調(diào)節(jié)性B細(xì)胞-文檔資料

1、2021/4/6,1,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 antibodie

2、s In 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 regul

3、atory 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 cel

4、ldecient 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,在骨髓發(fā)育，分布外周淋

5、巴器官， 參與特異性免疫,定位于大網(wǎng)膜、胸腔及腸黏膜固有層， 參與非特異性免疫,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 regul

6、atory 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. The roles o

7、f 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,Bodhankar S. IL-10-pr

8、oducing 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 Breg development IL-

9、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. Immune regulatory function

10、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 autoimmunityEAE,B-cell-deficient mice

11、(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 the inability of T cells to sw

12、itch 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 apoptotic cells, suggesting an autoant

13、ibody-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 generated a subset of B cells producing

14、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 established disease,Bregs in cancer,B

15、regs 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 generation,Olkhanud PB. Tumor-evoked regula

16、tory 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 production of IL-10 inhibits lymphoma depl

17、etion 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 mMT recipients relative to wild-type recip

18、ients 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 deplete most B cell but rapidly induces su

19、stained 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 producing IL-10, irrespective of their phenotype, ar

20、e 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, would provide a unique signature The question of whether all B cells producing IL-10, irrespective of the