Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination

Abstract

BackgroundAntibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies.MethodsWe screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control.ResultsOverall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE.ConclusionThis study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo animal model. Moreover, a high titer of species-specific MOG antibodies may be critical for demyelinating effects in mouse and rat animal models. Therefore, both the reactivity and titer of human MOG antibodies must be considered for future pathogenicity studies.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0984-5) contains supplementary material, which is available to authorized users.

International multicenter examination of MOG antibody assays

“…There are limited data on assay reproducibility between these centers. In this study, we compared the most frequently used assays for MOG-IgG detection, such as live and fixed immunofluorescence cell-based assays (CBA-IF), [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] live flow cytometry cell-based assays (CBA-FACS), 4,[18][19][20][21][22][23][24][25][26][27] and ELISA. 28,29…”

Distinct patterns of glia repair and remyelination in antibody‐mediated demyelination models of multiple sclerosis and neuromyelitis optica

“…MOG-IgG, however, is rarely identified in MS patients (Peschl, Schanda, et al, 2017). The MS patient-derived, myelin-specific rAbs used in this study (MS#30 and MS#49) are not directed against MOG (Blauth et al, 2015;Owens et al, 2009) and behave quite differently from patient-derived anti-MOG IgG.…”

HLA association in MOG-IgG– and AQP4-IgG–related disorders of the CNS in the Dutch population

“…However, although in vitro studies have demonstrated that human MOG-IgG activates complement and cellular-dependent cytotoxicity, in vivo rodent models could not confirm the human MOG-IgG to cause demyelination in these animals. 15,[42][43][44][45] Nevertheless, there are various possible explanations for the human MOG-IgG not being pathogenic in rodents, most importantly because human MOG-IgG simply does not recognize the rodent MOG protein. 39 Additionally to these immunologic studies, histopathologic findings from MOG-IgGseropositive patients show activated complement at sites of ongoing demyelinating.…”