title: B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology and Program in Immunology, University of California, San Francisco, CA 94143-0114, USA.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Weber
authors.forename: Thomas
authors.initials: T
authors.lastname: Prod'homme
authors.forename: Juan C
authors.initials: JC
authors.lastname: Patarroyo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Tara
authors.initials: T
authors.lastname: Karnezis
authors.forename: Klaus
authors.initials: K
authors.lastname: Lehmann-Horn
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Eastham-Anderson
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Slavin
authors.forename: Christopher
authors.initials: C
authors.lastname: Linington
authors.forename: Claude C A
authors.initials: CC
authors.lastname: Bernard
authors.forename: Flavius
authors.initials: F
authors.lastname: Martin
authors.forename: Scott S
authors.initials: SS
authors.lastname: Zamvil
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006023:Glycoproteins / Q000009:adverse effects; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000009:adverse effects; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D000906:Antibodies; D018951:Antigens, CD20; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006023:Glycoproteins; D053645:Interleukin-2 Receptor alpha Subunit; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55)