The membrane attack complex of complement causes severe demyelination associated with acute axonal injury.
Complement is implicated in pathology in the human demyelinating disease multiple sclerosis and in animal models that mimic the demyelination seen in multiple sclerosis. However, the components of the complement system responsible for demyelination in vivo remain unidentified. In this study, we show that C6-deficient (C6-) PVG/c rats, unable to form the membrane attack complex (MAC), exhibit no demyelination and significantly reduced clinical score in the Ab-mediated experimental autoimmune encephalomyelitis model when compared with matched C6-sufficient (C6+) rats. In C6+ rats, perivenous demyelination appeared, accompanied by abundant mononuclear cell infiltration and axonal injury. Neither demyelination nor axonal damage was seen in C6- rats, whereas levels of mononuclear cell infiltration were equivalent to those seen in C6+ rats. Reconstitution of C6 to C6- rats yielded pathology and clinical disease indistinguishable from that in C6+ rats. We conclude that demyelination and axonal damage occur in the presence of Ab and require activation of the entire complement cascade, including MAC deposition. In the absence of MAC deposition, complement activation leading to opsonization and generation of the anaphylatoxins C5a and C3a is insufficient to initiate demyelination.
Mead
Richard J
RJ
Complement Biology Group, Department of Medical Biochemistry, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, Wales, United Kingdom.
Singhrao
Sim K
SK
Neal
James W
JW
Lassmann
H
H
Morgan
B Paul
BP
D000818:Animals; D001369:Axons / Q000473:pathology*; D003167:Complement Activation; D003183:Complement C6 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D017353:Gene Deletion; D046911:Macromolecular Substances; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology; D051381:Rats; D013116:Spinal Cord / Q000473:pathology
D003183:Complement C6; D046911:Macromolecular Substances