The role of M3 muscarinic acetylcholine receptor reactive T cells in Sjögren's syndrome: A critical review

CD4+ T cells constitute the majority of infiltrating cells in salivary glands and lachrymal glands of patients with Sjögren's syndrome (SS). The pathophysiology of SS involves T cell recognition of antigens through the T cell antigen receptor, which triggers cytokine production and chronic inflammation. The M3 muscarinic acetylcholine receptor (M3R) molecule is expressed in exocrine glands, such as salivary glands and lachrymal glands, and plays an important role in exocrine secretion. Previous studies indicated the presence of M3R reactive T cells in peripheral blood of 40% of patients with SS and autoantibodies against M3R in sera of 9-100% of the same patients. Thus, M3R is considered a candidate receptor for autoantigen recognition by T and B cells. The relationship between B cell epitopes and the function of anti-M3R antibodies has been reported, suggesting the pathogenic role of anti-M3R antibodies in xerostomia commonly seen in SS patients. We generated new experimental mouse model, M3R-induced sialadenitis (MIS), using Rag1^-/- mice inoculated with splenocytes from M3R^-/- mice immunized with M3R synthetic peptides. Mice with MIS developed severe SS-like sialadenitis. Cell transfer experiments using M3R^-/-xIFNγ^-/- mice and M3R^-/-xIL-17^-/- mice showed that IFNγ and IL-17 are key cytokines in the pathogenesis of sialadenitis. These findings indicate the crucial roles of M3R-reactive Th1 and Th17 cells in autoimmune sialadenitis, and suggest that these cells, in addition to anti-M3R antibodies, are potential targets in new treatments for SS.