During the pathological process of neurodegeneration that causes diseases inflammation reactions are known to occur and it is believed that these reactions contribute to or are the cause of pathogenesis of this disease type. For example, inflammation is known to play an important role in ischemic stroke that occurs when an artery to the brain is blocked. One important auto-antigen linked to the pathogenesis of both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is the myelin oligodendrocyte glycoprotein (MOG), a minor component of the myelin sheath. Multiple sclerosis (MS), an inflammatory disease of the CNS, is characterized by localized myelin destruction and axonal degeneration and an autoimmune reaction against myelin antigens of the CNS that contributes to the immune-pathological mechanisms of this disease that up to this day is not very well understood. Furthermore, immune responses to abundant proteins of the CNS myelin sheath, proteolipid protein (PLP), and myelin basic protein (MBP) are thought to produce some of the pathological lesions in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). MOG is expressed specifically in the CNS by myelinating glial cells, the oligodendrocytes, and is a surface-exposed protein of the myelin sheath that has been identified as a prime target for demyelinating auto-antibodies in several species. A demyelination disease is a disease of the nervous system in which the myelin sheath of neurons is damaged. This glycoprotein is important in the process of the myelinization of nerves in the central nervous system (CNS) for primary demyelination in autoimmune diseases such as multiple sclerosis. MOG is found only in the CNS localized on the surface of myelin and oligodendrocyte cytoplasmic membranes. Schluesener et al., in 1987, showed that monoclonal antibodies against a myelin oligodendrocyte glycoprotein induce relapses and demyelination in CNS autoimmune disease. Next, Pham-Dinh et al., in 1995, were able to locate the gene encoding MOG to the major histocompatibility complex (MHC), both in human, by cytogenetics, and in mouse, by analysis of recombinants. The researchers selected yeast artificial chromosome clones (YAC) which contain the MOG gene and performed physical mapping of the human and the mouse MOG genes to characterize these YAC clones. Their results indicated that the gene is located at the distal end of the MHC class Ib region in both species. Structural characteristics revealed that the primary nuclear transcript of this gene is 15,561 bp in length. The human MOG gene contains 8 exons, separated by 7 introns and canonical intron/exon boundary sites are observed at each junction. The introns vary in size from 242 to 6484 bp and contain numerous repetitive DNA elements, including 14 Alu sequences within 3 introns. Another Alu element is located in the 3'-untranslated region of the gene. Alu sequences were classified with respect to subfamily assignments. Frenkel et al. in 2003 reported that the nasal vaccination with myelin oligodendrocyte glycoprotein reduces stroke size by inducing IL-10-producing CD4+ T cells. The researchers administered myelin oligodendrocyte glycoprotein 35-55 peptide into the nasal mucosa of C57BL/6 mice before middle cerebral artery occlusion (MCAO) surgery to induce an anti-inflammatory T cell response directed at CNS myelin. The modulation of cerebral inflammation by nasal vaccination with myelin antigens that increase IL-10 in the brain is thought to improve the outcome after stroke and enhance recovery mechanisms. Studies have shown that the MOG [35-55] peptide induces anti-MOG (35-55) autoantibody production in mice and these results provide support that MOG peptides are very useful for in vivo anti-MOG autoantibody studies. Ultimately, the 1.8-Å crystal structure of the myelin oligodendrocyte glycoprotein extracellular domain (MOGED) was determined by Clements et al., in 2003. MOGED adopts a classical Ig or Ig variable domain fold that was observed to form an antiparallel head-to-tail dimer. A dimeric form of native protein was observed, and MOGED was also shown to dimerize in solution, consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG (35-55) peptide, a major determinant that tends to cause encephalitis, is recognized by both T cells and demyelinating auto-antibodies, and is partly occluded within the dimer interface. The structure suggests a relationship between the dimeric form of MOG within the myelin sheath and a breakdown of immunological tolerance to the protein that is observed in multiple sclerosis. The peptide, MOG (35-55), is highly encephalitogenic and can induce strong T and B cell responses. For example, a single injection of this peptide produces a relapsing-remitting neurologic disease with extensive plaque-like demyelination. Because of the clinical, histopathologic, and immunologic similarities with multiple sclerosis (MS), this MOG induced demyelinating encephalomyelitis may serve as a model for investigating MS. Furthermore, this peptide plays an important role in demyelinating diseases, such as adrenoleukodystrophy, vanishing white matter disease, and MS. It is a target antigen that leads to autoimmune-mediated demyelination. Several studies have shown a role for antibodies against MOG in the pathogenesis of MS.
References
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