Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors.
The precise mechanisms leading to CNS inflammation and myelin destruction in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) remain the subject of intense debate. In both MS and EAE, autoantibodies (autoAbs) are thought to be involved in tissue destruction through recruiting Fc receptor (FcR)-bearing cells or direct cytotoxic effects through the activation of the complement pathway. Whereas intrathecal immunoglobulin (Ig) production and Ig deposition in inflammatory lesions is a hallmark of MS, mice deficient in B cells and Igs develop severe EAE. Paradoxically, mice of the same genetic background but deficient in FcRgamma are EAE-resistant. We found that the functional expression of FcRgamma on systemic accessory cells, but not CNS-resident cells, appears to be vital for the development of CNS inflammation, independent of antigen-presenting cell function or Ab involvement. On the other hand, we found that the injection of antimyelin oligodendrocyte glycoprotein-Abs drastically worsens disease severity, inflammation, and demyelination. Using FcRgamma(-/-) and C1q(-/-) mice, we could definitively establish that the demyelinating capacity of such autoAb in vivo relies entirely on complement activation and is FcR-independent.
Urich
Eduard
E
Neurology Department, Division of Neuroimmunology, University of Zurich, Y44-J38/J42, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Gutcher
Ilona
I
Prinz
Marco
M
Becher
Burkhard
B
D000818:Animals; D001323:Autoantibodies / Q000502:physiology*; D003167:Complement Activation / Q000235:genetics / Q000276:immunology*; D003165:Complement System Proteins / Q000502:physiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D001323:Autoantibodies; D017452:Receptors, IgG; D003165:Complement System Proteins