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Abnormal B‐cell cytokine responses a trigger of T‐cell–mediated disease in MS?
Author(s) -
BarOr Amit,
Fawaz Lama,
Fan Boli,
Darlington Peter J.,
Rieger Aja,
Ghorayeb Christine,
Calabresi Peter A.,
Waubant Emmanuelle,
Hauser Stephen L.,
Zhang Jiameng,
Smith Craig H.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21939
Subject(s) - cytokine , proinflammatory cytokine , immunology , tumor necrosis factor alpha , t cell , ex vivo , cd8 , b cell , medicine , in vivo , immune system , biology , inflammation , antibody , microbiology and biotechnology
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)‐α secretion, when activated in the context of the pathogen‐associated TLR9‐ligand CpG‐DNA, or the Th1 cytokine interferon‐γ, 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 TNFα. 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. ANN NEUROL 2010;67:452–461