Autoantibody-Mediated Demyelination Depends on Complement Activation but Not Activatory Fc-Receptors

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 49; pp. 18697 - 18702
• Main Authors: Urich, Eduard, Gutcher, Ilona, Prinz, Marco, Becher, Burkhard
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.12.2006; National Acad Sciences
• Subjects: Animals; Autoantibodies - physiology; Autoimmune diseases; B lymphocytes; Biological Sciences; Cellular biology; Complement Activation - genetics; Complement Activation - immunology; Complement System Proteins - physiology; Demyelinating diseases; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Immunization; Immunoglobulins; Inflammation; Lesions; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Multiple sclerosis; Natural killer cells; Nervous system; Receptors, IgG - deficiency; Receptors, IgG - genetics; Receptors, IgG - physiology; Spleen; T lymphocytes
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0607283103

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 FcRy are EAE-resistant. We found that the functional expression of FcRy on systemic accessory cells, but not CNS-resident cells, appears to be vital for the development of CNS inflammation, independent of antigenpresenting cell function or Ab involvement. On the other hand, we found that the injection of antimyelin oligodendrocyte glycoproteinAbs drastically worsens disease severity, inflammation, and demyelination. Using$FcR\gamma^{-/-}$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.