title: The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice.
abstract: The human neuromuscular disease myasthenia gravis (MG) is characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular end-plate with resultant failure of neuromuscular transmission. A role for complement (C) in AChR loss has been suggested based upon morphological identification of C at the end-plate in MG and from the effects of C inhibition in murine models. Here we provide further evidence implicating C, and specifically the membrane attack complex (MAC), in a mouse model of MG. Mice deficient in the C regulators Daf1 and/or Cd59a were tested in the model. Wild-type mice were resistant to disease while mice deficient in Daf1 had mild disease symptoms with evidence of C activation and AChR loss at end-plates. Cd59a-deficient mice had very mild disease with some muscle inflammation and essentially undamaged end-plates. In contrast, mice deficient in both C regulators developed a severe paralytic disease with marked muscle inflammation and loss of end-plates. Inhibition of MAC assembly abrogated clinical disease in these double-deficient mice, demonstrating conclusively that MAC formation was driving pathology in the model. These findings provoke us to suggest that current anti-C therapeutics targeting MAC assembly will be beneficial in MG patients resistant to conventional therapies.
authors.affiliation: Department of Pathology, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk
authors.forename: B P
authors.initials: BP
authors.lastname: Morgan
authors.forename: J
authors.initials: J
authors.lastname: Chamberlain-Banoub
authors.forename: J W
authors.initials: JW
authors.lastname: Neal
authors.forename: W
authors.initials: W
authors.lastname: Song
authors.forename: M
authors.initials: M
authors.lastname: Mizuno
authors.forename: C L
authors.initials: CL
authors.lastname: Harris
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018958:CD55 Antigens / Q000276:immunology; D018957:CD59 Antigens / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D003176:Complement C3 / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D004198:Disease Susceptibility; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009045:Motor Endplate / Q000276:immunology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D011950:Receptors, Cholinergic / Q000172:deficiency / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D011950:Receptors, Cholinergic