B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity

Ann Neurol. 2010 Sep;68(3):369-83. doi: 10.1002/ana.22081.

Abstract

Objective: Clinical studies indicate that anti-CD20 B-cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti-CD20-mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE).

Methods: Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35-55, which does not require B cells.

Results: In EAE induced by rMOG, B cells became activated and, when serving as antigen-presenting cells (APCs), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B-cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in MOG p35-55-induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naive B cells. In this setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B-cell depletion reduced the frequency of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs.

Interpretation: Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti-CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell-targeting agents for MS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / therapeutic use*
  • Antigens, CD20 / genetics
  • Antigens, CD20 / immunology*
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Cytokines / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology*
  • Female
  • Flow Cytometry / methods
  • Forkhead Transcription Factors / metabolism
  • Glycoproteins / adverse effects
  • Humans
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments / adverse effects
  • Statistics, Nonparametric
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology

Substances

  • Antibodies
  • Antigens, CD20
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Glycoproteins
  • Interleukin-2 Receptor alpha Subunit
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • myelin oligodendrocyte glycoprotein (35-55)