Role of the IL-12/IL-35 balance in Sjögren's syndrome.

An interferon (IFN) signature is involved in the pathogenesis of primary Sjögren's syndrome (pSS), but whether the signature is type 1 or 2 remains controversial. Mouse models and genetic studies suggested the involvement of T helper 1 and type 2 IFN pathways. Likewise, polymorphisms of interleukin 12A gene (IL-12A), which encodes for IL-12p35, have been associated with pSS. IL-12p35 subunit is shared by 2 heterodimers, IL-12 and IL-35.To confirm the genetic association of IL-12A polymorphism and pSS and elucidate the involvement of the IL-12/IL-35 balance in pSS by functional studies.The genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French controls. Functional studies were performed on sorted monocytes, stimulated or not. IL-12A mRNA and IL-12 and IL-35 protein levels were assessed by qRT-PCR and by ELISA and a multiplex kit for IL-35 and IL-12, respectively.We confirmed the association of the IL-12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in pSS patients carrying the risk allele (p=0.016). Serum level of IL-12p70 was greater in patients than controls (p=0.0001), especially patients with more active disease (p=0.05); conversely IL-35 level was decreased in patients (p=0.0001) especially in patients with a more active disease (p=0.05). In blood cellular subsets, both IL-12p35 and EBI-3 mRNAs were detected only in B cells with a trend toward a lower level among pSS patients.Our findings emphasize the involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 level was associated with low disease activity, in contrast to serum IL-12p70 level, which was rather associated with a more active disease.