Role of IL-22 pathway in primary Sjogren’s Syndrome

Objectives In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4+ T cells and by a subset of mucosal inflammatory natural killer (NK) cells expressing the receptor NKp44 (NKp44+NK cells). The aim of this study was to study the IL-22 pathway in the salivary glands of patients with primary Sjögren's syndrome (pSS) a chronic systemic autoimmune disease characterized by dysregulated innate and adaptive immune responses and by a higher rate of non-Hodgkin lymphomas. Methods Minor salivary gland biopsies were obtained from patients with pSS and fromsubject with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR, immunohistochemistry and fluorescence-activated cell sorting analysis were performed. Results IL-22 is overexpressed in salivary glands of pSS patients. Aberrant expression of IL-22R1 occurs in the salivary glands and in the PBMC of p-SS. In vitro IL-22 stimulation of isolated IL-22R1-bearing monocytes resulted in the increased expression of STAT3, IL-17 and IL-22 and in Th17 expansion suggesting that an abnormal IL-22 stimulatory pathway may contribute to the perpetuation of local and systemic inflammation in p-SS. Lymphomas of pSS patients also aberrantly expressed IL-22R1 on monocytes and neoplastic B-cells, suggesting a putative role of IL-22 pathway in the pSS associated lymphomagenesis. Rituximab (RTX), which has historically been used for the treatment of B-cell lymphoma, has also been considered to be effective in the therapy of pSS; RTX treatment significantly reduced the number of IL-22+ cells infiltrating the salivary glands of pSS patients and modulates IL-17 expression. Conclusions Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS and pSS associated lymphomas.