Increased expression of interleukin-21-inducible genes in minor salivary glands are associated with primary Sjögren's syndrome disease characteristics.

Objective To determine the upregulation of IL-21-inducible genes in minor salivary glands (MSGs) in 28 primary SS (pSS) patients and 12 non-pSS subjects and correlate it with disease characteristics. Methods RNA sequencing was utilized to compare IL-21-inducible genes expression in the MSGs between pSS and non-pSS subjects. The subgroups were characterized according to the IL-21 score calculated by seven IL-21-inducible genes. Furthermore, the disease characteristics and transcripts implicated in hypoxia and interferon signalling were assessed in two pSS subgroups. Results We observed that the expression of the IL-21-inducible genes (IL-21, IL-21R, JAK3, STAT1, HLA-B, CCR7 and CXCL10), the so-called IL-21 signature genes, was significantly increased in pSS patients. The upregulation of JAK3 expression may be induced by hypomethylation of the JAK3 promoter in pSS patients and putatively associated with POU2F2. The patients with increased IL-21 signature gene expression showed an increased EULAR Sjogren's Syndrome Disease Activity Index score and increased enrichment of B cells, memory B cells, CD4+ T cells and CD8+ T cells. Furthermore, the IL-21 scores in the anti-SSA+, SSB+, ANA+ and high IgG samples were higher than those in the respective antibody-negative samples and normal IgG. In addition, we found both hypoxia and IFN-relevant genes showed strong correlation with IL-21 signature gene expression, indicating their interaction in pSS. Conclusion IL-21 signature gene was associated with typical disease characteristics in pSS, which provides insight into the contribution of the IL-21 signalling pathway to the pathogenesis of the disease and might provide a novel treatment strategy for this subtype of pSS.