B细胞在系统性红斑狼疮发病机制中的作用
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摘要
系统性红斑狼疮是一种免疫细胞过度活化和自身抗体大量分泌的免疫系统疾病。极度活跃的多克隆B细胞几乎贯穿了所有SLE的发病机制,包括释放细胞因子、呈递抗原和产生自身抗体。因此,本文就B细胞在SLE发病中作用的相关研究进展进行综述。
Systemic lupus erythematosus( SLE) is an immune system disease characterized by over activation of immune cells and high secretion of autoantibodies.Extremely active B cells run through almost all the pathogenesis of SLE,including the release of cytokines,the presentation of antigens and the production of autoantibodies.Therefore,this article reviews the research progress on the role of B cells in the pathogenesis of SLE.
Systemic lupus erythematosus( SLE) is an immune system disease characterized by over activation of immune cells and high secretion of autoantibodies.Extremely active B cells run through almost all the pathogenesis of SLE,including the release of cytokines,the presentation of antigens and the production of autoantibodies.Therefore,this article reviews the research progress on the role of B cells in the pathogenesis of SLE.
引文
[1]Crispín JC,Liossis SN,Kis-Toth K,et al.Pathogenesis of human systemic lupus erythematosus:recent advances[J].Trends Mol Med,2010,16(2):47-57.
[2]Choi J,Kim ST.The pathogenesis of systemic lupus erythematosusan update[J].Curr Opin Immunol,2012,24(6):651-657.
[3]Lisnevskaia L,Murphy G.Systemic lupus erythematosus[J].Lancet(London,England),2014,384(9957):1878-1888.
[4]Rot her N.Disturbed T cell signaling and altered Th17 and regulatory T cell subsets in the pathogenesis of systemic lupus erythematosus[J].Fron Immunol,2015,6:610.
[5]Sang A,Zheng YY.Contributions of B cells to lupus pathogenesis[J].Mol Immunol,2014,62(2):329-338.
[6]Sinai P,Dozmorov IM,Song R,et al.T/B-cell interactions are more transient in response to weak stimuli in SLE-prone mice[J].Eur J Immunol,2014,44(12):3522-3531.
[7]Marshak-Rothstein A.Toll-like receptors in systemic autoimmune disease[J].Nat Rev Immunol,2006,6(11):823-835.
[8]Barreiro LB,Ben-Ali M,Quach H,et al.Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense[J].PLOS Genet,2009,5(7):e1000562.
[9]Petes C,Odoardi N.The toll for trafficking:toll-like receptor 7delivery to the endosome[J].Fron Immunol,2017,8:1075.
[10]Kassiotis G.Immune responses to endogenous retroelements:taking the bad with the good[J].Nat Rev Immunol,2016,16(4):207-219.
[11]The ofilopoulos AN,Kono DH.The multiple pathways to autoimmunity[J].Nat Immunol,2017,18(7):716-724.
[12]Green NM.Toll-like receptor driven B cell activation in the induction of systemic autoimmunity[J].Semin Immunol,2011,23(2):106-112.
[13]Christensen SR,Shupe J,Nickerson K,et al.Toll-like receptor 7and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus[J].Immunity,2006,25(3):417-428.
[14]Deane JA,Pisitkun P,Barrett RS,et al.Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation[J].Immunity,2007,27(5):801-810.
[15]Jackson SW,Scharping NE,Kolhatkar NS,et al.Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation[J].J Immunol,2014,192(10):4525-4532.
[16]Soni C,Wong EB,Domeier PP,et al.B cell-intrinsic TLR7signaling is essential for the development of spontaneous germinal centers[J].J Immunol,2014,193(9):4400-4414.
[17]Hwang SH,Lee H,Yamamoto M,et al.B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice[J].J Immunol,2012,189(12):5786-5796.
[18]Lee YH,Choi SJ,Ji JD.Association between toll-like receptor polymorphisms and systemic lupus erythematosus:a meta-analysis update[J].Lupus,2016,25(6):593-601.
[19]Kawasaki A,Furukawa H,Kondo Y,et al.TLR7 single-nucleotide polymorphisms in the 3'untranslated region and intron 2independently contribute to systemic lupus erythematosus in Japanese women:a case-control association study[J].Arthritis Res Ther,2011,13(2):R41.
[20]Lau CM,Broughton C,Tabor AS,et al.RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement[J].J Exp Med,2005,202(9):1171-1177.
[21]Tsubata T.Negative regulation of B cell responses and selftolerance to RNA-related lupus self-antigen[J].P JPN Acad,2018,94(1):35-44.
[22]Moulton VR.T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity[J].J Clin Invest,2015,125(6):2220-2227.
[23]Kyttaris VC.Novel Treatments in Lupus[J].Curr Rheumatol Rep,2017,19(3):10.
[24]Castro AG,Hauser TM,Cocks BG,et al.Molecular and functional characterization of mouse signaling lymphocytic activation molecule(SLAM):differential expression and responsiveness in Th1 and Th2 cells[J].J Immunol,1999,163(11):5860-5870.
[25]Tsao BP.The genetics of human systemic lupus erythematosus[J].Trends Immunol,2003,24(11):595-602.
[26]Li1án-Rico L,Hernández-Castro B,Doniz-Padilla L,et al.Analysis of expression and function of the co-stimulatory receptor SLAMF1 in immune cells from patients with systemic lupus erythematosus(SLE)[J].Lupus,2015,24(11):1184-1190.
[27]Karampetsou MP,Comte D,Kis-Toth K,et al.Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus[J].PLOS ONE,2017,12(10):e0186073.
[28]Karampetsou MP,Comte D,Suárez-Fueyo A,et al.SLAMF1engagement inhibits T cell-B cell interaction and diminishes IL-6production and plasmablast differentiation in systemic lupus erythematosus[J].Arthritis Rheumatol(Hoboken,N.J.),2018.
[29]Croft M,So T,Duan W.The significance of OX40 and OX40L to T-cell biology and immune disease[J].Immunol Rev,2009,229(1):173-191.
[30]Cortini A,Ellinghaus U,Malik TH,et al.B cell OX40L supports Tfollicular helper cell development and contributes to SLEpathogenesis[J].Ann Rheum Dis,2017,76(12):2095-2103.
[31]Liu Z.BAFF inhibition:a new class of drugs for the treatment of autoimmunity[J].Exp Cell Res,2011,317(9):1270-1277.
[32]Petri M,Stohl W,Chatham W,et al.Association of plasma Blymphocyte stimulator levels and disease activity in systemic lupus erythematosus[J].Arthritis Rheum,2008,58(8):2453-2459.
[33]Neusser MA,Lindenmeyer MT,Edenhofer I,et al.Intrarenal production of B-cell survival factors in human lupus nephritis[J].Modern Pathol,2011,24(1):98-107.
[34]Mackay F.Cracking the BAFF code[J].Nat Rev Immunol,2009,9(7):491-502.
[35]Figgett WA,Deliyanti D,Fairfax KA,et al.Deleting the BAFFreceptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell Numbers[J].J Autoimmun,2015,61:9-16.
[36]Jacobs HM,Thouvenel CD,Leach S,et al.Cutting Edge:BAFFpromotes autoantibody production via TACI-dependent activation of transitional B Cells[J].J Immunol,2016,196(9):3525-3531.
[37]Arkatkar T,Jacobs HM,Du SW,et al.TACI deletion protects against progressive murine lupus nephritis induced by BAFFoverexpression[J].Kidney Int,2018,94(4):728-740.
[38]Balomenos D,Rumold R.Interferon-gamma is required for lupuslike disease and lymphoaccumulation in MRL-lpr mice[J].J Clin Invest,1998,101(2):364-371.
[39]Lee SK,Silva DG,Martin JL,et al.Interferon-γexcess leads to pathogenic accumulation of follicular helper T cells and germinal centers[J].Immunity,2012,37(5):880-892.
[40]Domeier PP,Chodisetti SB,Soni C,et al.IFN-γreceptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity[J].J Exp Med,2016,213(5):715-732.
[41]Jackson SW,Jacobs HM,Arkatkar T,et al.B cell IFN-γreceptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6[J].J Exp Med,2016,213(5):733-750.
[42]Boe digheimer MJ,Martin DA,Amoura Z,et al.Safety,pharmacokinetics and pharmacodynamics of AMG 811,an antiinterferon-γmonoclonal antibody,in SLE subjects without or with lupus nephritis[J].Lupus Sci Med,2017,4(1):e000226.
[43]Wang JH,New JS,Xie S,et al.Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice[J].Arthritis Rheum,2013,65(10):2703-2712.
[44]Han JH,Umiker BR,Kazimirova AA,et al.Expression of an antiRNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression[J].Eur JImmunol,2014,44(1):215-226.
[45]Liu Z.Taming lupus-a new understanding of pathogenesis is leading to clinical advances[J].Nat Med,2012,18(6):871-882.
[46]Allen CD,Okada T.Germinal-center organization and cellular dynamics[J].Immunity,2007,27(2):190-202.
[47]Cappione A,Anolik JH,Pugh-Bernard A,et al.Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus[J].J Clin Invest,2005,115(11):3205-3216.
[48]Vin uesa CG,Sanz I.Dysregulation of germinal centres in autoimmune disease[J].Nat Rev Immunol,2009,9(12):845-857.
[49]Nem azee D.Receptor editing in lymphocyte development and central tolerance[J].Nat Rev Immunol,2006,6(10):728-740.
[50]Li X,Ptacek TS,Brown EE.Fcgamma receptors:structure,function and role as genetic risk factors in SLE[J].Genes Immun,2009,10(5):380-389.
[51]Ren D,Liu F,Dong G,et al.Activation of TLR7 increases CCND3expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus[J].Cell Mol Immunol,2016,13(6):764-775.
[52]Liu Z,Zou Y.Plasma cells in systemic lupus erythematosus:the long and short of it all[J].Eur J Immunol,2011,41(3):588-591.
[53]Zou ali M.B lymphocyte signaling pathways in systemic autoimmunity:implications for pathogenesis and treatment[J].Arthritis Rheum,2004,50(9):2730-2741.
[54]Liossis SN,Solomou EE,Dimopoulos MA,et al.B-cell kinase lyn deficiency in patients with systemic lupus erythematosus[J].JInvest Med,2001,49(2):157-165.
[55]Flores-Borja F,Kabouridis PS,Jury EC,et al.Decreased Lyn expression and translocation to lipid raft signaling domains in Blymphocytes from patients with systemic lupus erythematosus[J].Arthritis Rheum,2005,52(12):3955-3965.
[56]Green NM.Toll-like receptor driven B cell activation in the induction of systemic autoimmunity[J].Semin Immunol,2011,23(2):106-112.
[57]Geh D.Epratuzumab for the treatment of systemic lupus erythematosus[J].Exp Rev Clin Immunol,2018,14(4):245-258.
[58]Wallace DJ.Epratuzumab for systemic lupus erythematosus[J].Lupus,2013,22(4):400-405.
[59]Clowse ME,Wallace DJ,Furie RA,et al.Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus:results from two phase III randomized,doubleblind,placebo-controlled trials[J].Arthritis Rheumatol,2017,69(2):362-375.
[60]Clark EA.CD22:A regulator of innate and adaptive B cell responses and autoimmunity[J].Front Immunol,2018,9:2235.
[2]Choi J,Kim ST.The pathogenesis of systemic lupus erythematosusan update[J].Curr Opin Immunol,2012,24(6):651-657.
[3]Lisnevskaia L,Murphy G.Systemic lupus erythematosus[J].Lancet(London,England),2014,384(9957):1878-1888.
[4]Rot her N.Disturbed T cell signaling and altered Th17 and regulatory T cell subsets in the pathogenesis of systemic lupus erythematosus[J].Fron Immunol,2015,6:610.
[5]Sang A,Zheng YY.Contributions of B cells to lupus pathogenesis[J].Mol Immunol,2014,62(2):329-338.
[6]Sinai P,Dozmorov IM,Song R,et al.T/B-cell interactions are more transient in response to weak stimuli in SLE-prone mice[J].Eur J Immunol,2014,44(12):3522-3531.
[7]Marshak-Rothstein A.Toll-like receptors in systemic autoimmune disease[J].Nat Rev Immunol,2006,6(11):823-835.
[8]Barreiro LB,Ben-Ali M,Quach H,et al.Evolutionary dynamics of human Toll-like receptors and their different contributions to host defense[J].PLOS Genet,2009,5(7):e1000562.
[9]Petes C,Odoardi N.The toll for trafficking:toll-like receptor 7delivery to the endosome[J].Fron Immunol,2017,8:1075.
[10]Kassiotis G.Immune responses to endogenous retroelements:taking the bad with the good[J].Nat Rev Immunol,2016,16(4):207-219.
[11]The ofilopoulos AN,Kono DH.The multiple pathways to autoimmunity[J].Nat Immunol,2017,18(7):716-724.
[12]Green NM.Toll-like receptor driven B cell activation in the induction of systemic autoimmunity[J].Semin Immunol,2011,23(2):106-112.
[13]Christensen SR,Shupe J,Nickerson K,et al.Toll-like receptor 7and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus[J].Immunity,2006,25(3):417-428.
[14]Deane JA,Pisitkun P,Barrett RS,et al.Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation[J].Immunity,2007,27(5):801-810.
[15]Jackson SW,Scharping NE,Kolhatkar NS,et al.Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation[J].J Immunol,2014,192(10):4525-4532.
[16]Soni C,Wong EB,Domeier PP,et al.B cell-intrinsic TLR7signaling is essential for the development of spontaneous germinal centers[J].J Immunol,2014,193(9):4400-4414.
[17]Hwang SH,Lee H,Yamamoto M,et al.B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice[J].J Immunol,2012,189(12):5786-5796.
[18]Lee YH,Choi SJ,Ji JD.Association between toll-like receptor polymorphisms and systemic lupus erythematosus:a meta-analysis update[J].Lupus,2016,25(6):593-601.
[19]Kawasaki A,Furukawa H,Kondo Y,et al.TLR7 single-nucleotide polymorphisms in the 3'untranslated region and intron 2independently contribute to systemic lupus erythematosus in Japanese women:a case-control association study[J].Arthritis Res Ther,2011,13(2):R41.
[20]Lau CM,Broughton C,Tabor AS,et al.RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement[J].J Exp Med,2005,202(9):1171-1177.
[21]Tsubata T.Negative regulation of B cell responses and selftolerance to RNA-related lupus self-antigen[J].P JPN Acad,2018,94(1):35-44.
[22]Moulton VR.T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity[J].J Clin Invest,2015,125(6):2220-2227.
[23]Kyttaris VC.Novel Treatments in Lupus[J].Curr Rheumatol Rep,2017,19(3):10.
[24]Castro AG,Hauser TM,Cocks BG,et al.Molecular and functional characterization of mouse signaling lymphocytic activation molecule(SLAM):differential expression and responsiveness in Th1 and Th2 cells[J].J Immunol,1999,163(11):5860-5870.
[25]Tsao BP.The genetics of human systemic lupus erythematosus[J].Trends Immunol,2003,24(11):595-602.
[26]Li1án-Rico L,Hernández-Castro B,Doniz-Padilla L,et al.Analysis of expression and function of the co-stimulatory receptor SLAMF1 in immune cells from patients with systemic lupus erythematosus(SLE)[J].Lupus,2015,24(11):1184-1190.
[27]Karampetsou MP,Comte D,Kis-Toth K,et al.Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus[J].PLOS ONE,2017,12(10):e0186073.
[28]Karampetsou MP,Comte D,Suárez-Fueyo A,et al.SLAMF1engagement inhibits T cell-B cell interaction and diminishes IL-6production and plasmablast differentiation in systemic lupus erythematosus[J].Arthritis Rheumatol(Hoboken,N.J.),2018.
[29]Croft M,So T,Duan W.The significance of OX40 and OX40L to T-cell biology and immune disease[J].Immunol Rev,2009,229(1):173-191.
[30]Cortini A,Ellinghaus U,Malik TH,et al.B cell OX40L supports Tfollicular helper cell development and contributes to SLEpathogenesis[J].Ann Rheum Dis,2017,76(12):2095-2103.
[31]Liu Z.BAFF inhibition:a new class of drugs for the treatment of autoimmunity[J].Exp Cell Res,2011,317(9):1270-1277.
[32]Petri M,Stohl W,Chatham W,et al.Association of plasma Blymphocyte stimulator levels and disease activity in systemic lupus erythematosus[J].Arthritis Rheum,2008,58(8):2453-2459.
[33]Neusser MA,Lindenmeyer MT,Edenhofer I,et al.Intrarenal production of B-cell survival factors in human lupus nephritis[J].Modern Pathol,2011,24(1):98-107.
[34]Mackay F.Cracking the BAFF code[J].Nat Rev Immunol,2009,9(7):491-502.
[35]Figgett WA,Deliyanti D,Fairfax KA,et al.Deleting the BAFFreceptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell Numbers[J].J Autoimmun,2015,61:9-16.
[36]Jacobs HM,Thouvenel CD,Leach S,et al.Cutting Edge:BAFFpromotes autoantibody production via TACI-dependent activation of transitional B Cells[J].J Immunol,2016,196(9):3525-3531.
[37]Arkatkar T,Jacobs HM,Du SW,et al.TACI deletion protects against progressive murine lupus nephritis induced by BAFFoverexpression[J].Kidney Int,2018,94(4):728-740.
[38]Balomenos D,Rumold R.Interferon-gamma is required for lupuslike disease and lymphoaccumulation in MRL-lpr mice[J].J Clin Invest,1998,101(2):364-371.
[39]Lee SK,Silva DG,Martin JL,et al.Interferon-γexcess leads to pathogenic accumulation of follicular helper T cells and germinal centers[J].Immunity,2012,37(5):880-892.
[40]Domeier PP,Chodisetti SB,Soni C,et al.IFN-γreceptor and STAT1 signaling in B cells are central to spontaneous germinal center formation and autoimmunity[J].J Exp Med,2016,213(5):715-732.
[41]Jackson SW,Jacobs HM,Arkatkar T,et al.B cell IFN-γreceptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6[J].J Exp Med,2016,213(5):733-750.
[42]Boe digheimer MJ,Martin DA,Amoura Z,et al.Safety,pharmacokinetics and pharmacodynamics of AMG 811,an antiinterferon-γmonoclonal antibody,in SLE subjects without or with lupus nephritis[J].Lupus Sci Med,2017,4(1):e000226.
[43]Wang JH,New JS,Xie S,et al.Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice[J].Arthritis Rheum,2013,65(10):2703-2712.
[44]Han JH,Umiker BR,Kazimirova AA,et al.Expression of an antiRNA autoantibody in a mouse model of SLE increases neutrophil and monocyte numbers as well as IFN-I expression[J].Eur JImmunol,2014,44(1):215-226.
[45]Liu Z.Taming lupus-a new understanding of pathogenesis is leading to clinical advances[J].Nat Med,2012,18(6):871-882.
[46]Allen CD,Okada T.Germinal-center organization and cellular dynamics[J].Immunity,2007,27(2):190-202.
[47]Cappione A,Anolik JH,Pugh-Bernard A,et al.Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus[J].J Clin Invest,2005,115(11):3205-3216.
[48]Vin uesa CG,Sanz I.Dysregulation of germinal centres in autoimmune disease[J].Nat Rev Immunol,2009,9(12):845-857.
[49]Nem azee D.Receptor editing in lymphocyte development and central tolerance[J].Nat Rev Immunol,2006,6(10):728-740.
[50]Li X,Ptacek TS,Brown EE.Fcgamma receptors:structure,function and role as genetic risk factors in SLE[J].Genes Immun,2009,10(5):380-389.
[51]Ren D,Liu F,Dong G,et al.Activation of TLR7 increases CCND3expression via the downregulation of miR-15b in B cells of systemic lupus erythematosus[J].Cell Mol Immunol,2016,13(6):764-775.
[52]Liu Z,Zou Y.Plasma cells in systemic lupus erythematosus:the long and short of it all[J].Eur J Immunol,2011,41(3):588-591.
[53]Zou ali M.B lymphocyte signaling pathways in systemic autoimmunity:implications for pathogenesis and treatment[J].Arthritis Rheum,2004,50(9):2730-2741.
[54]Liossis SN,Solomou EE,Dimopoulos MA,et al.B-cell kinase lyn deficiency in patients with systemic lupus erythematosus[J].JInvest Med,2001,49(2):157-165.
[55]Flores-Borja F,Kabouridis PS,Jury EC,et al.Decreased Lyn expression and translocation to lipid raft signaling domains in Blymphocytes from patients with systemic lupus erythematosus[J].Arthritis Rheum,2005,52(12):3955-3965.
[56]Green NM.Toll-like receptor driven B cell activation in the induction of systemic autoimmunity[J].Semin Immunol,2011,23(2):106-112.
[57]Geh D.Epratuzumab for the treatment of systemic lupus erythematosus[J].Exp Rev Clin Immunol,2018,14(4):245-258.
[58]Wallace DJ.Epratuzumab for systemic lupus erythematosus[J].Lupus,2013,22(4):400-405.
[59]Clowse ME,Wallace DJ,Furie RA,et al.Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus:results from two phase III randomized,doubleblind,placebo-controlled trials[J].Arthritis Rheumatol,2017,69(2):362-375.
[60]Clark EA.CD22:A regulator of innate and adaptive B cell responses and autoimmunity[J].Front Immunol,2018,9:2235.