Abstract
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily. After activated by its ligand GITRL, GITR could influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases included rheumatoid arthritis and autoimmune thyroid disease. We previously reported that serum GITRL levels are increased in systemic lupus erythematosus (SLE) patients compared with healthy controls (HC). Here, we tested serum soluble GITR (sGITR) and GITRL levels in 41 primary Sjögren's syndrome (pSS) patients and 29 HC by ELISA and correlated sGITR and GITRL levels with clinical and laboratory variables. GITR and GITRL expression in labial salivary glands was detected by immunohistochemistry. pSS patients had significantly increased serum levels of sGITR and GITRL compared with controls (GITR: 5.66 ± 3.56 ng/mL versus 0.50 ± 0.31 ng/mL; P < 0.0001; GITRL: 6.17 ± 7.10 ng/mL versus 0.36 ± 0.28 ng/mL; P < 0.0001). Serum sGITR and GITRL levels were positively correlated with IgG (GITRL: r = 0.6084, P < 0.0001; sGITR: r = 0.6820, P < 0.0001) and ESR (GITRL: r = 0.8315, P < 0.0001; sGITR: r = 0.7448, P < 0.0001). Moreover, GITR and GITRL are readily detected in the lymphocytic foci and periductal areas of the LSGs. In contrast, the LSGs of HC subjects did not express GITR or GITRL. Our findings indicate the possible involvement of GITR-GITRL pathway in the pathogenesis of pSS. Further studies may facilitate the development of targeting this molecule pathway for the treatment of pSS.
Highlights
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily, which was originally discovered by Nocentini et al as a gene upregulated in dexamethasone-treated murine T cell hybridomas [1]
The results suggest that GITRL and soluble GITR (sGITR) overexpression is possibly involved in the pathogenesis of primary Sjogren’s syndrome (pSS)
Since previous studies have reported that the numbers of Treg are positively correlated with higher grade of infiltration at the salivary glands in pSS [32], we speculate that GITR/GITRL activation may participate in pSS pathogenesis by inhibiting Treg immunosuppressive activity and increasing T lymphocyte activation
Summary
Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is a type I transmembrane protein belonging to the TNFR superfamily, which was originally discovered by Nocentini et al as a gene upregulated in dexamethasone-treated murine T cell hybridomas [1]. GITR has low basal expression on naive murine CD4+ and CD8+ T cells as well as human T cells, similar to other TNFR family members such as 4-1BB and OX40 [2,3,4,5]. The significance of the differential ligand binding GITR-GITRL between human and murine cells remains largely unclear. Clinical and Developmental Immunology level, numerous studies have indicated that both T-cell activation and proinflammatory cytokine production are pivotally involved in pSS pathogenesis. There is increasing evidence indicating that GITR and GITRL are involved in the pathogenesis of autoimmune disease. Several studies have reported that the GITR/GITRL pathway plays an important role in autoimmune diseases, as demonstrated by experimental models of experimental autoimmune encephalomyelitis, collagen-induced arthritis and autoimmune diabetes [15,16,17]. The expression of the GITR and GITRL in the salivary glands of patients with pSS was examined by immunohistochemistry
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