title: Pathogenic role of anti-M3 muscarinic acetylcholine receptor immune response in Sjögren's syndrome.
abstract: M3 muscarinic acetylcholine receptor (M3R) is expressed in exocrine glands (e.g., salivary glands [SGs] and lachrymal glands), and plays a crucial role in exocrine secretion. M3R reactive T cells have been detected in circulating mononuclear cells of 40% of patients with Sjögren's syndrome (SS), and the major T cell epitopes of M3R in those patients with HLA-DR B1×0901 are located in the second loop of M3R. Moreover, autoantibodies (autoAbs) against M3R are also present in sera of around 50% of patients with SS, and several B cell epitopes, such as N-region, 1st, 2nd, and 3rd loop of M3R, have been identified. Functional analysis using human SG cell lines showed that autoAbs against the 2nd loop of M3R suppressed intracellular Ca(2+) influx, suggesting inhibition of saliva secretion. To clarify whether the M3R reactive immune response induces autoimmune sialadenitis (AIS), M3R(-/-) mice were immunized with M3R synthetic peptides and their splenocytes transferred into Rag1(-/-) mice. The recipients developed severe sialadenitis, and cell transfer studies indicated that T cells are key factors in the pathogenesis of AIS. These results indicate that the M3R immune reaction plays a key pathogenic role in AIS, suggesting that M3R molecule acts as an autoantigen in the pathogenesis of SS.
authors.affiliation: University of Tsukuba, Department of Internal Medicine, Ibaraki, Japan. tsumida@md.tsukuba.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sumida
authors.forename: Mana
authors.initials: M
authors.lastname: Iizuka
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Asashima
authors.forename: Hiroto
authors.initials: H
authors.lastname: Tsuboi
authors.forename: Isao
authors.initials: I
authors.lastname: Matsumoto
mesh_terms: D020816:Amino Acid Motifs / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015220:Calcium Channels / Q000276:immunology; D020013:Calcium Signaling / Q000276:immunology; D002460:Cell Line; D017690:Cell Transplantation; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016654:Genes, RAG-1 / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D043587:Receptor, Muscarinic M3 / Q000276:immunology*; D012463:Saliva / Q000378:metabolism; D012793:Sialadenitis / Q000276:immunology; D012859:Sjogren's Syndrome / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015220:Calcium Channels; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D059811:HLA-DRB1 Chains; D018398:Homeodomain Proteins; D020381:Interleukin-17; D043587:Receptor, Muscarinic M3; C064658:RAG-1 protein; D007371:Interferon-gamma