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

J Allergy Clin Immunol. 2018 Jul;142(1):258-268.e5. doi: 10.1016/j.jaci.2017.07.041. Epub 2017 Sep 12.

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.

Keywords: IL-12; IL-35; Sjögren syndrome; regulatory B cell; regulatory T cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Female
  • Genotype
  • Humans
  • Interleukin-12 Subunit p35 / blood
  • Interleukin-12 Subunit p35 / genetics*
  • Interleukin-12 Subunit p35 / immunology*
  • Interleukins / blood
  • Interleukins / immunology*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Sjogren's Syndrome / blood
  • Sjogren's Syndrome / genetics
  • Sjogren's Syndrome / immunology*

Substances

  • IL12A protein, human
  • Interleukin-12 Subunit p35
  • Interleukins
  • interleukin-35, human