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1、Bregs-Regulatory B cells 1234Contents6 5Introduction Traditionally, B cells have been thought to contribute to disease through production of antibodies In the past two decades, investigators have attributed additional functions to B cells, including antigen presentation, the production of multiple c

2、ytokines Recently, the ability of B cells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory B cells has emerged.Clues to Bregs existence199620021974B cells suppress DTHsuppressor B cells could regulatethe immune responseIL-10-producing

3、 B cells regulate autoimmunityCD19+CD1dhi B cells producing IL-10control Th2-driven colitis the term “regulatory B cells”, which defines B-cell subsets with regulatory properties, was first introduced B celldeficient mice develop chronic EAEB cells could restrain the severity of autoimmune disease19

4、80antigen-activated B cells could induce tolerance in recipient naive mice Support a suppressive framework for B cells and introduce alink with T-cell toleranceDevelopment and DifferentiationB cellB 2B 1Development and DifferentiationFO B cellT2 MZP B cellMZ B cellDevelopment and DifferentiationDeve

5、lopment and DifferentiationDevelopment and DifferentiationDevelopment and DifferentiationMizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol. 2006Phenotypical IdentificationPhenotypical IdentificationPhenotypical IdentificationPhenotypical IdentificationPhenotypical Identification There i

6、s no unique marker, or set of markers, that exclusively identifies the Bregs There is no master regulator transcription factor identified in Breg development IL-10 secretion is still a vital standard in the identification of BregsFunction of BregsMizoguchi A, Bhan AK. A case for regulatory B cells.

7、J Immunol. 2006Function of BregsFunction of BregsFunction of BregsBregs in autoimmunity Experimental autoimmune encephalomyelitis (EAE) Inflammatory Bowel Disease (IBD) Rheumatoid Arthritis (RA)Bregs in autoimmunityEAEB-cell-deficient mice (m mMT) failed to control EAE, and unlike the wild-type mice

8、, did not undergo spontaneous remission In the absence of IL-10 production by B cells, the pro-inflammatory type 1 immune response persisted and mice did not recover Lack of disease resolution was attributed to theinability of T cells to switch to a protective Th2 response Bregs in autoimmunityIBDm

9、mMT TCRa a-/- mice manifest an earlier onset of disease and an exacerbated intestinal inflammation compared with the TCRa a-/-miceThe amelioration of disease was paralleled by an increase in the clearance of apoptotic cells, suggesting an autoantibody-mediated protective mechanism Administration of

10、purified immunoglobulin from TCRa-/- mice with a mixture of monoclonal autoantibodies attenuate colitisBregs in autoimmunityRAStimulation of arthritogenic B cells with an agonisticanti-CD40 and collagen generated a subset of B cellsproducing IL-10This suppressive effect was associated with adownregu

11、lation of Th1 cytokines and was dependent upon the release of IL-10Transfer of collagen and anti-CD40-stimulated B cells to syngeneic immunized mice prevented the induction of arthritis and ameliorated established diseaseBregs in cancerBregs support lung metastases via Treg generationBregs in cancer

12、Bregs support lung metastases via Treg generationBregs in cancerRegulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapyBregs in transplantationGVHDAcute GVHD is initially augmented in m mMT recipients relative to wild-type recipients as a result of an increase in

13、donor T-cell proliferation, expansion, and inflammatory cytokine productionRecipient mice in which B cells are unableto produce IL-10 develop more severe acute GVHDthan recipient mice in which B cells are wild typeTBI deplete most B cell but rapidly induces sustained interleukin-10 generation from B

14、 cellsOutstanding questions and Futurue directions we need to better identify surface markers that, coupled with transcriptional factors, would provide a unique signature The question of whether all B cells producing IL-10, irrespective of their phenotype, are capable of suppression or whether multi

15、ple Breg subsets exist and if they are all equipollent is yet to be determinedOutstanding questions and Futurue directions We need to better identify surface markers that, coupled with transcriptional factors, would provide a unique signature The question of whether all B cells producing IL-10, irre

16、spective of their phenotype, are capable of suppression or whether multiple Breg subsets exist and if they are all equipollent is yet to be determinedOutstanding questions and Futurue directions There are virtually no data demonstrating whether Bregs migrate to the site of inflammation and whether they interact in situ with proinflammatory cells To what extent their suppressive effect is antigen specific is still debatable and largely unexplored. Most da