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

Peschl et al. Journal of Neuroinflammation (2017) 14:208 DOI 10.1186/s12974-017-0984-5 RESEARCH Open Access Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination Patrick Peschl1, Kathrin Schanda1, Bleranda Zeka2, Katherine Given3, Denise Böhm2, Klemens Ruprecht4, Albert Saiz5, Andreas Lutterotti6, Kevin Rostásy7, Romana Höftberger8, Thomas Berger1, Wendy Macklin3, Hans Lassmann2, Monika Bradl2, Jeffrey L. Bennett9 and Markus Reindl1* Abstract Background: Antibodies 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. Methods: We 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. Results: Overall, 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. Conclusion: This 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. Keywords: Myelin oligodendrocyte glycoprotein, MOG, Antibodies, Organotypic slice culture, EAE, Neuromyelitis optica spectrum disorders * Correspondence: 1 Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Peschl et al. Journal of Neuroinflammation (2017) 14:208 Background In the last decades, several studies reported that autoantibodies against the myelin oligodendrocyte glycoprotein (MOG) are associated with inflammatory demyelinating diseases of the central nervous system (CNS), such as acute disseminated encephalomyelitis (ADEM), monophasic or recurrent isolated optic neuritis (ON) or transverse myelitis (TM), pediatric multiple sclerosis (MS), aquaporin-4 (AQP4)-seronegative neuromyelitis optica spectrum disorders (NMOSD), and N-methyl D aspartate receptor (NMDAR) encephalitis with overlapping demyelinating syndromes [1–16]. Although MOG antibodies are rarely found in MS, MOG-seropositive patients show neuropathological features that are similar to MS pattern II pathology with demyelinated lesions, preserved axons and complement-mediated pathology [17–20]. MOG is a very well-studied antigen in experimental autoimmune encephalomyelitis (EAE), which is often used as a model for MS. These animal models have been developed using active immunization with MOG, transfer of MOG-specific T cells and antibodies, and mice transgenic for MOGspecific T and B cell receptors [21–27]. In EAE, it was demonstrated that MOG antibodies are strongly pathogenic only after inflammation and blood-brain barrier leakage induced by encephalitogenic T cells. Co-transfer of the mouse monoclonal anti-MOG antibody 8-18-C5 leads to severe complement-dependent lesions in a myelin basic protein (MBP)-induced EAE model in Lewis rats [21, 22, 28] and in vitro brain cell cultures [29]. Nevertheless, the effects of human MOG (hMOG) antibodies and their exact role in demyelinating diseases are still not fully understood. While hMOG antibodies can initiate both complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in an Fc-dependent manner [30–34], in vitro studies have demonstrated MOG antibody binding causes disturbances of thin filaments and microtubule cytoskeleton in oligodendrocytes [35] and cellular cytotoxic effects [2] independent of effector function. Previous in vivo studies have indicated that MOG antibodies trigger the activation of MOG-specific T cells by facilitating opsonization and accumulation in antigen-presenting cells in the CNS and periphery. This process then fosters T cells to recognize their autoantigen and activate in an Fc-dependent manner [36, 37]. Administration of hMOG antibodies into a MBP-T cellmediated EAE model in Lewis rats resulted in minor demyelination and axonal loss in the absence of excessive complement activation [38], and intracerebral injection of hMOG-IgG into murine brain resulted in complement-independent reversible demyelination and axonal loss [39]. It has become increasingly clear that only MOG antibodies recognizing correctly folded and glycosylated Page 2 of 14 MOG are disease relevant. Although MOG is highly conserved between different species, previous studies have shown that single amino acid exchanges between mouse MOG (mMOG) and hMOG led to a loss of binding ability of most hMOG antibodies to mMOG [40]. These experimental observations and the polyclonal nature of serum IgG reinforce that not all hMOG autoantibodies will be reactive to rodent MOG (...truncated)