Defining distinct features of anti-MOG antibody associated central nervous system demyelination

Abstract

Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. 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. Nowadays, AQP-4⁺ NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. 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). 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. 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. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG⁺ CNS demyelinating disease. 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 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.

Keywords: antibody; astrocytopathy; central nervous system; demyelinating disease; multiple sclerosis; myelin; myelin oligodendrocyte glycoprotein; neuromyelitis optica; neuromyelitis optica spectrum disorder; oligodendrocytopathy.

Figure 1.

Laboratory findings in central nervous system (CNS) demyelinating disorders. Signs of B-cell activation in multiple sclerosis (MS) occur predominantly within the CNS, whereas both neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody (ab) associated CNS demyelination are characterized by CNS-directed ab produced in the periphery. Data summarized from several studies.^,,,,,, AQP-4, aquaporin 4; MRZ, measles, rubella, varicella zoster virus.

Figure 2.

Representative histopathological findings in myelin oligodendrocyte glycoprotein (MOG) antibody (ab) associated central nervous system demyelination (MOG ab; left column, a, d, g), aquaporin 4 (AQP-4) ab⁺ neuromyelitis optica (NMO; middle column, b, e, h) and multiple sclerosis (MS; right column, c, f, i). Early active demyelinating lesions were stained for astrocytes/gliosis (glial fibrillary acidic protein; GFAP; upper panels a–c). AQP-4 (middle panels, d–f) and mature oligodendrocytes (Nogo A; lower panels g–i). NMO lesions show the characteristic dystrophic astrocytes (b, arrows) indicative of astrocytopathy whereas MOG ab (a) and MS (c) show reactive astrocytes (arrows) and a dense GFAP⁺ fibre network (upper panels). AQP-4 is preserved in MOG ab (d) and MS (f) whereas it is lost in NMO lesions (e) (middle panels). Mature oligodendrocytes are preserved in MOG ab (g) and MS (i) in contrast to NMO (h) where mature oligodendrocytes are significantly lost (lower panels) The Nogo A⁺ structures in (h) represent axonal spheroides (arrowheads) and not mature oligodendrocytes. Magnification: ×20 (scale bar 200 µm).