Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Although the cause of MS is still uncertain, many findings point toward an ongoing autoimmune response to myelin antigens. Because of its location on the outer surface of the myelin sheath and its pathogenicity in the experimental autoimmune encephalomyelitis model, myelin oligodendrocyte glycoprotein (MOG) is one of the potential disease-causing self antigens in MS. However, the role of MOG in the pathogenesis of MS has remained controversial. In this study we addressed the occurrence of autoantibodies to native MOG and its implication for demyelination and axonal loss in MS. We applied a high-sensitivity bioassay, which allowed detecting autoantibodies that bind to the extracellular part of native MOG. Antibodies, mostly IgG, were found in sera that bound with high affinity to strictly conformational epitopes of the extracellular domain of MOG. IgG but not IgM antibody titers to native MOG were significantly higher in MS patients compared with different control groups with the highest prevalence in primary progressive MS patients. Serum autoantibodies to native MOG induced death of MOGexpressing target cells in vitro. Serum from MS patients with high anti-MOG antibody titers stained white matter myelin in rat brain and enhanced demyelination and axonal damage when transferred to autoimmune encephalomyelitis animals. Overall these findings suggest a pathogenic antibody response to native MOG in a subgroup of MS patients.antibodies ͉ axonal damage ͉ demyelination ͉ lentiviral expression M ultiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, gliosis, and neurodegeneration (1). Inflammatory infiltrates composed of macrophages/microglia cells, T cells, and B cells are found in MS lesions (2). In a significant proportion of patients, demyelination appears to be antibody-mediated and complement-dependent, with loss of oligodendrocytes and axonal damage (3). Despite intensive studies, the etiology of disease still remains uncertain (4). It is believed that MS results from an autoimmune response to proteins expressed in oligodendrocytes or the myelin sheath (5). Myelin oligodendrocyte glycoprotein (MOG) is one candidate target self-antigen. MOG expression is confined to the CNS and sequestered at the outermost surface of the myelin sheath (6, 7). This allows easy access by antibodies from the extracellular space.MOG induces experimental autoimmune encephalomyelitis (EAE) in a variety of species (8-12). In contrast to other models, MOG protein elicited EAE is characterized by a pathogenic antibody response. Although anti-MOG antibodies cannot induce EAE on their own, they strongly enhance T cell and macrophage-initiated demyelination and may augment disease severity (12,13). Several studies suggest that the pathogenicity of antibodies resides in their ability to recognize native MOG protein with proper glycosylation and to fix complement, while the significance...

Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis

“…In the CSF, antigen microarrays in MS have detected antibodies to lipid (6) and ␣B-crystallin (23) and of note, the ␣B-crystallin reactive antibodies were of low affinity, detectable at 1:20 dilution (23). High-affinity autoreactive antibodies in the serum have not been consistently found in MS (24)(25)(26)(27)(28). We found that unique autoantibody signatures characterize RRMS, SPMS and PPMS based on reactivity to CNS antigens and HSP.…”

Chapter 4 B Cells and Autoantibodies in the Pathogenesis of Multiple Sclerosis and Related Inflammatory Demyelinating Diseases

“…New methods have therefore been developed that enable specific detection of antibodies to properly folded and glycosylated MOG protein. The first method involves labeling of MOG transfectants with serum or CSF antibodies Lalive et al, 2006;O'Connor et al, 2007;Zhou et al, 2006), but the frequency of anti-MOG in MS still varies considerably between these studies, suggesting heterogeneity in the studied patient populations. The second method is a sensitive radioimmunoassay with a tetrameric version of folded and glycosylated MOG protein.…”

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis

“…[14][15][16][17][18] In contrast, the clinical relevance of MOG antibodies in adults is unclear, as only a minority of patients with MS and NMO/NMOSD are seropositive. 16,[18][19][20][21][22][23][24] Herein, we provide evidence that MOG antibodies are a clinical biomarker of bilateral and/ or recurrent optic neuritis (BON) in adults and describe the characteristic clinical course, response to therapy, and visual outcomes of this condition.…”