Role of the IL-12/IL-35 balance in patients with Sjögren syndrome

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 1; pp. 258 - 268.e5
• Main Authors: Fogel, Olivier, Rivière, Elodie, Seror, Raphaèle, Nocturne, Gaetane, Boudaoud, Saida, Ly, Bineta, Gottenberg, Jacques-Eric, Le Guern, Véronique, Dubost, Jean-Jacques, Nititham, Joanne, Taylor, Kimberly E., Chanson, Philippe, Dieudé, Philippe, Criswell, Lindsey A., Jagla, Bernd, Thai, Alice, Mingueneau, Michael, Mariette, Xavier, Miceli-Richard, Corinne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2018; Elsevier Limited; Elsevier
• Subjects: Animal models; Celiac disease; Cytokines; Disease; Endocrinology and metabolism; Enzyme-linked immunosorbent assay; Gene expression; Gene polymorphism; Genomes; Human health and pathology; IL-12; IL-35; Interferon; Interleukin 1; Interleukin 12; Life Sciences; Lymphocytes B; Lymphocytes T; Lymphoma; Monocytes; Polymerase chain reaction; Population; regulatory B cell; regulatory T cell; Serum levels; Sjogren's syndrome; Sjögren syndrome; Statistical analysis; BAFF; GWAS; AIM; ASSESS; IL-35; regulatory T cell; eQTL; IL-12; Sjögren syndrome; Breg; RNAseq; SLE; regulatory B cell; ESSDAI; pSS; IL-12R; SNP; STAT4; EBI-3; PI; SSGC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2017.07.041

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. 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. 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. 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. 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.