Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?

Ann Neurol. 2010 Apr;67(4):452-61. doi: 10.1002/ana.21939.


Objective: To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS).

Methods: B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS.

Results: B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha.

Interpretation: We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal, Murine-Derived
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / physiology*
  • CD4-Positive T-Lymphocytes / physiology*
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Proliferation / drug effects
  • Cytokines / metabolism*
  • Double-Blind Method
  • Enzyme-Linked Immunosorbent Assay / methods
  • Female
  • Flow Cytometry / methods
  • Glatiramer Acetate
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Interferon-gamma / metabolism
  • Interleukin-10 / metabolism
  • Lymphotoxin-alpha
  • Male
  • Middle Aged
  • Mitogens / pharmacology
  • Multiple Sclerosis / blood
  • Multiple Sclerosis / immunology
  • Multiple Sclerosis / pathology*
  • Multiple Sclerosis / therapy
  • Muromonab-CD3 / pharmacology
  • Peptides / pharmacology
  • Phytohemagglutinins / pharmacology
  • Rituximab
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*
  • Time Factors
  • Tumor Necrosis Factor-alpha


  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Cytokines
  • Immunosuppressive Agents
  • Lymphotoxin-alpha
  • Mitogens
  • Muromonab-CD3
  • Peptides
  • Phytohemagglutinins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Rituximab
  • Glatiramer Acetate
  • Interferon-gamma