title: Abnormal B-cell cytokine responses a trigger of T-cell-mediated disease in MS?
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute and Hospital, McGill University, Montreal Quebec, Canada. amit.bar-or@mcgill.ca
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Lama
authors.initials: L
authors.lastname: Fawaz
authors.forename: Boli
authors.initials: B
authors.lastname: Fan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Darlington
authors.forename: Aja
authors.initials: A
authors.lastname: Rieger
authors.forename: Christine
authors.initials: C
authors.lastname: Ghorayeb
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Waubant
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hauser
authors.forename: Jiameng
authors.initials: J
authors.lastname: Zhang
authors.forename: Craig H
authors.initials: CH
authors.lastname: Smith
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008233:Lymphotoxin-alpha; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology / Q000473:pathology* / Q000628:therapy; D016853:Muromonab-CD3 / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D000069283:Rituximab; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D016207:Cytokines; D007166:Immunosuppressive Agents; D008233:Lymphotoxin-alpha; D008934:Mitogens; D016853:Muromonab-CD3; D010455:Peptides; D010835:Phytohemagglutinins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000069283:Rituximab; D000068717:Glatiramer Acetate; D007371:Interferon-gamma