B Cell Immunity

  • Lee Ann Garrett-SinhaEmail author


B cells and the antibodies they secrete are crucial for responding to certain pathogens, as shown by the clinical presentation of patients who lack B cells or antibodies. Such patients show increased susceptibility toward recurrent and/or severe bacterial infections, particularly with encapsulated bacteria. In this chapter, we review basic B cell biology in humans and in mice, including new insights that have been gained recently. Information covered in this chapter includes the types of B cells found in the body, the role of surface receptors in activating B cells, B cell interactions with T cells, formation of germinal centers, isotype switching, affinity maturation, and the production of memory B cells and antibody-secreting plasma cells. Although much has been learned about B cells and how they function in immune responses, questions still remain about the exact mechanisms that control their activation and differentiation programs. Future studies will help to fill in these details and give us a complete picture of how B cells contribute to immunity in response to infectious diseases.


Follicular B cell Marginal zone B cell B-1 B cell Regulatory B cell Memory B cell Plasma cell Somatic hypermutation Affinity maturation Germinal center T-dependent response T-independent response 


  1. 1.
    Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999;189(10):1639–48.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Rubtsov AV, Rubtsova K, Kappler JW, Jacobelli J, Friedman RS, Marrack P. CD11c-expressing B cells are located at the T cell/B cell border in spleen and are potent APCs. J Immunol. 2015;195(1):71–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Molnarfi N, Schulze-Topphoff U, Weber MS, Patarroyo JC, Prod’homme T, Varrin-Doyer M, et al. MHC class II-dependent B cell APC function is required for induction of CNS autoimmunity independent of myelin-specific antibodies. J Exp Med. 2013;210(13):2921–37.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Liu Q, Liu Z, Rozo CT, Hamed HA, Alem F, Urban JF Jr, et al. The role of B cells in the development of CD4 effector T cells during a polarized Th2 immune response. J Immunol. 2007;179(6):3821–30.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lino AC, Dorner T, Bar-Or A, Fillatreau S. Cytokine-producing B cells: a translational view on their roles in human and mouse autoimmune diseases. Immunol Rev. 2016;269(1):130–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Bao Y, Cao X. The immune potential and immunopathology of cytokine-producing B cell subsets: a comprehensive review. J Autoimmun. 2014;55:10–23.PubMedCrossRefGoogle Scholar
  7. 7.
    Clark MR, Mandal M, Ochiai K, Singh H. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol. 2014;14(2):69–80.PubMedCrossRefGoogle Scholar
  8. 8.
    Ichii M, Oritani K, Kanakura Y. Early B lymphocyte development: similarities and differences in human and mouse. World J Stem Cells. 2014;6(4):421–31.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Sen R, Oltz E. Genetic and epigenetic regulation of IgH gene assembly. Curr Opin Immunol. 2006;18(3):237–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Coffman RL, Cohn M. The class of surface immunoglobulin on virgin and memory B lymphocytes. J Immunol. 1977;118(5):1806–15.PubMedGoogle Scholar
  11. 11.
    Abney ER, Cooper MD, Kearney JF, Lawton AR, Parkhouse RM. Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity. J Immunol. 1978;120(6):2041–9.PubMedGoogle Scholar
  12. 12.
    Blattner FR, Tucker PW. The molecular biology of immunoglobulin D. Nature. 1984;307(5950):417–22.PubMedCrossRefGoogle Scholar
  13. 13.
    Stavnezer J, Schrader CE. IgH chain class switch recombination: mechanism and regulation. J Immunol. 2014;193(11):5370–8.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12(12):821–32.PubMedCrossRefGoogle Scholar
  16. 16.
    Oettgen HC, Burton OT. IgE and mast cells: the endogenous adjuvant. Adv Immunol. 2015;127:203–56.PubMedCrossRefGoogle Scholar
  17. 17.
    Victora GD, Nussenzweig MC. Germinal centers. Annu Rev Immunol. 2012;30:429–57.PubMedCrossRefGoogle Scholar
  18. 18.
    Alt FW, Bothwell AL, Knapp M, Siden E, Mather E, Koshland M, et al. Synthesis of secreted and membrane-bound immunoglobulin mu heavy chains is directed by mRNAs that differ at their 3′ ends. Cell. 1980;20(2):293–301.PubMedCrossRefGoogle Scholar
  19. 19.
    Shell SA, Martincic K, Tran J, Milcarek C. Increased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and loading of polyadenylation and cotranscriptional factors contribute to regulation of the ig heavy chain mRNA in plasma cells. J Immunol. 2007;179(11):7663–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Hobeika E, Nielsen PJ, Medgyesi D. Signaling mechanisms regulating B-lymphocyte activation and tolerance. J Mol Med (Berl). 2015;93(2):143–58.CrossRefGoogle Scholar
  21. 21.
    Batten M, Groom J, Cachero TG, Qian F, Schneider P, Tschopp J, et al. BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med. 2000;192(10):1453–66.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Thompson JS, Schneider P, Kalled SL, Wang L, Lefevre EA, Cachero TG, et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J Exp Med. 2000;192(1):129–35.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999;189(11):1747–56.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Shu HB, Hu WH, Johnson H. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol. 1999;65(5):680–3.PubMedCrossRefGoogle Scholar
  25. 25.
    Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999;285(5425):260–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Khare SD, Sarosi I, Xia XZ, McCabe S, Miner K, Solovyev I, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci U S A. 2000;97(7):3370–5.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Vossenkamper A, Spencer J. Transitional B cells: how well are the checkpoints for specificity understood? Arch Immunol Ther Exp. 2011;59(5):379–84.CrossRefGoogle Scholar
  28. 28.
    Allman D, Pillai S. Peripheral B cell subsets. Curr Opin Immunol. 2008;20(2):149–57.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Cariappa A, Boboila C, Moran ST, Liu H, Shi HN, Pillai S. The recirculating B cell pool contains two functionally distinct, long-lived, posttransitional, follicular B cell populations. J Immunol. 2007;179(4):2270–81.PubMedCrossRefGoogle Scholar
  30. 30.
    Cerutti A, Cols M, Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol. 2013;13(2):118–32.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Martin F, Kearney JF. Marginal-zone B cells. Nat Rev Immunol. 2002;2(5):323–35.PubMedCrossRefGoogle Scholar
  32. 32.
    Hayakawa K, Hardy RR, Herzenberg LA, Herzenberg LA. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med. 1985;161(6):1554–68.PubMedCrossRefGoogle Scholar
  33. 33.
    Hayakawa K, Hardy RR, Stall AM, Herzenberg LA, Herzenberg LA. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur J Immunol. 1986;16(10):1313–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Hayakawa K, Hardy RR, Honda M, Herzenberg LA, Steinberg AD, Herzenberg LA. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci U S A. 1984;81(8):2494–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ehrenstein MR, Notley CA. The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol. 2010;10(11):778–86.PubMedCrossRefGoogle Scholar
  36. 36.
    Suzuki K, Maruya M, Kawamoto S, Fagarasan S. Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity. Immunol Rev. 2010;237(1):180–90.PubMedCrossRefGoogle Scholar
  37. 37.
    Martin F, Oliver AM, Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity. 2001;14(5):617–29.PubMedCrossRefGoogle Scholar
  38. 38.
    Lopes-Carvalho T, Foote J, Kearney JF. Marginal zone B cells in lymphocyte activation and regulation. Curr Opin Immunol. 2005;17(3):244–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Rubtsov AV, Swanson CL, Troy S, Strauch P, Pelanda R, Torres RM. TLR agonists promote marginal zone B cell activation and facilitate T-dependent IgM responses. J Immunol. 2008;180(6):3882–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Shen P, Roch T, Lampropoulou V, O’Connor RA, Stervbo U, Hilgenberg E, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002;16(2):219–30.PubMedCrossRefGoogle Scholar
  42. 42.
    Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3(10):944–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Kaku H, Cheng KF, Al-Abed Y, Rothstein TL. A novel mechanism of B cell-mediated immune suppression through CD73 expression and adenosine production. J Immunol. 2014;193(12):5904–13.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Zhang HP, Wu Y, Liu J, Jiang J, Geng XR, Yang G, et al. TSP1-producing B cells show immune regulatory property and suppress allergy-related mucosal inflammation. Sci Rep. 2013;3:3345.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ding T, Yan F, Cao S, Ren X. Regulatory B cell: new member of immunosuppressive cell club. Hum Immunol. 2015;76(9):615–21.PubMedCrossRefGoogle Scholar
  46. 46.
    Ray A, Wang L, Dittel BN. IL-10-independent regulatory B-cell subsets and mechanisms of action. Int Immunol. 2015;27(10):531–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28(5):639–50.PubMedCrossRefGoogle Scholar
  48. 48.
    Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, et al. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol. 2007;178(12):7868–78.PubMedCrossRefGoogle Scholar
  49. 49.
    Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 2011;121(9):3645–56.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Neves P, Lampropoulou V, Calderon-Gomez E, Roch T, Stervbo U, Shen P, et al. Signaling via the MyD88 adaptor protein in B cells suppresses protective immunity during Salmonella typhimurium infection. Immunity. 2010;33(5):777–90.PubMedCrossRefGoogle Scholar
  51. 51.
    Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.PubMedCrossRefGoogle Scholar
  52. 52.
    Kjeldsen MK, Perez-Andres M, Schmitz A, Johansen P, Boegsted M, Nyegaard M, et al. Multiparametric flow cytometry for identification and fluorescence activated cell sorting of five distinct B-cell subpopulations in normal tonsil tissue. Am J Clin Pathol. 2011;136(6):960–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Kaminski DA, Wei C, Qian Y, Rosenberg AF, Sanz I. Advances in human B cell phenotypic profiling. Front Immunol. 2012;3:302.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Dunn-Walters DK, Isaacson PG, Spencer J. Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med. 1995;182(2):559–66.PubMedCrossRefGoogle Scholar
  55. 55.
    Tangye SG, Liu YJ, Aversa G, Phillips JH, de Vries JE. Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med. 1998;188(9):1691–703.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Weller S, Braun MC, Tan BK, Rosenwald A, Cordier C, Conley ME, et al. Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood. 2004;104(12):3647–54.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Descatoire M, Weller S, Irtan S, Sarnacki S, Feuillard J, Storck S, et al. Identification of a human splenic marginal zone B cell precursor with NOTCH2-dependent differentiation properties. J Exp Med. 2014;211(5):987–1000.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity. 2003;18(5):675–85.PubMedCrossRefGoogle Scholar
  59. 59.
    Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105(11):4390–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med. 2011;208(1):67–80.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Perez-Andres M, Grosserichter-Wagener C, Teodosio C, van Dongen JJ, Orfao A, van Zelm MC. The nature of circulating CD27+CD43+ B cells. J Exp Med. 2011;208(13):2565–6.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Descatoire M, Weill JC, Reynaud CA, Weller S. A human equivalent of mouse B-1 cells? J Exp Med. 2011;208(13):2563–4.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Griffin DO, Holodick NE, Rothstein TL. Human B1 cells are CD3-: a reply to “a human equivalent of mouse B-1 cells?” and “the nature of circulating CD27+CD43+ B cells”. J Exp Med. 2011;208(13):2566–9.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Yammani RD, Haas KM. Primate B-1 cells generate antigen-specific B cell responses to T cell-independent type 2 antigens. J Immunol. 2013;190(7):3100–8.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–41.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic Lupus Erythematosus patients. Immunity. 2010;32(1):129–40.PubMedCrossRefGoogle Scholar
  67. 67.
    Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol. 2007;178(10):6092–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Todd SK, Pepper RJ, Draibe J, Tanna A, Pusey CD, Mauri C, et al. Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford). 2014;53(9):1693–703.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Bortnick A, Murre C. Cellular and chromatin dynamics of antibody-secreting plasma cells. Wiley Interdisc Rev Dev Biol. 2015;5(2):136–49.CrossRefGoogle Scholar
  70. 70.
    Mandik L, Nguyen KA, Erikson J. Fas receptor expression on B-lineage cells. Eur J Immunol. 1995;25(11):3148–54.PubMedCrossRefGoogle Scholar
  71. 71.
    Cervenak L, Magyar A, Boja R, Laszlo G. Differential expression of GL7 activation antigen on bone marrow B cell subpopulations and peripheral B cells. Immunol Lett. 2001;78(2):89–96.PubMedCrossRefGoogle Scholar
  72. 72.
    Pascual V, Liu YJ, Magalski A, de Bouteiller O, Banchereau J, Capra JD. Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med. 1994;180(1):329–39.PubMedCrossRefGoogle Scholar
  73. 73.
    De Silva NS, Klein U. Dynamics of B cells in germinal centres. Nat Rev Immunol. 2015;15(3):137–48.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Daniel JA, Nussenzweig A. The AID-induced DNA damage response in chromatin. Mol Cell. 2013;50(3):309–21.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Heesters BA, Myers RC, Carroll MC. Follicular dendritic cells: dynamic antigen libraries. Nat Rev Immunol. 2014;14(7):495–504.PubMedCrossRefGoogle Scholar
  76. 76.
    Craft JE. Follicular helper T cells in immunity and systemic autoimmunity. Nat Rev Rheumatol. 2012;8(6):337–47.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Schwickert TA, Victora GD, Fooksman DR, Kamphorst AO, Mugnier MR, Gitlin AD, et al. A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med. 2011;208(6):1243–52.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kurosaki T, Kometani K, Ise W. Memory B cells. Nat Rev Immunol. 2015;15(3):149–59.PubMedCrossRefGoogle Scholar
  79. 79.
    Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K. Generation of memory B cells inside and outside germinal centers. Eur J Immunol. 2014;44(5):1258–64.PubMedCrossRefGoogle Scholar
  80. 80.
    Taylor JJ, Pape KA, Jenkins MK. A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med. 2012;209(3):597–606.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Kaji T, Ishige A, Hikida M, Taka J, Hijikata A, Kubo M, et al. Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. J Exp Med. 2012;209(11):2079–97.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Alugupalli KR, Leong JM, Woodland RT, Muramatsu M, Honjo T, Gerstein RM. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity. 2004;21(3):379–90.PubMedCrossRefGoogle Scholar
  83. 83.
    Obukhanych TV, Nussenzweig MC. T-independent type II immune responses generate memory B cells. J Exp Med. 2006;203(2):305–10.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Yang Y, Ghosn EE, Cole LE, Obukhanych TV, Sadate-Ngatchou P, Vogel SN, et al. Antigen-specific memory in B-1a and its relationship to natural immunity. Proc Natl Acad Sci U S A. 2012;109(14):5388–93.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Klein U, Rajewsky K, Kuppers R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998;188(9):1679–89.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Xiao Y, Hendriks J, Langerak P, Jacobs H, Borst J. CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation. J Immunol. 2004;172(12):7432–41.PubMedCrossRefGoogle Scholar
  87. 87.
    Tomayko MM, Steinel NC, Anderson SM, Shlomchik MJ. Cutting edge: hierarchy of maturity of murine memory B cell subsets. J Immunol. 2010;185(12):7146–50.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Anderson SM, Tomayko MM, Ahuja A, Haberman AM, Shlomchik MJ. New markers for murine memory B cells that define mutated and unmutated subsets. J Exp Med. 2007;204(9):2103–14.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Zuccarino-Catania GV, Sadanand S, Weisel FJ, Tomayko MM, Meng H, Kleinstein SH, et al. CD80 and PD-L2 define functionally distinct memory B cell subsets that are independent of antibody isotype. Nat Immunol. 2014;15(7):631–7.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Dogan I, Bertocci B, Vilmont V, Delbos F, Megret J, Storck S, et al. Multiple layers of B cell memory with different effector functions. Nat Immunol. 2009;10(12):1292–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Weisel FJ, Zuccarino-Catania GV, Chikina M, Shlomchik MJ. A temporal switch in the germinal center determines differential output of memory B and plasma cells. Immunity. 2016;44(1):116–30.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Bayles I, Milcarek C. Plasma cell formation, secretion, and persistence: the short and the long of it. Crit Rev Immunol. 2014;34(6):481–99.PubMedCrossRefGoogle Scholar
  93. 93.
    Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med. 2006;203(4):1081–91.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    O’Connor BP, Vogel LA, Zhang W, Loo W, Shnider D, Lind EF, et al. Imprinting the fate of antigen-reactive B cells through the affinity of the B cell receptor. J Immunol. 2006;177(11):7723–32.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Oracki SA, Walker JA, Hibbs ML, Corcoran LM, Tarlinton DM. Plasma cell development and survival. Immunol Rev. 2010;237(1):140–59.PubMedCrossRefGoogle Scholar
  96. 96.
    Bortnick A, Chernova I, Quinn WJ 3rd, Mugnier M, Cancro MP, Allman D. Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens. J Immunol. 2012;188(11):5389–96.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015;15(3):160–71.PubMedCrossRefGoogle Scholar
  98. 98.
    Benson MJ, Dillon SR, Castigli E, Geha RS, Xu S, Lam KP, et al. Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol. 2008;180(6):3655–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Belnoue E, Pihlgren M, McGaha TL, Tougne C, Rochat AF, Bossen C, et al. APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood. 2008;111(5):2755–64.PubMedCrossRefGoogle Scholar
  100. 100.
    O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med. 2004;199(1):91–8.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Cassese G, Arce S, Hauser AE, Lehnert K, Moewes B, Mostarac M, et al. Plasma cell survival is mediated by synergistic effects of cytokines and adhesion-dependent signals. J Immunol. 2003;171(4):1684–90.PubMedCrossRefGoogle Scholar
  102. 102.
    Rozanski CH, Utley A, Carlson LM, Farren MR, Murray M, Russell LM, et al. CD28 promotes plasma cell survival, sustained antibody responses, and BLIMP-1 upregulation through its distal PYAP proline motif. J Immunol. 2015;194(10):4717–28.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Njau MN, Kim JH, Chappell CP, Ravindran R, Thomas L, Pulendran B, et al. CD28-B7 interaction modulates short- and long-lived plasma cell function. J Immunol. 2012;189(6):2758–67.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Medvedovic J, Ebert A, Tagoh H, Busslinger M. Pax5: a master regulator of B cell development and leukemogenesis. Adv Immunol. 2011;111:179–206.PubMedCrossRefGoogle Scholar
  105. 105.
    Garrett-Sinha LA. Review of Ets1 structure, function, and roles in immunity. Cell Mol life Sci : CMLS. 2013;70:3375–90.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Carotta S, Wu L, Nutt SL. Surprising new roles for PU.1 in the adaptive immune response. Immunol Rev. 2010;238(1):63–75.PubMedCrossRefGoogle Scholar
  107. 107.
    Boller S, Grosschedl R. The regulatory network of B-cell differentiation: a focused view of early B-cell factor 1 function. Immunol Rev. 2014;261(1):102–15.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Gardam S, Brink R. Non-canonical NF-kappaB signaling initiated by BAFF influences B cell biology at multiple junctures. Front Immunol. 2014;4:509.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Kaileh M, Sen R. NF-kappaB function in B lymphocytes. Immunol Rev. 2012;246(1):254–71.PubMedCrossRefGoogle Scholar
  110. 110.
    Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011;50(1):87–96.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Kane A, Deenick EK, Ma CS, Cook MC, Uzel G, Tangye SG. STAT3 is a central regulator of lymphocyte differentiation and function. Curr Opin Immunol. 2014;28:49–57.PubMedCrossRefGoogle Scholar
  112. 112.
    De Silva NS, Simonetti G, Heise N, Klein U. The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunol Rev. 2012;247(1):73–92.PubMedCrossRefGoogle Scholar
  113. 113.
    Lien C, Fang CM, Huso D, Livak F, Lu R, Pitha PM. Critical role of IRF-5 in regulation of B-cell differentiation. Proc Natl Acad Sci U S A. 2010;107(10):4664–8.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Wang H, Morse HC 3rd. IRF8 regulates myeloid and B lymphoid lineage diversification. Immunol Res. 2009;43(1–3):109–17.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Basso K, Dalla-Favera R. Roles of BCL6 in normal and transformed germinal center B cells. Immunol Rev. 2012;247(1):172–83.PubMedCrossRefGoogle Scholar
  116. 116.
    Igarashi K, Ochiai K, Itoh-Nakadai A, Muto A. Orchestration of plasma cell differentiation by Bach2 and its gene regulatory network. Immunol Rev. 2014;261(1):116–25.PubMedCrossRefGoogle Scholar
  117. 117.
    Kwon K, Hutter C, Sun Q, Bilic I, Cobaleda C, Malin S, et al. Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. Immunity. 2008;28(6):751–62.PubMedCrossRefGoogle Scholar
  118. 118.
    Su GH, Chen HM, Muthusamy N, Garrett-Sinha LA, Baunoch D, Tenen DG, et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J. 1997;16(23):7118–29.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Lee CH, Melchers M, Wang H, Torrey TA, Slota R, Qi CF, et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J Exp Med. 2006;203(1):63–72.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Chiu YK, Lin IY, Su ST, Wang KH, Yang SY, Tsai DY, et al. Transcription factor ABF-1 suppresses plasma cell differentiation but facilitates memory B cell formation. J Immunol. 2014;193(5):2207–17.PubMedCrossRefGoogle Scholar
  121. 121.
    Heise N, De Silva NS, Silva K, Carette A, Simonetti G, Pasparakis M, et al. Germinal center B cell maintenance and differentiation are controlled by distinct NF-kappaB transcription factor subunits. J Exp Med. 2014;211(10):2103–18.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD. The genetic network controlling plasma cell differentiation. Semin Immunol. 2011;23(5):341–9.PubMedCrossRefGoogle Scholar
  123. 123.
    Glimcher LH. XBP1: the last two decades. Ann Rheum Dis. 2010;69(Suppl 1):i67–71.PubMedCrossRefGoogle Scholar
  124. 124.
    Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, et al. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. J Exp Med. 2014;211(5):827–40.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Cirillo E, Giardino G, Gallo V, D’Assante R, Grasso F, Romano R, et al. Severe combined immunodeficiency – an update. Ann N Y Acad Sci. 2015;1356:90–106.PubMedCrossRefGoogle Scholar
  126. 126.
    Vihinen M, Mattsson PT, Smith CI. Bruton tyrosine kinase (BTK) in X-linked agammaglobulinemia (XLA). Front Biosci. 2000;5:D917–28.PubMedGoogle Scholar
  127. 127.
    Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545–56. quiz 57PubMedCrossRefGoogle Scholar
  128. 128.
    Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A. Selective IgA deficiency: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Scand J Immunol. 2017;85(1):3–12.PubMedCrossRefGoogle Scholar
  129. 129.
    Wahn V, von Bernuth H. Short review: IgG subclass deficiencies in children: facts and fiction. Pediatr Allergy Immunol. 2017;28(6):521–4.PubMedCrossRefGoogle Scholar
  130. 130.
    Qamar N, Fuleihan RL. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014;46(2):120–30.PubMedCrossRefGoogle Scholar
  131. 131.
    Mogensen TH. STAT3 and the Hyper-IgE syndrome: clinical presentation, genetic origin, pathogenesis, novel findings and remaining uncertainties. JAKSTAT. 2013;2(2):23435.Google Scholar
  132. 132.
    Buchbinder D, Nugent DJ, Fillipovich AH. Wiskott-Aldrich syndrome: diagnosis, current management, and emerging treatments. Appl Clin Genet. 2014;7:55–66.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    McKinnon PJ. ATM and ataxia telangiectasia. EMBO Rep. 2004;5(8):772–6.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Al Ustwani O, Kurzrock R, Wetzler M. Genetics on a WHIM. Br J Haematol. 2014;164(1):15–23.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry, Center of Excellence in Bioinformatics and Life SciencesState University of New York at BuffaloBuffaloUSA

Personalised recommendations