10 – 12 The respective studies revealed that anti-MOG ab determined by functionally meaningful cell-based assays are rare in adult MS, while they define a subgroup of paediatric patients with acquired CNS demyelination. 9 Methodological improvements towards cellular expression of MOG and accordingly its recognition within a biosimilar context basically zeroed this association. In this regard, early enzyme linked immunosorbent assay (ELISA)-based investigations suggested that ab response against MOG may occur frequently in patients with MS, and that the humoral response against this and other myelin antigens may predict disease severity. These studies however often generated nonconclusive and internally conflicting data, substantially adding to the complexity of the subject. 8 Accordingly, adaptive immune responses against MOG have been widely investigated in patients with MS and related demyelinating disorders. Using an adequate immunization regimen, a disease-consolidating humoral response against MOG can be raised. 7 Peripheral injection of MOG can induce several experimental, primarily T-cell-mediated models of MS in a wide range of species. Since it is not expressed in the thymus and in peripheral organs it is thought that mechanisms to ensure immunological tolerance against MOG are less well established compared with other CNS antigens. Here, myelin oligodendrocyte glycoprotein (MOG) exposed on its outer most lamella is a prime candidate. 6 Based on the leading pathology of demyelination, possible autoantigens have been primarily projected into the myelin sheath and the oligodendrocyte. 4 Despite exhaustive investigations, no common autoantigen has been identified so far, 5 likely relating to the fact that MS is a heterogeneous disorder and may comprise several disease entities. 1 – 3 In multiple sclerosis (MS), intrathecal immunoglobulin (Ig) production by clonally expanded and locally supported plasma cells remains a hallmark diagnostic finding, and ab depositions along with complement activation can be found in areas of active CNS demyelination. In addition to its diagnostic value, we furthermore provide mechanistic insight on how this peripheral anti-MOG ab response may be of pathogenetic relevance in triggering acute flares of inflammatory CNS demyelination.ī cells, plasma cells and plasma cell secreted antibodies (ab) may play an important role in the development of central nervous system (CNS) demyelinating disorders, a notion that was significantly revived by the fulminant success of anti-CD20-mediated B-cell depletion in recent clinical trials. By comparing this clearly distinct cohort to AQP-4 + NMO as well as MS, we propose that MOG + CNS demyelinating disease represents a distinct novel disease entity. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG + CNS demyelinating disease. Using pathophysiologically meaningful cell-based assays, this humoral response is extremely rare in adult MS and absent in classical AQP-4 + NMO, sharply differentiating the evolving group from both established disorders. Recent investigations discovered that a subgroup of these AQP-4 – NMOSD patients produce an ab response against myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. Delineating these patients concomitantly revealed that not all patients presenting with clinically NMO-suggestive disease phenotype express AQP-4 ab, which created the pathogenetically undefined category of NMO spectrum disorders (NMOSD). Nowadays, AQP-4 + NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Indeed, the greatest success so far in deciphering the pathogenesis of a CNS demyelinating disorder resulted from the discovery of anti-aquaporin (AQP)-4 antibodies (ab), which allowed progressive delineation of neuromyelitis optica (NMO), formerly considered a variant of the most common CNS demyelinating disorder, multiple sclerosis (MS), as a distinct disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease.
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