|
| Article Authors: | Martin S Weber; Thomas Prod'homme; Juan C Patarroyo; Nicolas Molnarfi; Tara Karnezis; Klaus Lehmann-Horn; Dimitry M Danilenko; Jeffrey Eastham-Anderson; Anthony J Slavin; Christopher Linington; Claude C A Bernard; Flavius Martin; Scott S Zamvil |
|---|
| Article Title: | B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity. |
|---|
|
| Reference ID: | 1020988 |
|---|
| 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. |
|---|
| Affiliations: | Department of Neurology and Program in Immunology, University of California, San Francisco, CA 94143-0114, USA. |
|---|
| Date: | 2010 |
|---|
| Reference Type: | Literature |
|---|
| PubMed ID: | 20641064 |
|---|
| Journal: | Ann Neurol |
|---|
| Journal Volume: | 68 |
|---|
| Article Pages: | 369-83 |
|---|
| Journal ISSN: | 1531-8249 |
|---|
| Article Chemical List: | Antibodies;Antigens, CD20;Cytokines;Forkhead Transcription Factors;Foxp3 protein, mouse;Glycoproteins;Interleukin-2 Receptor alpha Subunit;Peptide Fragments;myelin oligodendrocyte glycoprotein (35-55) |
|---|
| Article MeSH List: | Animals; Antibodies(therapeutic use); Antigens, CD20(genetics; immunology); B-Lymphocytes(drug effects; immunology); CD4-Positive T-Lymphocytes(drug effects; immunology); Cytokines(metabolism); Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental(drug therapy; genetics; immunology; physiopathology); Female; Flow Cytometry(methods); Forkhead Transcription Factors(metabolism); Glycoproteins(adverse effects); Humans; Interleukin-2 Receptor alpha Subunit(metabolism); Lymphocyte Activation(drug effects; immunology); Mice; Mice, Inbred C57BL; Mice, Transgenic; Peptide Fragments(adverse effects); Statistics, Nonparametric; T-Lymphocytes, Regulatory(drug effects; immunology) |
|---|
| Curation Last Updated: | 2012-05-31 20:48:24 |
|---|
