Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model

Priyanka Khare, Dilip K. Challa, Siva Charan Devanaboyina, Ramraj Velmurugan, Samuel Hughes, Benjamin M. Greenberg, Raimund J. Ober, E. Sally Ward

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)104-115
Number of pages12
JournalJournal of Autoimmunity
Volume86
DOIs
StatePublished - Jan 2018

Keywords

  • Autoantibodies
  • EAE
  • Fc engineering
  • Fcγ receptors
  • MOG
  • MS

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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