Demyelination in primate autoimmune encephalomyelitis and acute multiple sclerosis lesions: A case for antigen-specific antibody mediation

Abstract

Neuropathological and ultrastructural features of central nervous system demyelination were compared in marmoset experimental autoimmune encephalomyelitis (EAE) induced with myelin/oligodendrocyte glycoprotein (MOG), and in 3 cases of multiple sclerosis (MS) displaying recent lesions. At the edges of EAE and MS lesions, a zone of myelin vacuolation was common, whereas in the lesion proper, myelin sheaths were consistently transformed into vesiculated membranous networks. These networks became dissociated from axons by cell processes from macrophages. Oligodendrocytes were remarkably spared and evidence of myelin repair was present but not prominent. Axonal pathology was more common in the MS material than in marmoset EAE. Immunocytochemistry, using gold‐labeled encephalitogenic peptides of MOG and silver enhancement to detect MOG autoantibodies, revealed the presence of MOG‐specific autoantibodies over vesiculated myelin networks. Gold‐labeled antibody to IgG also gave a positive reaction. Gold‐labeled peptide of myelin basic protein did not react with MOG/EAE tissue, but the same conjugate gave positive staining in MS (and in marmoset EAE induced by whole white matter), perhaps indicating broader spectrum immunoreactivity or sensitization to myelin antigens. Thus, vesicular disruption of myelin was a constant feature in these evolving, highly active lesions in primate EAE and MS and appeared causally related to the deposition of antigen‐specific autoantibodies. Ann Neurol 1999;46:144–160

Myelin/Oligodendrocyte Glycoprotein-Induced Autoimmune Encephalomyelitis in Common Marmosets: The Encephalitogenic T Cell Epitope pMOG24–36 Is Presented by a Monomorphic MHC Class II Molecule

“…The close immunological relationship between nonhuman primates and humans (14 -16) and the fact that marmoset EAE shares essential clinical, radiological, and pathological features with MS (8,9,17) warrant the use of this animal model for the study of genetic and immunological mechanisms leading to CNS inflammation and demyelination in MS. The pathogenesis of EAE in common marmosets involves, as in rodents, at least two separate pathogenic pathways.…”

“…MS patients appear to display a significantly higher level of T cell reactivity to MOG than control individuals (12,13,18,21). Moreover, anti-MOG Abs are localized in CNS areas where myelin disintegration and lesion formation are taking place (8,17). Finally, in its pathological expression, MOG-induced EAE closely resembles MS (8, 9, 21, 22).…”

Antibody Cross-Reactivity between Myelin Oligodendrocyte Glycoprotein and the Milk Protein Butyrophilin in Multiple Sclerosis

“…Reports of enhanced MOG-specific T cell (25)(26)(27)(28) and Ab (28 -31) responses in MS patients suggest that autoimmunity to MOG may play a similar role in the pathogenesis of human disease. This concept is supported by the demonstration of MOG-reactive Abs associated with disintegrating vesicular myelin debris in acute demyelinating MS lesions (22,32) and a recent report that MOG-specific Ab can be used as a prognostic marker early in the course of disease (33).…”

Commentary: Sorting the wheat from the chaff: identifying demyelinating components of the myelin oligodendrocyte glycoprotein (MOG)‐specific autoantibody repertoire

“…Unfortunately, this is not the case in mouse models of EAE, in which demyelination can occur even in the absence of a functional B cell response [21,22]. In this species, antibody-independent demyelination involves a TNFmediated signaling event [23,24], but the precise mechanisms are still poorly understood.The immunopathology of antibody-mediated demyelination in rat and marmoset models of MOG-induced EAE reproduces that seen in the majority of MS patients [3,4,[25][26][27][28] It is therefore perhaps not surprising that active immunization with MOG Igd induces a complex autoimmune response and severe EAE in susceptible species/strains [18]. The encephalitogenic MOG-specific T cell response is an absolute requirement to initiate disease, but its ability to mediate demyelination and induce an MS-like pathology varies between species [18].…”