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

Silke Kinzel, Klaus Lehmann-Horn, Sebastian Torke, Darius Hausler, Anne Winkler, Christine Stadelmann, Natalie Payne, Linda Feldmann, Albert Saiz, Markus Reindl, Patrice H Lalive, Claude C Bernard, Wolfgang Bruck, Martin S Weber

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30 Citations (Scopus)

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 naive 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.
Original languageEnglish
Pages (from-to)43-58
Number of pages16
JournalActa Neuropathologica
Volume132
Issue number1
DOIs
Publication statusPublished - 1 Jul 2016

Keywords

  • Auto-antibodies
  • Opsonization
  • Myeloid antigen-presenting cells
  • Fc receptor
  • Experimental autoimmune encephalomyelitis
  • Multiple sclerosis

Cite this

Kinzel, S., Lehmann-Horn, K., Torke, S., Hausler, D., Winkler, A., Stadelmann, C., ... Weber, M. S. (2016). Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen. Acta Neuropathologica, 132(1), 43-58. https://doi.org/10.1007/s00401-016-1559-8