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.