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.
Journal
Arthritis & rheumatology (Hoboken, N.J.)
ISSN: 2326-5205
Titre abrégé: Arthritis Rheumatol
Pays: United States
ID NLM: 101623795
Informations de publication
Date de publication:
12 2022
12 2022
Historique:
revised:
03
05
2022
received:
25
08
2021
accepted:
10
06
2022
pubmed:
22
6
2022
medline:
17
12
2022
entrez:
21
6
2022
Statut:
ppublish
Résumé
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. 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). 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. We identified the predominance of IFNα as a driver of primary SS variability, with IFNα demonstrating an association with HLA gene polymorphisms.
Identifiants
pubmed: 35726083
doi: 10.1002/art.42265
pmc: PMC10092541
doi:
Substances chimiques
Interferon-alpha
0
HLA-DQ Antigens
0
Types de publication
Multicenter Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1991-2002Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR065953
Pays : United States
Investigateurs
Emmanuelle Dernis
(E)
Valerie Devauchelle-Pensec
(V)
Philippe Dieude
(P)
Jean-Jacques Dubost
(JJ)
Anne-Laure Fauchais
(AL)
Vincent Goeb
(V)
Eric Hachulla
(E)
Pierre Yves Hatron
(PY)
Claire Larroche
(C)
Véronique Le Guern
(V)
Jacques Morel
(J)
Aleth Perdriger
(A)
Carinne Salliot
(C)
Stephanie Rist
(S)
Alain Saraux
(A)
Jean Sibilia
(J)
Olivier Vittecoq
(O)
Gaétane Nocturne
(G)
Philippe Ravaud
(P)
Raphaèle Seror
(R)
Laurent Abel
(L)
Andres Alcover
(A)
Hugues Aschard
(H)
Kalla Astrom
(K)
Philippe Bousso
(P)
Pierre Bruhns
(P)
Ana Cumano
(A)
Caroline Demangel
(C)
Ludovic Deriano
(L)
James Di Santo
(J)
Françoise Dromer
(F)
Gérard Eberl
(G)
Jost Enninga
(J)
Jacques Fellay
(J)
Odile Gelpi
(O)
Ivo GompertsBoneca
(I)
Milena Hasan
(M)
Serge Hercberg
(S)
Olivier Lantz
(O)
Claude Leclerc
(C)
Hugo Mouquet
(H)
Sandra Pellegrini
(S)
Stanislas Pol
(S)
Antonio Rausell
(A)
Lars Rogge
(L)
Anavaj Sakuntabhai
(A)
Olivier Schwartz
(O)
Benno Schwikowski
(B)
Spencer Shorte
(S)
Vassili Soumelis
(V)
Frédéric Tangy
(F)
Eric Tartour
(E)
Antoine Toubert
(A)
Mathilde Touvier
(M)
Marie-Noëlle Ungeheuer
(MN)
Matthew L Albert
(ML)
Darragh Duffy
(D)
Lluis Quintana-Murci
(L)
Informations de copyright
© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
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