title: The inhibitory effects of antimuscarinic autoantibodies in the sera of primary Sjogren syndrome patients on the gastrointestinal motility.
abstract: Impairment of gastrointestinal tract (GI) function, including delayed gastric emptying and colonic dysmotility, are common features of primary Sjögren's syndrome (SS). However, the pathogenesis remains largely unknown. The aim of the current study was to investigate the role of functional autoantibodies to the muscarinic receptor in mediating GI dysfunction associated with primary SS. The effect of SS or normal immunoglobulin G (IgG) on smooth muscle (SM) motility was assessed by comparing the amplitude of carbachol (CCh) or electrical field stimulation (EFS) - induced muscle contraction before and after IgG application. Muscarinic receptor type 3 (M3R) played a dominant role in both colon and gastric SM contraction, while M2R was partly involved in gastric smooth muscle contraction. Preincubation for 1h of the colon and gastric SM strips with 1mg/ml purified IgG from the sera of four primary SS patients (SS IgG) significantly inhibited carbachol-induced smooth muscle contraction (CISC) over a range of CCh concentrations, whereas IgG from healthy controls had little effect. Incubation of the colon SM strips with SS IgG also inhibited EFS-induced colon muscle contraction, which was mimicked by the M3R-selective blocker, 4-DAMP. SR1403330, an NK1 antagonist, had little effect on EFS-mediated colonic SM contraction. The results suggest that autoantibodies isolated from primary SS patients' sera inhibit muscarinic receptor-mediated cholinergic neurotransmission in mouse colon and stomach, which may provide clues for explaining the GI dysfunction seen in patients with primary SS.
authors.affiliation: Department of Physiology, School of Dentistry, Seoul National University and Dental Research Institute, Seoul, Republic of Korea. Electronic address: kppark@snu.ac.kr.
authors.forename: Kyungpyo
authors.initials: K
authors.lastname: Park
authors.forename: Sowon
authors.initials: S
authors.lastname: Park
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jackson
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000276:immunology; D012859:Sjogren's Syndrome / Q000097:blood / Q000276:immunology*; D013270:Stomach / Q000187:drug effects / Q000276:immunology / Q000502:physiology
chemical_list: D001323:Autoantibodies; D018679:Cholinergic Agonists; D003959:Diamines; D018727:Muscarinic Antagonists; D010880:Piperidines; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D002217:Carbachol; C054938:methoctramine
keywords: 1,1-dimethyl-4-diphenyl acetoxy piperidinium iodide; 4-DAMP; Antibodies; CCh; CISC; Carbachol; Carbachol (CCh); EFS; GI; GI dysfunction; IgG; M3R; Muscarinic receptor; NK1; PLC; SM; SS; Sjögren's syndrome; Sjögren's syndrome (SS); carbachol-induced smooth muscle contraction; electrical field stimulation; gastrointestinal tract; immunoglobulin G; muscarinic receptor type 3; neurokinin 1; phospholipase C; smooth muscle