The membrane attack pathway of complement drives pathology in passively induced experimental autoimmune myasthenia gravis in mice.
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.
Morgan
B P
BP
Department of Pathology, School of Medicine, Cardiff University, Cardiff, UK. morganbp@cardiff.ac.uk
Chamberlain-Banoub
J
J
Neal
J W
JW
Song
W
W
Mizuno
M
M
Harris
C L
CL
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
D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D011950:Receptors, Cholinergic