A Potential Role of Autoantibodies against Muscarinic Type 3 Receptor in Pathogenesis of Sjogren’s Syndrome

Abstract

Sjögren's Syndrome (SS) is a systemic autoimmune disease characterized by focal mononuclear cell infiltration into target organs such as salivary and lacrimal glands, leading to sicca symptoms. SS is characterized by the production of numerous circulating autoantibodies. The anti-muscarinic autoantibodies against the type 3 receptor (anti-M3R autoantibodies) in primary SS patients' sera has recently been studied as its possible involvement in the pathogenesis of SS and a capable diagnostic marker, since M3R plays critical roles in exocrine secretion and smooth muscle contraction. Anti-M3R autoantibodies in the sera of SS patients were detectable with high sensitivity and specificity and had broad inhibitory effects on the exocrine secretion and the smooth muscle contraction mediated by parasympathetic neurons. In Salivary Gland Epithelial Cells (SGECs), the inhibitory effect of SS autoantibodies on M3R function were verified at the cellular and molecular levels; anti-M3R autoantibodies inhibited carbachol-induced [Ca 2+ ]i increase and the activities of ion channels and membrane transporters, that are dependent on [Ca 2+ ]i. Anti-M3R autoantibodies appear to inhibit M3R function in two ways: acute desensitization of M3R by direct occupation of agonist binding sites of the receptor and the resulting receptor internalization. Abundant anti-M3R autoantibodies may bind to the remaining unoccupied M3Rs, thereby causing progressive and long-term loss of M3R function. Anti-M3R positivity in SS patients was also associated with some clinical manifestations such as leucopenia, anemia, and thrombocytopenia. In this review, we will discuss the prevalence of anti-M3R autoantibodies in the sera of SS patients, the inhibitory effect of anti-M3R autoantibodies in various tissues, and the potential role of anti-M3R autoantibodies with SGECs in the pathogenesis of SS.