Journal
JOURNAL OF AUTOIMMUNITY
Volume 86, Issue -, Pages 104-115Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jaut.2017.09.002
Keywords
Autoantibodies; EAE; Fc gamma receptors; Fc engineering; MOG; MS
Categories
Funding
- National Multiple Sclerosis Society [RG 4308]
- UTSW CONQUER Project
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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 Fc gamma Rs (hFc gamma Rs). Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFc gamma Rs 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 Fc gamma R and complement (C1q) binding, we reveal that Fc gamma Rs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific Fc gamma Rs reveals that Fc gamma RIIA is more important than Fc gamma RIIIA 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. (C) 2017 The Authors. Published by Elsevier Ltd.
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