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1、.,Bregs-Regulatory B cells,.,Introduction,1,Clues to Bregs existence,2,Development and differentiation,3,4,Contents,Phenotypical Identification,6,Bregs in diseases,Function of Bregs,5,.,Introduction,Traditionally, Bcells have been thought to contribute to disease through production of antibodies In
2、the past two decades, investigators have attributed additional functions to B cells, including antigen presentation, the production of multiple cytokines Recently, the ability of Bcells to negatively regulate cellular immune responses and inflammation has been described and the concept of regulatory
3、 Bcells has emerged.,.,Clues to Bregs existence,2002,B cells suppress DTH,IL-10-producing B cells regulate autoimmunity CD19+CD1dhi B cells producing IL-10 control Th2-driven colitis,the term “regulatory B cells”, which defines B-cell subsets with regulatory properties, was first introduced,B cellde
4、cient mice develop chronic EAE,B cells could restrain the severity of autoimmune disease,1980,antigen-activated B cells could induce tolerance in recipient naive mice,Support a suppressive framework for B cells and introduce a link with T-cell tolerance,.,Development and Differentiation,在骨髓发育，分布外周淋巴
5、器官， 参与特异性免疫,定位于大网膜、胸腔及肠黏膜固有层， 参与非特异性免疫,.,Development and Differentiation,FO B cell,T2 MZP B cell,MZ B cell,LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008,.,Development and Differentiation,.,Development and Differentiation,Mauri C, Ehrenstein MR. The short history of
6、regulatory B cells. Trends Immunol. 2008,.,Development and Differentiation,Mauri C, Ehrenstein MR. The short history of regulatory B cells. Trends Immunol. 2008,.,Development and Differentiation,Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol. 2006,.,Phenotypical Identification,He Y.
7、The roles of regulatory B cells in cancer. J Immunol Res. 2014.,.,Phenotypical Identification,Mauri C. Immune regulatory function of B cells. Annu Rev Immunol. 2012,.,Phenotypical Identification,Mauri C. Immune regulatory function of B cells. Annu Rev Immunol. 2012,.,Phenotypical Identification,Bodh
8、ankar S. IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metab Brain Dis. 2013,.,Phenotypical Identification,There is no unique marker, or set of markers, that exclusively identifies the Bregs There is no master regulator transcription factor identified in B
9、reg development IL-10 secretion is still a vital standard in the identification of Bregs,.,Function of Bregs,Mizoguchi A, Bhan AK. A case for regulatory B cells. J Immunol. 2006,.,Function of Bregs,Mauri C. Immune regulatory function of B cells. Annu Rev Immunol. 2012,.,Function of Bregs,Mauri C. Im
10、mune regulatory function of B cells. Annu Rev Immunol. 2012,.,Mauri C. Immune regulatory function of B cells. Annu Rev Immunol. 2012,Function of Bregs,.,Bregs in autoimmunity,Experimental autoimmune encephalomyelitis (EAE) Inflammatory Bowel Disease (IBD) Rheumatoid Arthritis (RA),.,Bregs in autoimm
11、unityEAE,B-cell-deficient mice (mMT) failed to control EAE, and unlike the wild-type mice, 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
12、 the inability of T cells to switch to a protective Th2 response,.,Bregs in autoimmunityIBD,mMT TCRa-/- mice manifest an earlier onset of disease and an exacerbated intestinal inammation compared with the TCRa-/-mice,The amelioration of disease was paralleled by an increase in the clearance of apopt
13、otic cells, suggesting an autoantibody-mediated protective mechanism,Administration of purified immunoglobulin from TCRa-/- mice with a mixture of monoclonal autoantibodies attenuate colitis,.,Bregs in autoimmunityRA,Stimulation of arthritogenic B cells with an agonistic anti-CD40 and collagen gener
14、ated a subset of B cells producing IL-10,This suppressive effect was associated with a downregulation of Th1 cytokines and was dependent upon the release of IL-10,Transfer of collagen and anti-CD40-stimulated B cells to syngeneic immunized mice prevented the induction of arthritis and ameliorated es
15、tablished disease,.,Bregs in cancer,Bregs support lung metastases via Treg generation,Olkhanud PB. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells. Cancer Res. 2011,.,Bregs in cancer,Bregs support lung metastases via Treg gene
16、ration,Olkhanud PB. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4 T cells to T-regulatory cells. Cancer Res. 2011,.,Bregs in cancer,Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy,Horikawa M. Regulatory B cell p
17、roduction of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. J Clin Invest. 2011,.,Bregs in transplantationGVHD,Rowe V.Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation. Blood. 2006,Acute GVHD is initially augmented in
18、 mMT recipients relative to wild-type recipients as a result of an increase in donor T-cell proliferation, expansion, and inflammatory cytokine production,Recipient mice in which B cells are unable to produce IL-10 develop more severe acute GVHD than recipient mice in which B cells are wild type,TBI
19、 deplete most B cell but rapidly induces sustained interleukin-10 generation from B cells,.,Outstanding 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 produci
20、ng IL-10, irrespective of their phenotype, are capable of suppression or whether multiple Breg subsets exist and if they are all equipollent is yet to be determined,.,Outstanding questions and Futurue directions,We need to better identify surface markers that, coupled with transcriptional factors, w
21、ould provide a unique signature The question of whether all B cells producing IL-10, irrespective of their phenotype, are capable of suppression or whether multiple Breg subsets exist and if they are all equipollent is yet to be determined,.,Outstanding questions and Futurue directions,There are vir
22、tually 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 data have focused on the suppressive function that Bregs have on T cells. Study of the interaction of Bregs with other cells of the immune system might unravel additional undiscovered functions.,.,Thanks!,