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Objective. The aim of this study was to evaluate the role of rituximab (RTX) in modulating the expression of the IL-17/IL-23 pathway in the salivary glands (SGs) of patients with primary SS (pSS).Methods. Consecutive SG biopsies were obtained from 15 patients with pSS before and after 1 year of RTX therapy. The SG expression of IL-17, IL-23p19 and p-STAT3 was evaluated by immunohistochemistry at baseline and after RTX therapy. The role of mast cells in pSS patients in modulating the Th17 response and the immunologic effect of RTX on mast cells were also studied in in vitro experiments.Results. IL-17 was overexpressed in the SGs of patients with pSS mainly by infiltrating T cells and mast cells. After RTX therapy, the SG expression of IL-17, but not of IL-23p19 and p-STAT3, was significantly reduced and was accompanied by the depletion of tissue mast cells. In in vitro experiments with heterologous peripheral lymphocytes RTX significantly induced the apoptosis of isolated mast cells. Finally, mast cells isolated from peripheral blood mononuclear cells of pSS patients in vitro significantly increased Th17 lymphocytes.Conclusion. RTX acts on pSS patients by globally reducing the expression of IL-17 and specifically inducing a pronounced apoptotic depletion of mast cells. [ABSTRACT FROM PUBLISHER]

Objective. CD4+CD25lowGITR+ T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS).Methods. CD4+CD25lowGITR+ cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4+CD25lowGITR+ cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry.Results. Results indicated that conventional CD4+CD25high regulatory T cells (Tregs) are decreased, whereas CD4+CD25lowGITR+ cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4+CD25lowGITR+ cells display Treg markers, including FoxP3, TGF-β and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4+CD25lowGITR+ cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4+CD25lowGITR+ cell expansion was evident only in patients with inactive disease, while conventional CD4+CD25high Treg number was not associated with disease activity.Conclusion. The present data demonstrate that circulating CD4+ cells expressing GITR, but with low levels of CD25 (CD4+CD25lowGITR+), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4+CD25lowGITR+ cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies. [ABSTRACT FROM PUBLISHER]