生发中心的发生与发展
|
摘要
生发中心(germinal centers,GCs)位于次级淋巴组织(secondary lymphoid organs,SLOs),是淋巴细胞(lymphocytes)与基质细胞(stromal cells)的短暂聚集地,促进体液免疫过程。在生发中心中,B细胞经历了克隆扩增(clonal expansion)、体细胞高频突变(somatic hypermutation,SHM)、亲和力选择(affinity selection)以及分化为浆细胞(plasma cells,PCs)和记忆B细胞(memory B cells,BMEM)等过程。但在生发中心中,亮区(light zone,LZ)和暗区(dark zone,DZ)各自的功能以及亲和力选择的具体机制仍不清楚。在过去10年中,活体镜检法(intravital microscopy,IVM)使人们可以直接地研究生发中心中进行的的一系列动态反应,并取得了一定的进展。表明在暗区进行体细胞高频突变以及B细胞增殖过程,亮区则发生亲和力选择反应。B细胞在暗区与亮区间发生区域流动(interzonal migration),滤泡辅助性T细胞(T follicular helper cells,Tfh)在调控B细胞从亮区重新回到暗区,促进亲和力选择过程中发挥着重要作用。本文结合最新的研究进展,对生发中心中发生的一系列动态反应,以及其在疫苗设计和疾病治疗中的作用进行综述。
Germinal centers( GCs) are transient convergences of lymphocytes and stromal cells that promote long-lived humoral immunity within secondary lymphoid organs( SLOs). B cells undergo clonal expansion,somatic hypermutation( SHM),affinity selection and eventually differentiate into plasma cells( PCs) and memory B cells( BMEM) in GCs. However,the specific function of light zone and dark zone,and the mechanism by which B cells are selected remains unclear. Given the dynamic nature of GC,seminal application of intravital microscopy( IVM) has enabled the scientists to directly study GC features and make tremendous progress since the last decade. Recent studies show that B cell division and SHM are restricted to the DZ. Affinity selection is restricted to LZ and there is a net vector of B cell movement from the DZ to the LZ. Notably,the decision to return from the LZ to the DZ and undergo clonal expansion is controlled by T cells. In this paper,a series of dynamic reactions in GCs and their roles in vaccine design and disease treatment are reviewed.
Germinal centers( GCs) are transient convergences of lymphocytes and stromal cells that promote long-lived humoral immunity within secondary lymphoid organs( SLOs). B cells undergo clonal expansion,somatic hypermutation( SHM),affinity selection and eventually differentiate into plasma cells( PCs) and memory B cells( BMEM) in GCs. However,the specific function of light zone and dark zone,and the mechanism by which B cells are selected remains unclear. Given the dynamic nature of GC,seminal application of intravital microscopy( IVM) has enabled the scientists to directly study GC features and make tremendous progress since the last decade. Recent studies show that B cell division and SHM are restricted to the DZ. Affinity selection is restricted to LZ and there is a net vector of B cell movement from the DZ to the LZ. Notably,the decision to return from the LZ to the DZ and undergo clonal expansion is controlled by T cells. In this paper,a series of dynamic reactions in GCs and their roles in vaccine design and disease treatment are reviewed.
引文
[1]De Silva NS,Klein U.Dynamics of B cells in germinal centres[J].Nat Rev Immunol,2015,15(3):137-148
[2]Calado DP,Sasaki Y,Godinho SA,et al.The cell-cycle regulator c-Myc is essential for the formation and Maintenance of germinal centers[J].Nat Immunol,2012,13(11):1092-1100
[3]Crotty S.T follicular helper cell differentiation,function,and roles in disease[J].Immunity,2014,41(4):529-542
[4]Shaffer AL,Lin KI,Kuo TC,et al.Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program[J].Immunity,2002,17(1):51-62
[5]Hoyer BF,Moser K,Hauser AE,et al.Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice[J].J Exp Med,2004,199(11):1577-1584
[6]Huang H,Benoist C,Mathis D.Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis[J].Proc Natl Acad Sci U S A,2010,107(10):4658-4663
[7]Aguzzi A,Kranich J,Krautler NJ.Follicular dendritic cells:origin,phenotype,and function in health and disease[J].Trends Immunol,2014,35(3):105-113
[8]Mattsson J,Yrlid U,Stensson A,et al.Complement activation and complement receptors on follicular dendritic cells are critical for the function of a targeted adjuvant[J].J Immunol,2011,187(7):3641-3652
[9]Phan TG,Green JA,Gray EE,et al.Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation[J].Nat Immunol,2009,10(7):786-793
[10]Ditzel HJ.The K/Bx N mouse:a model of human inflammatory arthritis[J].Trends Mol Med,2004,10(1):40-45
[11]Yau IW,Cato MH,Jellusova J,et al.Censoring of self-reactive B cells by follicular dendritic cell-displayed self-antigen[J].J Immunol,2013,191(3):1082-1090
[12]Allen CD,Ansel KM,Low C,et al.Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5[J].Nat Immunol,2004,5(9):943-952
[13]Xu H,Li X,Liu D,et al.Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility[J].Nature,2013,496(7446):523-527
[14]Weinstein JS,Bertino SA,Hernandez SG,et al.B cells in T follicular helper cell development and function:separable roles in delivery of ICOS ligand and antigen[J].J Immunol,2014,192(7):3166-3179
[15]Quah BJ,Barlow VP,Mc Phun V,et al.Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer[J].Proc Natl Acad Sci U S A,2008,105(11):4259-4264
[16]Stavnezer J,Schrader CE.Ig H chain class switch recombination:mechanism and regulation[J].J Immunol,2014,193(11):5370-5378
[17]Heesters BA,Lindqvist M,Vagefi PA,et al.Follicular dendritic cells retain infectious HIV in cycling endosomes[J].PLo S Pathog,2015,11(12):e1005285
[18]Dustin ML.The immunological synapse[J].Cancer Immunol Res,2014,2(11):1023-1033
[19]Onabajo OO,Mattapallil JJ.Expansion or depletion of T follicular helper cells during HIV infection consequenes for B cell responses[J].Curr HIV Res,2013,11(8):595-600
[20]Lu P,Shih C,Qi H.Ephrin B1-mediated repulsion and signaling control germinal center T cell territoriality and function[J].Science,2017,356(6339).pii:eaai9264
[21]Suurmond J,Diamond B.Autoantibodies in systemic autoimmune diseases:specificity and pathogenicity[J].J Clin Invest,2015,125(6):2194-2202
[22]Tas JM,Mesin L,Pasqual G,et al.Visualizing antibody affinity maturation in germinal centers[J].Science,2016,351(6277):1048-1054
[23]Davies EG,Thrasher AJ.Update on the hyper immunoglobulin M syndromes[J].Br J Haematol,2010,149(2):167-180
[24]Bannard O,Horton RM,Allen CD,et al.Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection[J].Immunity,2013,39(5):912-924
[25]Zhang X,Ing S,Fraser A,et al.Follicular helper T cells:new insights into mechanisms of autoimmune diseases[J].Ochsner J,2013,13(1):131-139
[26]Suan D,Sundling C,Brink R.Plasma cell and memory B cell differentiation from the germinal center[J].Curr Opin Immunol,2017,45:97-102
[2]Calado DP,Sasaki Y,Godinho SA,et al.The cell-cycle regulator c-Myc is essential for the formation and Maintenance of germinal centers[J].Nat Immunol,2012,13(11):1092-1100
[3]Crotty S.T follicular helper cell differentiation,function,and roles in disease[J].Immunity,2014,41(4):529-542
[4]Shaffer AL,Lin KI,Kuo TC,et al.Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program[J].Immunity,2002,17(1):51-62
[5]Hoyer BF,Moser K,Hauser AE,et al.Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice[J].J Exp Med,2004,199(11):1577-1584
[6]Huang H,Benoist C,Mathis D.Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis[J].Proc Natl Acad Sci U S A,2010,107(10):4658-4663
[7]Aguzzi A,Kranich J,Krautler NJ.Follicular dendritic cells:origin,phenotype,and function in health and disease[J].Trends Immunol,2014,35(3):105-113
[8]Mattsson J,Yrlid U,Stensson A,et al.Complement activation and complement receptors on follicular dendritic cells are critical for the function of a targeted adjuvant[J].J Immunol,2011,187(7):3641-3652
[9]Phan TG,Green JA,Gray EE,et al.Immune complex relay by subcapsular sinus macrophages and noncognate B cells drives antibody affinity maturation[J].Nat Immunol,2009,10(7):786-793
[10]Ditzel HJ.The K/Bx N mouse:a model of human inflammatory arthritis[J].Trends Mol Med,2004,10(1):40-45
[11]Yau IW,Cato MH,Jellusova J,et al.Censoring of self-reactive B cells by follicular dendritic cell-displayed self-antigen[J].J Immunol,2013,191(3):1082-1090
[12]Allen CD,Ansel KM,Low C,et al.Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5[J].Nat Immunol,2004,5(9):943-952
[13]Xu H,Li X,Liu D,et al.Follicular T-helper cell recruitment governed by bystander B cells and ICOS-driven motility[J].Nature,2013,496(7446):523-527
[14]Weinstein JS,Bertino SA,Hernandez SG,et al.B cells in T follicular helper cell development and function:separable roles in delivery of ICOS ligand and antigen[J].J Immunol,2014,192(7):3166-3179
[15]Quah BJ,Barlow VP,Mc Phun V,et al.Bystander B cells rapidly acquire antigen receptors from activated B cells by membrane transfer[J].Proc Natl Acad Sci U S A,2008,105(11):4259-4264
[16]Stavnezer J,Schrader CE.Ig H chain class switch recombination:mechanism and regulation[J].J Immunol,2014,193(11):5370-5378
[17]Heesters BA,Lindqvist M,Vagefi PA,et al.Follicular dendritic cells retain infectious HIV in cycling endosomes[J].PLo S Pathog,2015,11(12):e1005285
[18]Dustin ML.The immunological synapse[J].Cancer Immunol Res,2014,2(11):1023-1033
[19]Onabajo OO,Mattapallil JJ.Expansion or depletion of T follicular helper cells during HIV infection consequenes for B cell responses[J].Curr HIV Res,2013,11(8):595-600
[20]Lu P,Shih C,Qi H.Ephrin B1-mediated repulsion and signaling control germinal center T cell territoriality and function[J].Science,2017,356(6339).pii:eaai9264
[21]Suurmond J,Diamond B.Autoantibodies in systemic autoimmune diseases:specificity and pathogenicity[J].J Clin Invest,2015,125(6):2194-2202
[22]Tas JM,Mesin L,Pasqual G,et al.Visualizing antibody affinity maturation in germinal centers[J].Science,2016,351(6277):1048-1054
[23]Davies EG,Thrasher AJ.Update on the hyper immunoglobulin M syndromes[J].Br J Haematol,2010,149(2):167-180
[24]Bannard O,Horton RM,Allen CD,et al.Germinal center centroblasts transition to a centrocyte phenotype according to a timed program and depend on the dark zone for effective selection[J].Immunity,2013,39(5):912-924
[25]Zhang X,Ing S,Fraser A,et al.Follicular helper T cells:new insights into mechanisms of autoimmune diseases[J].Ochsner J,2013,13(1):131-139
[26]Suan D,Sundling C,Brink R.Plasma cell and memory B cell differentiation from the germinal center[J].Curr Opin Immunol,2017,45:97-102