title: Antibodies interfering with the type 3 muscarinic receptor pathway inhibit gastrointestinal motility and cholinergic neurotransmission in Sjögren's syndrome.
abstract: OBJECTIVE
  In primary Sjögren's syndrome (SS), impairment of the gastrointestinal (GI) tract is common, and includes reduced esophageal motor function, delayed gastric emptying, and abnormalities in colonic motility; the pathogenesis is as yet unknown. We undertook this study to investigate the role of functional antibodies to the type 3 muscarinic receptor (M3R) in GI dysfunction associated with primary SS.
  
  
  METHODS
  Muscle strip and whole-organ functional assays were used to determine whether IgG with anti-M3R activity from patients with primary SS disrupted neurotransmission in tissue from throughout the mouse GI tract. Specificity of the autoantibody for the M3R was determined using knockout mice that were deficient in the expression of muscarinic receptor subtypes.
  
  
  RESULTS
  Functional antibodies to the M3R inhibited neuronally mediated contraction of smooth muscle from throughout the GI tract and disrupted complex contractile motility patterns in the colon. The autoantibodies were not active on tissue from mice that lacked the M3R, providing compelling evidence of the direct interaction of patient autoantibodies with the M3R.
  
  
  CONCLUSIONS
  Our results indicate that anti-M3R autoantibodies have the potential to mediate multiple dysfunctions of the GI tract in primary SS, ranging from reduced esophageal motor activity to altered colonic motility. We hypothesize that altered GI motility forms part of a broader autonomic dysfunction mediated by pathogenic anti-M3R autoantibodies in primary SS.
authors.affiliation: Seoul National University and Dental Research Institute, Seoul, Korea.
authors.forename: Kyungpyo
authors.initials: K
authors.lastname: Park
authors.forename: Rainer V
authors.initials: RV
authors.lastname: Haberberger
authors.forename: Tom P
authors.initials: TP
authors.lastname: Gordon
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jackson
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D001323:Autoantibodies / Q000276:immunology*; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D002945:Cisplatin; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007069:Ifosfamide; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin; D009119:Muscle Contraction / Q000187:drug effects / Q000276:immunology; D009130:Muscle, Smooth / Q000187:drug effects / Q000276:immunology; D043587:Receptor, Muscarinic M3 / Q000276:immunology* / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D018679:Cholinergic Agonists; D043587:Receptor, Muscarinic M3; D016685:Mitomycin; D002217:Carbachol; D000109:Acetylcholine; D002945:Cisplatin; D007069:Ifosfamide