title: Passive transfer of Sjogren's syndrome IgG produces the pathophysiology of overactive bladder.
abstract: OBJECTIVE
  The presence, in patients with primary and secondary Sjogren's syndrome (SS), of autoantibodies that acutely inhibit M(3) muscarinic receptor (M3R)-mediated bladder contractions is difficult to reconcile with the fact that symptoms of detrusor overactivity and other features of cholinergic hyperresponsiveness occur in this disease. This study was undertaken to examine the in vivo effects of these autoantibodies on bladder function by examining bladder responsiveness and compliance following passive transfer of patient IgG to mice.
  
  
  METHODS
  Contractile responses of isolated bladder strips both to the muscarinic agonist carbachol and to electrically evoked acetylcholine release were measured 48 hours after injection of mice with patient or control IgG. A whole bladder assay with intact neuronal pathways was developed to assess bladder wall compliance on filling cystometry. Expression of M3R in bladders from IgG-injected mice was assessed by immunohistochemistry.
  
  
  RESULTS
  Passive transfer of SS IgG with inhibitory anti-M3R activity produced a paradoxical increase in contractile responses of detrusor strips to cholinergic stimulation. Cystometry of whole bladders revealed a corresponding decrease in bladder wall compliance and phasic detrusor contractions upon filling, replicating the urodynamic features of an overactive bladder. The features of cholinergic hyperresponsiveness were associated with increased postsynaptic M3R expression and were reproduced by injecting mice with a rabbit antibody against the second extracellular loop of M3R.
  
  
  CONCLUSIONS
  These findings are consistent with the notion that there is initial inhibition of parasympathetic neurotransmission by antagonistic autoantibodies to M3R, which produces a compensatory increase in M3R expression in vivo. The enhanced cholinergic responses during bladder distention result in detrusor overactivity. We conclude that the overactive bladder associated with SS is an autoantibody-mediated disorder of the autonomic nervous system, which may be part of a wider spectrum of cholinergic hyperresponsiveness.
authors.affiliation: Flinders Medical Centre and University, Bedford Park, Adelaide, South Australia 5000, Australia.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Jackson
authors.forename: Vicki
authors.initials: V
authors.lastname: Maughan
authors.forename: Dana
authors.initials: D
authors.lastname: Cavill
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Smith
authors.forename: Sally A
authors.initials: SA
authors.lastname: Waterman
authors.forename: Tom P
authors.initials: TP
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage* / Q000276:immunology*; D066298:In Vitro Techniques; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018721:Muscarinic Agonists / Q000494:pharmacology; D011817:Rabbits; D043587:Receptor, Muscarinic M3 / Q000276:immunology / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000276:immunology*; D001743:Urinary Bladder / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D014549:Urinary Incontinence / Q000276:immunology / Q000503:physiopathology*; D014563:Urodynamics
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D018721:Muscarinic Agonists; D043587:Receptor, Muscarinic M3; D002217:Carbachol