Antibody and complement-mediated glial response and demyelination

Multiple Sclerosis (MS) is a CNS disease driven by inflammatory and neurodegenerative components. Although MS is thought to be a T cell-mediated disease, many MS lesions show deposition of immunoglobulin and activated complement (C). Detection of oligoclonal bands in cerebrospinal fluid, a sign of intrathecally-synthesized IgG, is characteristic of MS. B cells and antibody-producing plasma cells are also present in the meninges and perivascular space. Myelin oligodendrocyte glycoprotein (MOG) is a candidate autoantigen in MS . Injection of anti-MOG into rats with pre-established experimental allergic encephalomyelitis (EAE) increased disease severity and demyelination. The related disease Neuromyelitis Optica (NMO) is known to be mediated by antibodies, and pathology can be transferred to mice by intrathecal injection of NMO IgG + C. Mice lacking the C regulator CD59a develop more severe demyelination and axonal damage in NMO and EAE. This indicates that C regulation plays an important role in controlling CNS pathology. We hypothesized that anti-MOG antibodies could induce C-dependent demyelinating pathology. In this study, we investigated the role of C and antibodies in CNS demyelination. Injection of anti-MOG Mab with C into corpus callosum of C57BL/6 mice induced demyelination after 2 days. Demyelination was enhanced by CD59a blockade using a specific Mab. In the absence of exogenous complement, but with CD59a blockade, demyelination was still detectable though reduced. Control Mabs did not induce demyelination. Antibody-mediated damage was accompanied by an inflammatory response involving activation of astrocytes and microglia. Astrocyte response (shown by staining with anti-GFAP) was C-dependent, varied with dose of anti-MOG, and was not enhanced by CD59a blockade. By contrast, microglial response (shown by staining with anti-Iba1) was independent of dose of anti-MOG, and was also induced by anti-CD59a + C. Studies are ongoing to determine whether CD59a expression by microglia plays any role in their response. Other anti-myelin as well as anti-axonal specificities are also being examined The finding that blocking the endogenous C regulator CD59a enhances antibody-mediated demyelination points to a role for C in CNS pathology as well as raises questions about source of C in the CNS. This has relevance to understanding pathogenic mechanisms in MS.