Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis.
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-alpha 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.
Duddy
Martin
M
Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, and Department of Neurology, Ottawa General Hospital, Canada.
Niino
Masaaki
M
Adatia
Femina
F
Hebert
Sherry
S
Freedman
Mark
M
Atkins
Harry
H
Kim
Ho Jin
HJ
Bar-Or
Amit
A
D000328:Adult; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis* / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011446:Prospective Studies; D016192:Resting Phase, Cell Cycle / Q000187:drug effects / Q000276:immunology*
D016207:Cytokines; D008942:Mitoxantrone