Role of the IL-12/IL-35 balance in patients with Sjögren syndrome - 04/07/18
, Corinne Miceli-Richard, MD, PhD a, ⁎∗ Abstract |
Background |
An interferon signature is involved in the pathogenesis of primary Sjögren syndrome (pSS), but whether the signature is type 1 or type 2 remains controversial. Mouse models and genetic studies suggest the involvement of TH1 and type 2 interferon pathways. Likewise, polymorphisms of the IL-12A gene (IL12A), which encodes for IL-12p35, have been associated with pSS. The IL-12p35 subunit is shared by 2 heterodimers: IL-12 and IL-35.
Objective |
We sought to confirm genetic association of the IL12A polymorphism and pSS and elucidate involvement of the IL-12/IL-35 balance in patients with pSS by using functional studies.
Methods |
The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French control subjects. Functional studies were performed on sorted monocytes, irrespective of whether they were stimulated. IL12A mRNA expression and IL-12 and IL-35 protein levels were assessed by using quantitative RT-PCR and ELISA and a multiplex kit for IL-35 and IL-12, respectively.
Results |
We confirmed association of the IL12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in patients with pSS carrying the risk allele (P = .016). Serum levels of IL-12p70 were greater in patients than control subjects (P = .0001), especially in patients with more active disease (P = .05); conversely, IL-35 levels were decreased in patients (P = .0001), especially in patients with more active disease (P = .05). In blood cellular subsets both IL12p35 and EBV-induced gene protein 3 (EBI3) mRNAs were detected only in B cells, with a trend toward a lower level among patients with pSS.
Conclusion |
Our findings emphasize involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 levels were associated with low disease activity, in contrast with serum IL-12p70 levels, which were associated with more active disease.
Le texte complet de cet article est disponible en PDF.Key words : IL-35, IL-12, regulatory T cell, regulatory B cell, Sjögren syndrome
Abbreviations used : AIM, ASSESS, BAFF, Breg, EBI-3, eQTL, ESSDAI, GWAS, IL-12R, PI, pSS, RNAseq, SLE, SNP, SSGC, STAT4
Plan
| Support was obtained from the French Ministry of Health: PHRC no. 2006-AOM06133, PHRC 2010-AOM10188 (ASSESS cohort sponsored by Direction de la Recherche Clinique, Assistance Publique-Hôpitaux de Paris); the French Ministry of Research: ANR-2010-BLAN-113301 and ANR-10-LABX-LERMIT; and Fondation pour la Recherche Médicale DEQ20150934719: Sjögren's syndrome and Autoimmunity-associated Lymphomas (SAIL). O.F. received a grant from the French Ministry of Health: année-recherche. E.R. is the recipient of a PhD fellowship from Arthritis Fondation Courtin, Arthritis R&D (CIFRE 2016/1406). |
|
| Disclosure of potential conflict of interest: E. Rivière has a PhD Fellowship from Arthritis Foundation. R. Seror has consultancies with BMS, Roche, UCB, GlaxoSmithKline, HGS, Nordic, and Pfizer and has received institutional grant funding from Pfizer and travel expenses for outside work from Roche and BMS. J.-E. Gottenberg has a consultancy with UCB and has received institutional grant funding from BMS and speaking fees from Sanofi Aventis. A. Thai and M. Mingueneau are employed by Biogen. X. Mariette has received consultant fees from BMS, GlaxoSmithKline, Medimmune, Pfizer and UCB; has received institutional grant funding from Biogen, GlaxoSmithKline and Pfizer; and has received travel expenses for outside work from Pfizer. C. Miceli-Richard is on the Board of Novartis, Abbvie, and Pfizer; consults for Pfizer; has institutional grant funding from Pfizer, MSD, and Roche; received speaking fees from Janssen, Pfizer, and Novartis; and received travel expenses for outside work from Pfizer, Janssen, Abbvie, and Roche. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 142 - N° 1
P. 258 - juillet 2018 Retour au numéro
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