Deficiency of decay accelerating factor and CD59 leads to crisis in experimental myasthenia.
In myasthenia gravis (MG), neuromuscular transmission is disrupted due to the production of autoantibodies against acetylcholine receptors (AChR). In previous work, we showed that decay accelerating factor (DAF or CD55), an intrinsic cell surface complement regulator that disables C3/C5 amplification convertases, protects against receptor loss and muscle weakness. In this study, we examined whether, and if so, to what extent CD59, a downstream intrinsic cell surface regulator that prevents assembly of membrane attack complexes (MACs), contributes to this protection. Twenty-four hours after anti-AChR injection, we found that CD59a-/- mice did not significantly differ from WTs, all Daf1-/- CD59a-/- mice either died or required euthanasia. At 48h, Daf1-/- were significantly weaker than CD59a-/- and WT mice, and for these mice immunohistochemistry revealed marked C9 deposition at postsynaptic junctions, radioimmunoassays showed reductions in AChR levels, and electron microscopy demonstrated massive junctional damage. These data indicate that DAF serves as the initial shield that protects the neuromuscular junction whereas CD59 is a further barrier. They argue that complement inhibitor, particularly if targeted to the receptor, could then have therapeutic value in human MG.
Kaminski
Henry J
HJ
Department of Neurology, Case Western Reserve University, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA. Henry.Kaminski@case.edu
Kusner
Linda L
LL
Richmonds
Chelliah
C
Medof
M Edward
ME
Lin
Feng
F
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology*; D018957:CD59 Antigens / Q000235:genetics / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D004195:Disease Models, Animal; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D018908:Muscle Weakness / Q000209:etiology; D018482:Muscle, Skeletal / Q000378:metabolism; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000473:pathology / Q000648:ultrastructure; D011950:Receptors, Cholinergic / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018958:CD55 Antigens; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D011950:Receptors, Cholinergic