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* Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Canada; and
Department of Neurology and
Department of Haematology, Ottawa General Hospital, Ottawa, Canada
Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-
are largely produced by memory B cells. These results point to an in vivo switch in the cytokine "program" of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 M.D. and M.N. contributed equally to this study.
2 Address correspondence and reprint requests to Dr. Amit Bar-Or, Montreal Neurological Institute, 3801 University Street, 111 Montreal, Quebec, Canada. E-mail address: amit.bar-or{at}mcgill.ca
3 Abbreviations used in this paper: MS, multiple sclerosis; CD40L, CD40 ligand; EAE, experimental autoimmune encephalitis; GC, germinal center; LT, lymphotoxin; NMO, neuromyelitis optica; RRMS, relapsing remitting MS; SPMS, secondary progressive MS.
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