Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model. (January 2018)

• Record Type: Journal Article
• Authors: Khare, Priyanka; Challa, Dilip K.; Devanaboyina, Siva Charan; Velmurugan, Ramraj; Hughes, Samuel; Greenberg, Benjamin M.; Ober, Raimund J.; Ward, E. Sally
• Is Part Of: Journal of autoimmunity. Volume 86(2018)
• Page Start: 104
• Page End: 115
• Publication Date: 2018-01
• Subjects: Autoantibodies -- EAE -- Fcγ receptors -- Fc engineering -- MOG -- MS; AUC area under the curve -- CDC complement dependent cytotoxicity -- CNS central nervous system -- EAE experimental autoimmune encephalomyelitis -- HC healthy control -- HEL hen egg lysozyme -- MOG myelin oligodendrocyte glycoprotein -- MS multiple sclerosis -- WT wild type; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2017.09.002
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets. Highlights: Circulating antibodies from MS patients recognize both human and mouse MOG. MOG-specific antibodies from MS patients exacerbate EAE in a humanized mouse model. Binding of chimeric anti-MOG antibodies to FcγRs is necessary and sufficient to exacerbate EAE in a humanized mouse model. The activating receptor, FcγRIIA, plays a major role in antibody-mediated EAE exacerbation in a humanized mouse model.