Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development. However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Nieuwenhuis P, Opstelten D. 1.  1984. Functional anatomy of germinal centers. Am. J. Anat. 170:421–35 [Google Scholar]
  2. Fugmann SD, Lee AI, Shockett PE, Villey IJ, Schatz DG. 2.  2000. The RAG proteins and V(D)J recombination: complexes, ends, and transposition. Annu. Rev. Immunol. 18:495–527 [Google Scholar]
  3. Plotkin SA, Orenstein WA, Offit PA. 3.  2008. Vaccines Philadelphia: Elsevier
  4. Goodnow CC. 4.  1992. Transgenic mice and analysis of B-cell tolerance. Annu. Rev. Immunol. 10:489–518 [Google Scholar]
  5. Cornall RJ, Goodnow CC, Cyster JG. 5.  1995. The regulation of self-reactive B cells. Curr. Opin. Immunol. 7:804–11 [Google Scholar]
  6. Nemazee D. 6.  2017. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17:281–94 [Google Scholar]
  7. Chan TD, Wood K, Hermes JR, Butt D, Jolly CJ. 7.  et al. 2012. Elimination of germinal-center-derived self-reactive B cells is governed by the location and concentration of self-antigen. Immunity 37:893–904 [Google Scholar]
  8. Brink R. 8.  2014. The imperfect control of self-reactive germinal center B cells. Curr. Opin. Immunol. 28:97–101 [Google Scholar]
  9. Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC. 9.  2003. Predominant autoantibody production by early human B cell precursors. Science 301:1374–77 [Google Scholar]
  10. Nemazee DA, Burki K. 10.  1989. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337:562–66 [Google Scholar]
  11. Hartley SB, Cooke MP, Fulcher DA, Harris AW, Cory S. 11.  et al. 1993. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72:325–35 [Google Scholar]
  12. Russell DM, Dembic Z, Morahan G, Miller JF, Burki K, Nemazee D. 12.  1991. Peripheral deletion of self-reactive B cells. Nature 354:308–11 [Google Scholar]
  13. Ota T, Ota M, Duong BH, Gavin AL, Nemazee D. 13.  2011. Liver-expressed Igκ superantigen induces tolerance of polyclonal B cells by clonal deletion not κ to λ receptor editing. J. Exp. Med. 208:617–29 [Google Scholar]
  14. Yau IW, Cato MH, Jellusova J, Hurtado de Mendoza T, Brink R, Rickert RC. 14.  2013. Censoring of self-reactive B cells by follicular dendritic cell-displayed self-antigen. J. Immunol. 191:1082–90 [Google Scholar]
  15. Gay D, Saunders T, Camper S, Weigert M. 15.  1993. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177:999–1008 [Google Scholar]
  16. Tiegs SL, Russell DM, Nemazee D. 16.  1993. Receptor editing in self-reactive bone marrow B cells. J. Exp. Med. 177:1009–20 [Google Scholar]
  17. Nemazee D. 17.  2006. Receptor editing in lymphocyte development and central tolerance. Nat. Rev. Immunol. 6:728–40 [Google Scholar]
  18. Quach TD, Manjarrez-Orduno N, Adlowitz DG, Silver L, Yang H. 18.  et al. 2011. Anergic responses characterize a large fraction of human autoreactive naive B cells expressing low levels of surface IgM. J. Immunol. 186:4640–48 [Google Scholar]
  19. Zikherman J, Parameswaran R, Weiss A. 19.  2012. Endogenous antigen tunes the responsiveness of naive B cells but not T cells. Nature 489:160–64 [Google Scholar]
  20. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ. 20.  et al. 1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334:676–82 [Google Scholar]
  21. Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC. 21.  1991. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353:765–69 [Google Scholar]
  22. Goodnow CC, Crosbie J, Jorgensen H, Brink RA, Basten A. 22.  1989. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342:385–91 [Google Scholar]
  23. Sabouri Z, Schofield P, Horikawa K, Spierings E, Kipling D. 23.  et al. 2014. Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. PNAS 111:E2567–75 [Google Scholar]
  24. Akkaraju S, Canaan K, Goodnow CC. 24.  1997. Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J. Exp. Med. 186:2005–12 [Google Scholar]
  25. Aplin BD, Keech CL, de Kauwe AL, Gordon TP, Cavill D, McCluskey J. 25.  2003. Tolerance through indifference: autoreactive B cells to the nuclear antigen La show no evidence of tolerance in a transgenic model. J. Immunol. 171:5890–900 [Google Scholar]
  26. Brink R. 26.  2006. Regulation of B cell self-tolerance by BAFF. Semin. Immunol. 18:276–83 [Google Scholar]
  27. Mond JJ, Lees A, Snapper CM. 27.  1995. T cell-independent antigens type 2. Annu. Rev. Immunol. 13:655–92 [Google Scholar]
  28. Harwood NE, Batista FD. 28.  2010. Early events in B cell activation. Annu. Rev. Immunol. 28:185–210 [Google Scholar]
  29. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW. 29.  et al. 1999. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 286:1735–38 [Google Scholar]
  30. Enders A, Bouillet P, Puthalakath H, Xu Y, Tarlinton DM, Strasser A. 30.  2003. Loss of the pro-apoptotic BH3-only Bcl-2 family member Bim inhibits BCR stimulation-induced apoptosis and deletion of autoreactive B cells. J. Exp. Med. 198:1119–26 [Google Scholar]
  31. Bretscher P, Cohn M. 31.  1970. A theory of self-nonself discrimination. Science 169:1042–49 [Google Scholar]
  32. Cooke MP, Heath AW, Shokat KM, Zeng Y, Finkelman FD. 32.  et al. 1994. Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179:425–38 [Google Scholar]
  33. Healy JI, Dolmetsch RE, Timmerman LA, Cyster JG, Thomas ML. 33.  et al. 1997. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6:419–28 [Google Scholar]
  34. Fulcher DA, Basten A. 34.  1994. Reduced life span of anergic self-reactive B cells in a double-transgenic model. J. Exp. Med. 179:125–34 [Google Scholar]
  35. Phan TG, Amesbury M, Gardam S, Crosbie J, Hasbold J. 35.  et al. 2003. B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive B cells. J. Exp. Med. 197:845–60 [Google Scholar]
  36. Eris JM, Basten A, Brink R, Doherty K, Kehry MR, Hodgkin PD. 36.  1994. Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. PNAS 91:4392–96 [Google Scholar]
  37. Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC. 37.  1996. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 87:319–29 [Google Scholar]
  38. Garrone P, Neidhardt EM, Garcia E, Galibert L, van Kooten C, Banchereau J. 38.  1995. Fas ligation induces apoptosis of CD40-activated human B lymphocytes. J. Exp. Med. 182:1265–73 [Google Scholar]
  39. Rathmell JC, Cooke MP, Ho WY, Grein J, Townsend SE. 39.  et al. 1995. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature 376:181–84 [Google Scholar]
  40. Rathmell JC, Goodnow CC. 40.  1994. Effects of the lpr mutation on elimination and inactivation of self-reactive B cells. J. Immunol. 153:2831–42 [Google Scholar]
  41. Rubio CF, Kench J, Russell DM, Yawger R, Nemazee D. 41.  1996. Analysis of central B cell tolerance in autoimmune-prone MRL/lpr mice bearing autoantibody transgenes. J. Immunol. 157:65–71 [Google Scholar]
  42. Ho WY, Cooke MP, Goodnow CC, Davis MM. 42.  1994. Resting and anergic B cells are defective in CD28-dependent costimulation of naive CD4+ T cells. J. Exp. Med. 179:1539–49 [Google Scholar]
  43. Rathmell JC, Fournier S, Weintraub BC, Allison JP, Goodnow CC. 43.  1998. Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4+ T cells. J. Exp. Med. 188:651–59 [Google Scholar]
  44. Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H. 44.  2007. Autoreactivity in human IgG+ memory B cells. Immunity 26:205–13 [Google Scholar]
  45. Tiller T, Kofer J, Kreschel C, Busse CE, Riebel S. 45.  et al. 2010. Development of self-reactive germinal center B cells and plasma cells in autoimmune Fc γRIIB-deficient mice. J. Exp. Med. 207:2767–78 [Google Scholar]
  46. Chan TD, Gatto D, Wood K, Camidge T, Basten A, Brink R. 46.  2009. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J. Immunol. 183:3139–49 [Google Scholar]
  47. Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R. 47.  2006. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J. Exp. Med. 203:1081–91 [Google Scholar]
  48. Schwickert TA, Victora GD, Fooksman DR, Kamphorst AO, Mugnier MR. 48.  et al. 2011. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J. Exp. Med. 208:1243–52 [Google Scholar]
  49. Toyama H, Okada S, Hatano M, Takahashi Y, Takeda N. 49.  et al. 2002. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17:329–39 [Google Scholar]
  50. Fukuda T, Yoshida T, Okada S, Hatano M, Miki T. 50.  et al. 1997. Disruption of the Bcl6 gene results in an impaired germinal center formation. J. Exp. Med. 186:439–48 [Google Scholar]
  51. Dent AL, Shaffer AL, Yu X, Allman D, Staudt LM. 51.  1997. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276:589–92 [Google Scholar]
  52. Kitano M, Moriyama S, Ando Y, Hikida M, Mori Y. 52.  et al. 2011. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34:961–72 [Google Scholar]
  53. Victora GD, Nussenzweig MC. 53.  2012. Germinal centers. Annu. Rev. Immunol. 30:429–57 [Google Scholar]
  54. Huang C, Gonzalez DG, Cote CM, Jiang Y, Hatzi K. 54.  et al. 2014. The BCL6 RD2 domain governs commitment of activated B cells to form germinal centers. Cell Rep 8:1497–508 [Google Scholar]
  55. Gatto D, Paus D, Basten A, Mackay CR, Brink R. 55.  2009. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31:259–69 [Google Scholar]
  56. Pereira JP, Kelly LM, Xu Y, Cyster JG. 56.  2009. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460:1122–26 [Google Scholar]
  57. Nojima T, Haniuda K, Moutai T, Matsudaira M, Mizokawa S. 57.  et al. 2011. In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivo. Nat. Commun. 2:465 [Google Scholar]
  58. Gatto D, Brink R. 58.  2010. The germinal center reaction. J. Allergy Clin. Immunol. 126:898–907 [Google Scholar]
  59. Corcoran LM, Tarlinton DM. 59.  2016. Regulation of germinal center responses, memory B cells and plasma cell formation—an update. Curr. Opin. Immunol. 39:59–67 [Google Scholar]
  60. Mesin L, Ersching J, Victora GD. 60.  2016. Germinal center B cell dynamics. Immunity 45:471–82 [Google Scholar]
  61. Vinuesa CG, Linterman MA, Yu D, MacLennan IC. 61.  2016. Follicular helper T cells. Annu. Rev. Immunol. 34:335–68 [Google Scholar]
  62. Allen CD, Ansel KM, Low C, Lesley R, Tamamura H. 62.  et al. 2004. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5:943–52 [Google Scholar]
  63. Victora GD, Schwickert TA, Fooksman DR, Kamphorst AO, Meyer-Hermann M. 63.  et al. 2010. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143:592–605 [Google Scholar]
  64. Krautler NJ, Suan D, Butt D, Bourne K, Hermes JR. 64.  et al. 2017. Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J. Exp. Med. 214:1259–67 [Google Scholar]
  65. Krautler NJ, Kana V, Kranich J, Tian Y, Perera D. 65.  et al. 2012. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150:194–206 [Google Scholar]
  66. Wang X, Cho B, Suzuki K, Xu Y, Green JA. 66.  et al. 2011. Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J. Exp. Med. 208:2497–510 [Google Scholar]
  67. Allen CD, Cyster JG. 67.  2008. Follicular dendritic cell networks of primary follicles and germinal centers: phenotype and function. Semin. Immunol. 20:14–25 [Google Scholar]
  68. Gatto D, Brink R. 68.  2013. B cell localization: regulation by EBI2 and its oxysterol ligand. Trends Immunol 34:336–41 [Google Scholar]
  69. El Shikh ME, El Sayed RM, Sukumar S, Szakal AK, Tew JG. 69.  2010. Activation of B cells by antigens on follicular dendritic cells. Trends Immunol 31:205–11 [Google Scholar]
  70. Goodnow CC, Vinuesa CG, Randall KL, Mackay F, Brink R. 70.  2010. Control systems and decision-making for antibody production. Nat. Immunol. 11:681–88 [Google Scholar]
  71. Ma CS, Phan TG. 71.  2017. Here, there and everywhere: T follicular helper cells on the move. Immunology 152:382–87 [Google Scholar]
  72. Wing JB, Ise W, Kurosaki T, Sakaguchi S. 72.  2014. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41:1013–25 [Google Scholar]
  73. Wang CJ, Heuts F, Ovcinnikovs V, Wardzinski L, Bowers C. 73.  et al. 2015. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. PNAS 112:524–29 [Google Scholar]
  74. Amiezer M, Phan TG. 74.  2016. Disentangling Tfr cells from Treg cells and Tfh cells: how to untie the Gordian knot. Eur. J. Immunol. 46:1101–4 [Google Scholar]
  75. Swartzendruber DC, Congdon CC. 75.  1963. Electron microscope observations on tingible body macrophages in mouse spleen. J. Cell Biol. 19:641–46 [Google Scholar]
  76. Smith JP, Lister AM, Tew JG, Szakal AK. 76.  1991. Kinetics of the tingible body macrophage response in mouse germinal center development and its depression with age. Anat. Rec. 229:511–20 [Google Scholar]
  77. Liu YJ, Johnson GD, Gordon J, MacLennan IC. 77.  1992. Germinal centres in T-cell-dependent antibody responses. Immunol. Today 13:17–21 [Google Scholar]
  78. Zaheen A, Boulianne B, Parsa JY, Ramachandran S, Gommerman JL, Martin A. 78.  2009. AID constrains germinal center size by rendering B cells susceptible to apoptosis. Blood 114:547–54 [Google Scholar]
  79. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M. 79.  et al. 2004. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304:1147–50 [Google Scholar]
  80. Kranich J, Krautler NJ, Heinen E, Polymenidou M, Bridel C. 80.  et al. 2008. Follicular dendritic cells control engulfment of apoptotic bodies by secreting Mfge8. J. Exp. Med. 205:1293–302 [Google Scholar]
  81. Rahman ZS, Shao WH, Khan TN, Zhen Y, Cohen PL. 81.  2010. Impaired apoptotic cell clearance in the germinal center by Mer-deficient tingible body macrophages leads to enhanced antibody-forming cell and germinal center responses. J. Immunol. 185:5859–68 [Google Scholar]
  82. Suan D, Sundling C, Brink R. 82.  2017. Plasma cell and memory B cell differentiation from the germinal center. Curr. Opin. Immunol. 45:97–102 [Google Scholar]
  83. Shinnakasu R, Kurosaki T. 83.  2017. Regulation of memory B and plasma cell differentiation. Curr. Opin. Immunol. 45:126–31 [Google Scholar]
  84. Phan TG, Paus D, Chan TD, Turner ML, Nutt SL. 84.  et al. 2006. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203:2419–24 [Google Scholar]
  85. Shinnakasu R, Inoue T, Kometani K, Moriyama S, Adachi Y. 85.  et al. 2016. Regulated selection of germinal-center cells into the memory B cell compartment. Nat. Immunol. 17:861–69 [Google Scholar]
  86. Suan D, Krautler NJ, Maag JLV, Butt D, Bourne K. 86.  et al. 2017. CCR6 defines memory B cell precursors in mouse and human germinal centers revealing light-zone location and predominant low antigen affinity. Immunity 47:1142–53 [Google Scholar]
  87. Wang Y, Shi J, Yan J, Xiao Z, Hou X. 87.  et al. 2017. Germinal-center development of memory B cells driven by IL-9 from follicular helper T cells. Nat. Immunol. 18:921–30 [Google Scholar]
  88. Charles ED, Orloff MI, Nishiuchi E, Marukian S, Rice CM, Dustin LB. 88.  2013. Somatic hypermutations confer rheumatoid factor activity in hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum 65:2430–40 [Google Scholar]
  89. Cho MJ, Lo AS, Mao X, Nagler AR, Ellebrecht CT. 89.  et al. 2014. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat. Commun. 5:4167 [Google Scholar]
  90. Thomas JW, Hulbert C. 90.  1996. Somatically mutated B cell pool provides precursors for insulin antibodies. J. Immunol. 157:763–71 [Google Scholar]
  91. Wellmann U, Letz M, Herrmann M, Angermuller S, Kalden JR, Winkler TH. 91.  2005. The evolution of human anti-double-stranded DNA autoantibodies. PNAS 102:9258–63 [Google Scholar]
  92. Mietzner B, Tsuiji M, Scheid J, Velinzon K, Tiller T. 92.  et al. 2008. Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. PNAS 105:9727–32 [Google Scholar]
  93. Guo W, Smith D, Aviszus K, Detanico T, Heiser RA, Wysocki LJ. 93.  2010. Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity. J. Exp. Med. 207:2225–37 [Google Scholar]
  94. Di Zenzo G, Di Lullo G, Corti D, Calabresi V, Sinistro A. 94.  et al. 2012. Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. J. Clin. Investig. 122:3781–90 [Google Scholar]
  95. Hargreaves CE, Grasso M, Hampe CS, Stenkova A, Atkinson S. 95.  et al. 2013. Yersiniaenterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves’ disease. J. Immunol. 190:5373–81 [Google Scholar]
  96. Amara K, Steen J, Murray F, Morbach H, Fernandez-Rodriguez BM. 96.  et al. 2013. Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 210:445–55 [Google Scholar]
  97. Meyer S, Woodward M, Hertel C, Vlaicu P, Haque Y. 97.  et al. 2016. AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies. Cell 166:582–95 [Google Scholar]
  98. Shokat KM, Goodnow CC. 98.  1995. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375:334–38 [Google Scholar]
  99. Pulendran B, Kannourakis G, Nouri S, Smith KG, Nossal GJ. 99.  1995. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 375:331–34 [Google Scholar]
  100. Han S, Zheng B, Dal Porto J, Kelsoe G. 100.  1995. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl: IV. Affinity-dependent, antigen-driven B cell apoptosis in germinal centers as a mechanism for maintaining self-tolerance. J. Exp. Med. 182:1635–44 [Google Scholar]
  101. Nagaoka H, Gonzalez-Aseguinolaza G, Tsuji M, Nussenzweig MC. 101.  2000. Immunization and infection change the number of recombination activating gene (RAG)-expressing B cells in the periphery by altering immature lymphocyte production. J. Exp. Med. 191:2113–20 [Google Scholar]
  102. Khalil AM, Cambier JC, Shlomchik MJ. 102.  2012. B cell receptor signal transduction in the GC is short-circuited by high phosphatase activity. Science 336:1178–81 [Google Scholar]
  103. Nowosad CR, Spillane KM, Tolar P. 103.  2016. Germinal center B cells recognize antigen through a specialized immune synapse architecture. Nat. Immunol. 17:870–77 [Google Scholar]
  104. Smith KG, Nossal GJ, Tarlinton DM. 104.  1995. FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen. PNAS 92:11628–32 [Google Scholar]
  105. Liu YJ, Barthelemy C, de Bouteiller O, Arpin C, Durand I, Banchereau J. 105.  1995. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity 2:239–48 [Google Scholar]
  106. Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG. 106.  et al. 1994. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76:969–76 [Google Scholar]
  107. Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA. 107.  et al. 1995. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 81:935–46 [Google Scholar]
  108. Hao Z, Duncan GS, Seagal J, Su YW, Hong C. 108.  et al. 2008. Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity 29:615–27 [Google Scholar]
  109. Takahashi Y, Ohta H, Takemori T. 109.  2001. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14:181–92 [Google Scholar]
  110. Butt D, Chan TD, Bourne K, Hermes JR, Nguyen A. 110.  et al. 2015. FAS inactivation releases unconventional germinal center B cells that escape antigen control and drive IgE and autoantibody production. Immunity 42:890–902 [Google Scholar]
  111. Reed JH, Jackson J, Christ D, Goodnow CC. 111.  2016. Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization. J. Exp. Med. 213:1255–65 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error