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Lookup NU author(s): Professor Fai NgORCiD, Dr Jessica Tarn
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. 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.
Author(s): 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, Gottenberg JE, Dernis E, Devauchelle-Pensec V, Dieude P, Dubost J-J, Fauchais A-L, Goeb V, Hachulla E, Hatron PY, Larroche C, Le Guern V, Morel J, Perdriger A, Salliot C, Rist S, Saraux A, Sibilia J, Vittecoq O, Nocturne G, Ravaud P, Seror R, Abel L, Alcover A, Aschard H, Astrom K, Bousso P, Bruhns P, Cumano A, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Gelpi O, GompertsBoneca I, Hasan M, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rausell A, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Touvier M, Ungeheuer M-N, Albert ML, Duffy D, Quintana-Murci L
Publication type: Article
Publication status: Published
Journal: Arthritis and Rheumatology
Year: 2022
Volume: 74
Issue: 12
Pages: 1991-2002
Print publication date: 14/12/2022
Online publication date: 20/06/2022
Acceptance date: 10/06/2022
Date deposited: 22/11/2022
ISSN (print): 2326-5191
ISSN (electronic): 2326-5205
Publisher: John Wiley and Sons Inc.
URL: https://doi.org/10.1002/art.42265
DOI: 10.1002/art.42265
PubMed id: 35726083
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