Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen

Acta Neuropathol. 2016 Jul;132(1):43-58. doi: 10.1007/s00401-016-1559-8. Epub 2016 Mar 29.

Abstract

In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.

Keywords: Auto-antibodies; Experimental autoimmune encephalomyelitis; Fc receptor; Multiple sclerosis; Myeloid antigen-presenting cells; Opsonization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology*
  • Coculture Techniques
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Female
  • HEK293 Cells
  • Humans
  • Immunoglobulin G / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Multiple Sclerosis / immunology*
  • Myelin-Oligodendrocyte Glycoprotein / antagonists & inhibitors*
  • Myelin-Oligodendrocyte Glycoprotein / genetics
  • Myelin-Oligodendrocyte Glycoprotein / immunology*
  • Myelin-Oligodendrocyte Glycoprotein / metabolism
  • Neuromyelitis Optica / immunology*
  • Receptors, IgG / deficiency
  • Receptors, IgG / genetics
  • T-Lymphocytes / immunology

Substances

  • Autoantibodies
  • Fcgr1 protein, mouse
  • Immunoglobulin G
  • MOG protein, human
  • Myelin-Oligodendrocyte Glycoprotein
  • Receptors, IgG