transcription Factor, 030104 developmental biology, Gene Expression Regulation, Case-Control Studies, Gain of Function Mutation, Cancer research, type I interferon, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chromatin Immunoprecipitation Sequencing, H3K4me3, Interferons, Chromatin immunoprecipitation, Protein Binding, Signal Transduction, 030215 immunology, medicine.drug
Abstract

International audience; STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

Published
2019
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2. Lymphocytes are a major source of circulating soluble dipeptidyl peptidase 4

Author

Armanda Casrouge, Alessandro Aiuti, Silvia Sánchez-Ramón, A V Sauer, Matthew L. Albert, Marta Tejera-Alhambra, R Barreira da Silva, ICAReB, Molly A. Ingersoll, C Cancrini, Immunobiologie des Cellules dendritiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], IRCCS San Raffaele Scientific Institute [Milan, Italie], Genentech, Inc. [San Francisco], Hospital General Universitario 'Gregorio Marañón' [Madrid], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Università degli Studi di Roma Tor Vergata [Roma], Funding was provided by the Institut Pasteur (Pasteur‐Roux post‐doctoral fellowship to R. B. S.), the Ligue Contre le Cancer (M. L. A.), the Fondation ARC pour la recherche sur le cancer (M. L. A.), the Italian Ministero della Salute (GR‐2011‐02346985 to A. V. S.), the European Union Seventh Framework Programme Marie Curie Action (PCIG11‐GA‐2012‐3221170 to M. A. I.) and the French government's Invest in the Future Program, managed by the Agence Nationale de la Recherche (LabEx Immuno‐Onco to A. C., R. B. d. S., M. A. I. and M. L. A.)., The authors thank the numerous patients and healthy volunteers who kindly donated peripheral blood for these experiments. We thank Immacolata Brigida for data management and H. Saklani for providing tetramers. We thank James Di Santo and Darragh Duffy for critical reading of the manuscript. We would like to acknowledge Marie‐Noelle Unheheuer for her role in leadership of the Clinical Investigation and Access to BioResources platform (ICAReB)., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), European Project: 3221170,European Union Seventh Framework Programme Marie Curie Action, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, Chemokine, Bodily Secretions, Lymphocyte, T cell, Dipeptidyl Peptidase 4, T-Lymphocytes, Immunology, T cells, chemokines, 03 medical and health sciences, Mice, 0302 clinical medicine, Immune system, Orthomyxoviridae Infections, medicine, Immunology and Allergy, Animals, Humans, Dipeptidyl peptidase-4, Mice, Knockout, Transplantation Chimera, biology, Chemistry, Membrane Proteins, Original Articles, 3. Good health, Hematopoiesis, Mice, Inbred C57BL, immunodeficiency diseases, Haematopoiesis, Disease Models, Animal, Settore MED/02, 030104 developmental biology, medicine.anatomical_structure, Solubility, Influenza A virus, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Severe Combined Immunodeficiency, Bone marrow, CD8, Biomarkers
Abstract

Summary Dipeptidyl peptidase 4 (DPP4, CD26) is a serine protease that is expressed constitutively by many haematopoietic and non-haematopoietic tissues. It exists as a membrane-associated protein, as well as in an active, soluble form (herein called sDPP4), present at high concentrations in bodily fluids. Despite the proposed use of sDPP4 as a biomarker for multiple diseases, its cellular sources are not well defined. Here, we report that individuals with congenital lymphocyte immunodeficiency had markedly lower serum concentrations of sDPP4, which were restored upon successful treatment and restoration of lymphocyte haematopoiesis. Using irradiated lymphopenic mice and wild-type to Dpp4–/– reciprocal bone marrow chimeric animals, we found that haematopoietic cells were a major source of circulating sDPP4. Furthermore, activation of human and mouse T lymphocytes resulted in increased sDPP4, providing a mechanistic link between immune system activation and sDPP4 concentration. Finally, we observed that acute viral infection induced a transient increase in sDPP4, which correlated with the expansion of antigen-specific CD8+ T cell responses. Our study demonstrates that sDPP4 concentrations are determined by the frequency and activation state of lymphocyte populations. Insights from these studies will support the use of sDPP4 concentration as a biomarker for inflammatory and infectious diseases.

Published
2018
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3. Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy

Author

Matthew L. Albert, Yoann Barthe, Armanda Casrouge, Arnaud Fontanet, Stanislas Pol, Sylvie Lagaye, Hélène Fontaine, Vincent Mallet, Philippe Sultanik, Christophe Hézode, Estelle Mottez, Laurent Abel, Etienne Gayat, Céline Dorival, Fabrice Carrat, Jean-Pierre Bronowicki, Ioannis Theodorou, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'hépatologie, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Epidémiologie, systèmes d'information, modélisation, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Departement d'Hépatho-Gastro-Enterologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre Hospitalier Universitaire Henri Mondor, Centre d'Immunologie Humaine (CIH), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service de santé publique [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Immunité et Infection, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-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), Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York]-Rockefeller Branch, Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of anesthesiology and critical care medicine, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Département Infection et Epidémiologie - Department of Infection and Epidemiology, Institut Pasteur [Paris], The CUPIC Cohort study was sponsored and funded by The National Agency for research on Aids and Viral Hepatitis (ANRS), with support by the French Association for the Study of the Liver(AFEF). The authors also wish to acknowledge the Center for Human Immunology for its support of the research project., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP), CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre Hospitalier Universitaire Henri Mondor, Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR113-Université Pierre et Marie Curie - Paris 6 (UPMC), Rockefeller Branch-rockefeller university, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Centre Hospitalier Universitaire Henri Mondor, Centre d'Immunologie Humaine ( CIH ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR113-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Département Infection et Epidémiologie

Subjects
Male, MESH : Aged, MESH : Prospective Studies, MESH : Viral Load, MESH : Hepatitis C, Chronic/blood, Hepacivirus, MESH : Virus Replication/drug effects, Polyethylene Glycols, MESH: Molecular Targeted Therapy, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Molecular Targeted Therapy, Prospective Studies, MESH: Ribavirin/therapeutic use, MESH : Proline/analogs & derivatives, MESH: Treatment Outcome, MESH : Hepacivirus/drug effects, MESH: Viral Nonstructural Proteins/metabolism, MESH: Middle Aged, MESH: RNA, Viral/blood, virus diseases, MESH : beta 2-Glycoprotein I/blood, Blood proteins, 3. Good health, beta 2-Glycoprotein I, Area Under Curve, MESH: Hepacivirus/genetics, Drug Therapy, Combination, Oligopeptides, Apolipoprotein H, MESH : Biomarkers/blood, MESH: Hepatitis C, Chronic/drug therapy, Proline, MESH: Hepatitis C, Chronic/blood, virological response, MESH: Proline/analogs & derivatives, MESH : Antiviral Agents/therapeutic use, Antiviral Agents, MESH : Proline/therapeutic use, Boceprevir, MESH : Recombinant Proteins/therapeutic use, Humans, chronic hepatitis C, MESH : Middle Aged, Protease Inhibitors, MESH: Interferon-alpha/therapeutic use, MESH : Predictive Value of Tests, Aged, MESH: Polyethylene Glycols/therapeutic use, MESH : Hepacivirus/genetics, MESH: Humans, Surrogate endpoint, MESH : Humans, MESH: beta 2-Glycoprotein I/blood, MESH: ROC Curve, digestive system diseases, chemistry, MESH: Protease Inhibitors/therapeutic use, Immunology, MESH: Female, Biomarkers, Time Factors, MESH : Viral Nonstructural Proteins/antagonists & inhibitors, MESH : Hepatitis C, Chronic/diagnosis, MESH : Protease Inhibitors/therapeutic use, Viral Nonstructural Proteins, Virus Replication, MESH : Polyethylene Glycols/therapeutic use, HCV protease inhibitor, Telaprevir, MESH: Virus Replication/drug effects, MESH: Proline/therapeutic use, chemistry.chemical_compound, apolipoprotein H, MESH: Hepacivirus/drug effects, MESH : RNA, Viral/blood, MESH : Female, MESH: Hepatitis C, Chronic/diagnosis, MESH : Viral Nonstructural Proteins/metabolism, MESH: Aged, Middle Aged, Viral Load, MESH: Hepacivirus/growth & development, Recombinant Proteins, MESH: Predictive Value of Tests, MESH : Hepacivirus/enzymology, Treatment Outcome, RNA, Viral, biomarker, [SDV.IMM]Life Sciences [q-bio]/Immunology, Biomarker (medicine), Female, France, MESH: Viral Load, MESH : Oligopeptides/therapeutic use, MESH : Time Factors, medicine.drug, MESH : Hepatitis C, Chronic/drug therapy, MESH : Molecular Targeted Therapy, MESH: Biomarkers/blood, MESH: Hepacivirus/enzymology, MESH : Male, MESH : Ribavirin/therapeutic use, MESH : Interferon-alpha/therapeutic use, MESH : Treatment Outcome, Biology, Predictive Value of Tests, MESH: Recombinant Proteins/therapeutic use, Ribavirin, medicine, MESH : France, NS3, MESH: Viral Nonstructural Proteins/antagonists & inhibitors, Hepatology, MESH : Drug Therapy, Combination, MESH: Time Factors, Interferon-alpha, Hepatitis C, Chronic, MESH : Hepacivirus/growth & development, MESH: Male, MESH: Prospective Studies, MESH: France, MESH: Drug Therapy, Combination, ROC Curve, MESH: Antiviral Agents/therapeutic use, MESH: Oligopeptides/therapeutic use, MESH: Area Under Curve, MESH : Area Under Curve, MESH : ROC Curve
Abstract

International audience; BACKGROUND & AIMS:Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort.METHODS:We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results.RESULTS:We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication.CONCLUSION:These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection

Published
2015
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4. Muscle resident macrophages control the immune cell reaction in a mouse model of notexin-induced myoinjury

Author

Matthew L. Albert, Fabrice Chrétien, Madly Brigitte, Anne Plonquet, Romain K. Gherardi, Caroline Charlier, Yasmine Baba-Amer, Shahragim Tajbakhsh, Adeline Henri, Clémentine Schilte, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Immunobiologie des Cellules Dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immunologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Pasteur [Paris], Biologie Moléculaire du Développement, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Chemokine, Chemokine CXCL1, Neurotoxins, Immunology, CX3C Chemokine Receptor 1, Mice, Nude, Mice, Transgenic, Inflammation, Biology, Immunoenzyme Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, medicine, Animals, Immunology and Allergy, Myocyte, Macrophage, Pharmacology (medical), Fluorescent Antibody Technique, Indirect, Muscle, Skeletal, Chemokine CCL2, Bone Marrow Transplantation, 030304 developmental biology, Elapid Venoms, Mice, Knockout, 0303 health sciences, Innate immune system, Epimysium, Macrophages, Monocyte, Skeletal muscle, Flow Cytometry, CD11c Antigen, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Neutrophil Infiltration, Connective Tissue, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Receptors, Chemokine, medicine.symptom, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE:Skeletal muscle may be the site of a variety of poorly understood immune reactions, particularly after myofiber injury, which is typically observed in inflammatory myopathies. This study was undertaken to explore both the cell dynamics and functions of resident macrophages and dendritic cells (DCs) in damaged muscle, using a mouse model of notexin-induced myoinjury to study innate immune cell reactions.METHODS:The myeloid cell reaction to notexin-induced myoinjury was analyzed by microscopy and flow cytometry. Bone marrow (BM) transplantation studies were used to discriminate resident from exudate monocyte/macrophages. Functional tests included cytokine screening and an alloantigenic mixed leukocyte reaction to assess the antigen-presenting cell (APC) function. Selective resident macrophage depletion was obtained by injection of diphtheria toxin (DT) into CD11b-DT receptor-transgenic mice transplanted with DT-insensitive BM.RESULTS:The connective tissue surrounding mouse muscle/fascicle tissue (the epimysium/perimysium) after deep muscle injury displayed a resident macrophage population of CD11b+F4/80+CD11c-Ly-6C-CX3CR1- cells, which concentrated first in the epimysium. These resident macrophages were being used by leukocytes as a centripetal migration pathway, and were found to selectively release 2 chemokines, cytokine-induced neutrophil chemoattractant and monocyte chemoattractant protein 1, and to crucially contribute to massive recruitment of neutrophils and monocytes from the blood. Early epimysial inflammation consisted of a predominance of Ly-6C(high)CX3CR1(low)CD11c- cells that were progressively substituted by Ly-6C(low)CX3CR1(high) cells displaying an intermediate, rather than high, level of CD11c expression. These CD11c(intermediate) cells were derived from circulating CCR2+ monocytes, functionally behaved as immature APCs in the absence of alloantigenic challenge, and migrated to draining lymph nodes while acquiring the phenotype of mature DCs (CD11c+Ia+CD80+ cells, corresponding to an inflammatory DC phenotype).CONCLUSION:The results in this mouse model show that resident macrophages in the muscle epimysium/perimysium orchestrate the innate immune response to myoinjury, which is linked to adaptive immunity through the formation of inflammatory DCs.

Published
2010
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5. Interleukin-7/Interferon Axis Drives T Cell and Salivary Gland Epithelial Cell Interactions in Sjögren's Syndrome.

Author

Rivière E, Pascaud J, Virone A, Dupré A, Ly B, Paoletti A, Seror R, Tchitchek N, Mingueneau M, Smith N, Duffy D, Cassard L, Chaput N, Pengam S, Gauttier V, Poirier N, Mariette X, and Nocturne G

Subjects
Adult, Aged, Cells, Cultured, Epithelial Cells drug effects, Female, Humans, Interleukin-7 Receptor alpha Subunit immunology, Male, Middle Aged, Salivary Glands drug effects, Signal Transduction drug effects, T-Lymphocytes drug effects, Epithelial Cells metabolism, Interferon-alpha pharmacology, Interferon-gamma pharmacology, Interleukin-7 pharmacology, Salivary Glands metabolism, Sjogren's Syndrome metabolism, T-Lymphocytes metabolism
Abstract

Objective: Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin-7 (IL-7)/IFN axis., Methods: Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I-C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL-7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti-IL-7 receptor (IL-7R) antagonist antibody (OSE-127), and transcriptomic analysis was performed using the NanoString platform., Results: Serum IL-7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I-C), IFNα, or IFNγ secreted IL-7. IL-7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti-IL-7R antibody showed decreased IFN-stimulated gene expression., Conclusion: These results suggest the presence of an IL-7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL-7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti-IL-7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest., (© 2020, American College of Rheumatology.)

Published
2021
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