B-Cell Repertoire Changes in Mouse Models of Aging

  • Jean L. Scholz
  • William J. QuinnIII
  • Michael P. Cancro


Changes in the antibody repertoire are a well-established feature of immunosenescence. These reflect an aggregate of age-associated alterations in the generation, numbers, and proportions of B-cell subsets; as well as the homeostatic and selective processes governing them. A basic understanding of these relationships, coupled with integrated assessments of how they change with age, should reveal mechanisms underlying the immunosenescent phenotype. Mouse models provide powerful tools for these analyses, allowing controlled manipulation of key genetic, cellular, and microenvironmental factors. Here we summarize current understanding of how primary and antigen-experienced murine B-cell repertoires are established, as well as how they shift with age.


Aged Mouse Curr Opin Immunol Receptor Editing Semin Immunol Surrogate Light Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Allman D, Lindsley RC, DeMuth W, Rudd K, Shinton SA, Hardy RR (2001) Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J Immunol 167(12):6834–6840PubMedGoogle Scholar
  2. 2.
    Allman D, Miller JP (2003) Common lymphoid progenitors, early B-lineage precursors, and IL-7: characterizing the trophic and instructive signals underlying early B cell development. Immunol Res 27(2–3):131–140PubMedGoogle Scholar
  3. 3.
    Allman D, Miller JP (2005) The aging of early B-cell precursors. Immunol Rev 205:18–29PubMedGoogle Scholar
  4. 4.
    Allman D, Miller JP (2005) B cell development and receptor diversity during aging. Curr Opin Immunol 17(5):463–467PubMedGoogle Scholar
  5. 5.
    Allman D, Srivastava B, Lindsley RC (2004) Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells. Immunol Rev 197:147–160PubMedGoogle Scholar
  6. 6.
    Allman DM, Ferguson SE, Cancro MP (1992) Peripheral B cell maturation. I. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J Immunol 149(8):2533–2540PubMedGoogle Scholar
  7. 7.
    Allman DM, Ferguson SE, Lentz VM, Cancro MP (1993) Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J Immunol 151(9):4431–4444PubMedGoogle Scholar
  8. 8.
    Angelin-Duclos C, Cattoretti G, Lin KI, Calame K (2000) Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J Immunol 165(10):5462–5471PubMedGoogle Scholar
  9. 9.
    Arce S, Luger E, Muehlinghaus G, Cassese G, Hauser A, Horst A, Lehnert K, Odendahl M, Honemann D, Heller KD et al (2004) CD38 low IgG-secreting cells are precursors of various CD38 high-expressing plasma cell populations. J Leukoc Biol 75(6):1022–1028PubMedGoogle Scholar
  10. 10.
    Aspinall R, Andrew D (2000) Immunosenescence: potential causes and strategies for reversal. Biochem Soc Trans 28(2):250–254PubMedGoogle Scholar
  11. 11.
    Aw D, Silva AB, Palmer DB (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120(4):435–446PubMedGoogle Scholar
  12. 12.
    Barrat FS, Lesourd BM, Louise AS, Boulouis H, Thibault DJ, Neway T, Pilet CA (1999) Pregnancies modulate B lymphopoiesis and myelopoiesis during murine ageing. Immunology 98(4):604–611PubMedGoogle Scholar
  13. 13.
    Ben-Yehuda A, Szabo P, LeMaoult J, Manavalan JS, Weksler ME (1998) Increased VH 11 and VH Q52 gene use by splenic B cells in old mice associated with oligoclonal expansions of CD5 + B cells. Mech Ageing Dev 103(2):111–121PubMedGoogle Scholar
  14. 14.
    Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253–300PubMedGoogle Scholar
  15. 15.
    Borisova TK (2006) Role of cytokines in immune response to T-independent antigens, type 2. Zh Mikrobiol Epidemiol Immunobiol (1):44–47Google Scholar
  16. 16.
    Busslinger M (2004) Transcriptional control of early B cell development. Annu Rev Immunol 22:55–79PubMedGoogle Scholar
  17. 17.
    Busslinger M, Urbanek P (1995) The role of BSAP (Pax-5) in B-cell development. Curr Opin Genet Dev 5(5):595–601PubMedGoogle Scholar
  18. 18.
    Cancro MP (2004) The BLyS family of ligands and receptors: an archetype for niche-specific homeostatic regulation. Immunol Rev 202:237–249PubMedGoogle Scholar
  19. 19.
    Cancro MP (2005) B cells and aging: gauging the interplay of generative, selective, and homeostatic events. Immunol Rev 205:48–59PubMedGoogle Scholar
  20. 20.
    Cancro MP, Kearney JF (2004) B cell positive selection: road map to the primary repertoire? J Immunol 173(1):15–19PubMedGoogle Scholar
  21. 21.
    Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K, Nussenzweig MC (2001) Contribution of receptor editing to the antibody repertoire. Science 291(5508):1541–1544PubMedGoogle Scholar
  22. 22.
    Chen C, Nagy Z, Prak EL, Weigert M (1995) Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3(6):747–755PubMedGoogle Scholar
  23. 23.
    Clarke SH, McCray SK (1993) VH CDR3-dependent positive selection of murine VH12- expressing B cells in the neonate. European J Immunol 23:3327–3334Google Scholar
  24. 24.
    Dal Porto JM, Haberman AM, Kelsoe G, Shlomchik MJ (2002) Very low affinity B cells form germinal centers, become memory B cells, and participate in secondary immune responses when higher affinity competition is reduced. J Exp Med 195(9):1215–1221PubMedGoogle Scholar
  25. 25.
    Dal Porto JM, Haberman AM, Shlomchik MJ, Kelsoe G (1998) Antigen drives very low affinity B cells to become plasmacytes and enter germinal centers. J Immunol 161(10):5373–5381PubMedGoogle Scholar
  26. 26.
    DeKoter RP, Lee HJ, Singh H (2002) PU.1 regulates expression of the interleukin-7 receptor in lymphoid progenitors. Immunity 16(2):297–309PubMedGoogle Scholar
  27. 27.
    Doria G, D’Agostaro G, Poretti A (1978) Age-dependent variations of antibody avidity. Immunology 35(4):601–611PubMedGoogle Scholar
  28. 28.
    Driver DJ, McHeyzer-Williams LJ, Cool M, Stetson DB, McHeyzer-Williams MG (2001) Development and maintenance of a B220- memory B cell compartment. J Immunol 167(3):1393–1405PubMedGoogle Scholar
  29. 29.
    Eaton-Bassiri AS, Mandik-Nayak L, Seo SJ, Madaio MP, Cancro MP, Erikson J (2000) Alterations in splenic architecture and the localization of anti-double-stranded DNA B cells in aged mice. Int Immunol 12(6):915–926PubMedGoogle Scholar
  30. 30.
    Erikson J, Mandik L, Bui A, Eaton A, Noorchashm H, Nguyen KA, Roark JH (1998) Selfreactive B cells in nonautoimmune and autoimmune mice. Immunol Res 17(1–2):49–61PubMedGoogle Scholar
  31. 31.
    Fairfax KA, Corcoran LM, Pridans C, Huntington ND, Kallies A, Nutt SL, Tarlinton DM (2007) Different kinetics of blimp-1 induction in B cell subsets revealed by reporter gene. J Immunol 178(7):4104–4111PubMedGoogle Scholar
  32. 32.
    Feeney AJ, Goebel P, Espinoza CR(2004) Many levels of control of V gene rearrangement frequency. Immunol Rev 200:44–56PubMedGoogle Scholar
  33. 33.
    Forsdyke DR (2005) “Altered-self” or “near-self” in the positive selection of lymphocyte repertoires? Immunol Lett 100(2):103–106PubMedGoogle Scholar
  34. 34.
    Franceschi C, Passeri M, De Benedictis G, Motta L (1998) Immunosenescence. Aging (Milano) 10(2):153–154Google Scholar
  35. 35.
    Frasca D, Nguyen D, Van Der Put E, Riley RL, Blomberg BB (2003) The age-related decrease in E47 DNA-binding does not depend on increased Id inhibitory proteins in bone marrow-derived B cell precursors. Front Biosci 8:a110–a116PubMedGoogle Scholar
  36. 36.
    Frasca D, Riley RL, Blomberg BB (2004) Effect of age on the immunoglobulin class switch. Crit Rev Immunol 24(5):297–320PubMedGoogle Scholar
  37. 37.
    Frasca D, Riley RL, Blomberg BB (2005) Humoral immune response and B-cell functions including immunoglobulin class switch are downregulated in aged mice and humans. Semin Immunol 17(5):378–384PubMedGoogle Scholar
  38. 38.
    Frasca D, Riley RL, Blomberg BB (2007) Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF. Exp Gerontol 42(3):192–203PubMedGoogle Scholar
  39. 39.
    Frasca D, Van Der Put E, Riley RL, Blomberg BB (2004) Age-related differences in the E2A-encoded transcription factor E47 in bone marrow-derived B cell precursors and in splenic B cells. Exp Gerontol 39(4):481–489PubMedGoogle Scholar
  40. 40.
    Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, Busslinger M (2004) Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. Genes Dev 18(4):411–422PubMedGoogle Scholar
  41. 41.
    Gay D, Saunders T, Camper S, Weigert M (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 177(4):999–1008PubMedGoogle Scholar
  42. 42.
    Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M (2001) Immunosenescence and infectious diseases. Microbes Infect 3(10):851–857PubMedGoogle Scholar
  43. 43.
    Goidl EA, Innes JB, Weksler ME (1976) Immunological studies of aging. II. Loss of IgG and high avidity plaque-forming cells and increased suppressor cell activity in aging mice. J Exp Med 144(4):1037–1048PubMedGoogle Scholar
  44. 44.
    Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211(2):144–156PubMedGoogle Scholar
  45. 45.
    Han S, Yang K, Ozen Z, Peng W, Marinova E, Kelsoe G, Zheng B (2003) Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice. J Immunol 170(3):1267–1273PubMedGoogle Scholar
  46. 46.
    Hardy RR CC, Shinton SA, Kemp JD, Hayakawa K (1991) Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J Exp Med 173(5):1213–1225PubMedGoogle Scholar
  47. 47.
    Hardy RR, Hayakawa K (1991) A developmental switch in B lymphopoiesis. Proc Natl Acad Sci U S A 88(24):11550–11554PubMedGoogle Scholar
  48. 48.
    Hardy RR, Hayakawa K (2001) B cell development pathways. Annu Rev Immunol 19:595–621PubMedGoogle Scholar
  49. 49.
    Hardy RR, Hayakawa K, Parks DR, Herzenberg LA, Herzenberg LA (1984) Murine B cell differentiation lineages. J Expt Med 159:1169–1178Google Scholar
  50. 50.
    Harless SM, Lentz VM, Sah AP, Hsu BL, Clise-Dwyer K, Hilbert DM, Hayes CE, Cancro MP (2001) Competition for BLyS-mediated signaling through Bcmd/BR3 regulates peripheral B lymphocyte numbers. Curr Biol 11(24):1986–1989PubMedGoogle Scholar
  51. 51.
    Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, Silver J, Hardy RR (1999) Positive selection of natural autoreactive B cells. Science 285(5424):113–116PubMedGoogle Scholar
  52. 52.
    Hayakawa K, Hardy RR (2000) Development and function of B-1 cells. Curr Opin Immunol 12(3):346–353PubMedGoogle Scholar
  53. 53.
    Hayakawa K, Li YS, Wasserman R, Sauder S, Shinton S, Hardy RR (1997) B lymphocyte developmental lineages. Ann N Y Acad Sci 815:15–29PubMedGoogle Scholar
  54. 54.
    Hayakawa K, Shinton SA, Asano M, Hardy RR (2000) B-1 cell definition. Curr Top Microbiol Immunol 252:15–22PubMedGoogle Scholar
  55. 55.
    Haynes L, Eaton SM, Swain SL (2002) Effect of age on naive CD4 responses: impact on effector generation and memory development. Springer Semin Immunopathol 24(1):53–60PubMedGoogle Scholar
  56. 56.
    Hondowicz BD, Alexander ST, Quinn WJ 3rd, Pagan AJ, Metzgar MH, Cancro MP, Erikson J (2007) The role of BLyS/BLyS receptors in anti-chromatin B cell regulation. Int Immunol 19(4):465–475PubMedGoogle Scholar
  57. 57.
    Hsu BL, Harless SM, Lindsley RC, Hilbert DM, Cancro MP (2002) Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators. J Immunol 168(12):5993–5996PubMedGoogle Scholar
  58. 58.
    Hsu MC, Toellner KM, Vinuesa CG, Maclennan IC (2006) B cell clones that sustain longterm plasmablast growth in T-independent extrafollicular antibody responses. Proc Natl Acad Sci U S A 103(15):5905–5910PubMedGoogle Scholar
  59. 59.
    Johnson K, Angelin-Duclos C, Park S, Calame KL (2003) Changes in histone acetylation are associated with differences in accessibility of V(H) gene segments to V-DJ recombination during B-cell ontogeny and development. Mol Cell Biol 23(7):2438–2450PubMedGoogle Scholar
  60. 60.
    Johnson KM, Owen K, Witte PL (2002) Aging and developmental transitions in the B cell lineage. Int Immunol 14(11):1313–1323PubMedGoogle Scholar
  61. 61.
    Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ (1999). Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11(5):547–554PubMedGoogle Scholar
  62. 62.
    Jung D, Giallourakis C, Mostoslavsky R, Alt FW (2006) Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu Rev Immunol 24:541–570PubMedGoogle Scholar
  63. 63.
    Kearney JF (2005) Innate-like B cells. Springer Semin Immunopathol 26(4):377–383PubMedGoogle Scholar
  64. 64.
    Kee BL, Murre C (1998) Induction of early B cell factor (EBF) and multiple B lineage genes by the basic helix-loop-helix transcription factor E12. J Exp Med 188(4):699–713PubMedGoogle Scholar
  65. 65.
    Kee BL, Paige CJ (1995) Murine B cell development: commitment and progression from multipotential progenitors to mature B lymphocytes. Int Rev Cytol 157:129–179PubMedGoogle Scholar
  66. 66.
    Kee BL, Quong MW, Murre C (2000) E2A proteins: essential regulators at multiple stages of B-cell development. Immunol Rev 175:138–149PubMedGoogle Scholar
  67. 67.
    Kline GH, Hayden TA, Klinman NR (1999) B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J Immunol 162(6):3342–3349PubMedGoogle Scholar
  68. 68.
    Koipally J, Kim J, Jones B, Jackson A, Avitahl N, Winandy S, Trevisan M, Nichogiannopoulou A, Kelley C, Georgopoulos K (1999) Ikaros chromatin remodeling complexes in the control of differentiation of the hemo-lymphoid system. Cold Spring Harb Symp Quant Biol 64:79–86PubMedGoogle Scholar
  69. 69.
    Labrie JE 3rd, Sah AP, Allman DM, Cancro MP, Gerstein RM (2004) Bone marrow microenvironmental changes underlie reduced RAG-mediated recombination and B cell generation in aged mice. J Exp Med 200(4):411–423PubMedGoogle Scholar
  70. 70.
    Lesley R, Xu Y, Kalled SL, Hess DM, Schwab SR, Shu HB, Cyster JG (2004) Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20(4):441–453PubMedGoogle Scholar
  71. 71.
    Jin F, Freitas A, Szabo P, Weksler ME (2001) Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia in old mice. Eur J Immunol 31(2):500–505PubMedGoogle Scholar
  72. 72.
    Liu P, Keller JR, Ortiz M, Tessarollo L, Rachel RA, Nakamura T, Jenkins NA, Copeland NG (2003) Bcl11a is essential for normal lymphoid development. Nat Immunol 4(6):525–532PubMedGoogle Scholar
  73. 73.
    Loder F, Mutschler B, Ray RJ, Paige CJ, Sideras P, Torres R, Lamers MC, Carsetti R (1999) B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med 190(1):75–89PubMedGoogle Scholar
  74. 74.
    Lopes-Carvalho T, Foote J, Kearney JF (2005) Marginal zone B cells in lymphocyte activation and regulation. Curr Opin Immunol 17(3):244–250PubMedGoogle Scholar
  75. 75.
    Lopes-Carvalho T, Kearney JF (2004) Development and selection of marginal zone B cells. Immunol Rev 197:192–205PubMedGoogle Scholar
  76. 76.
    YF, Cerny J (2002) Repertoire of antibody response in bone marrow and the memory response are differentially affected in aging mice. J Immunol 169(9):4920–4927Google Scholar
  77. 77.
    Malaguarnera L, Ferlito L, Imbesi RM, Gulizia GS, Di Mauro S, Maugeri D, Malaguarnera M, Messina A (2001) Immunosenescence: a review. Arch Gerontol Geriatr 32(1):1–14PubMedGoogle Scholar
  78. 78.
    Manz RA, Arce S, Cassese G, Hauser AE, Hiepe F, Radbruch A (2002) Humoral immunity and long-lived plasma cells. Curr Opin Immunol 14(4):517–521PubMedGoogle Scholar
  79. 79.
    Manz RA, Radbruch A (2002) Plasma cells for a lifetime? Eur J Immunol 32(4):923–927PubMedGoogle Scholar
  80. 80.
    Manz RA, Thiel A, Radbruch A (1997) Lifetime of plasma cells in the bone marrow. Nature 388(6638):133–134PubMedGoogle Scholar
  81. 81.
    Martin DA, Bradl H, Collins TJ, Roth E, Jack HM, Wu GE (2003) Selection of Ig mu heavy chains by complementarity-determining region 3 length and amino acid composition. J Immunol 171(9):4663–4671PubMedGoogle Scholar
  82. 82.
    Martin F, Kearney JF (2000) Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12(1):39–49PubMedGoogle Scholar
  83. 83.
    Martin F, Kearney JF (2002) Marginal-zone B cells. Nat Rev Immunol 2(5):323–335PubMedGoogle Scholar
  84. 84.
    Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14(5):617–629PubMedGoogle Scholar
  85. 85.
    McHeyzer-Williams LJ, Cool M, McHeyzer-Williams MG (2000) Antigen-specific B cell memory: expression and replenishment of a novel b220(-) memory B cell compartment. J Exp Med 191(7):1149–1166PubMedGoogle Scholar
  86. 86.
    McHeyzer-Williams LJ, Driver DJ, McHeyzer-Williams MG (2001) Germinal center reaction. Curr Opin Hematol 8(1):52–59PubMedGoogle Scholar
  87. 87.
    McHeyzer-Williams LJ, McHeyzer-Williams MG (2005) Antigen-specific memory B cell development. Annu Rev Immunol 23:487–513PubMedGoogle Scholar
  88. 88.
    McHeyzer-Williams MG, McLean MJ, Lalor PA, Nossal GJ (1993) Antigen-driven B cell differentiation in vivo. J Exp Med 178(1):295–307PubMedGoogle Scholar
  89. 89.
    McHeyzer-Williams MG, Nossal GJ, Lalor PA (1991) Molecular characterization of single memory B cells. Nature 350(6318):502–505PubMedGoogle Scholar
  90. 90.
    Medina KL, Singh H (2005) Gene regulatory networks orchestrating B cell fate specification, commitment, and differentiation. Curr Top Microbiol Immunol 290:1–14PubMedGoogle Scholar
  91. 91.
    Mehr R, Shahaf G, Sah A, Cancro M (2003) Asynchronous differentiation models explain bone marrow labeling kinetics and predict reflux between the pre- and immature B cell pools. Int Immunol 15(3):301–312PubMedGoogle Scholar
  92. Melchers F (1997) Control of the sizes and contents of precursor B cell repertoires in bone marrow. Ciba Found Symp 204:172–182; discussion 182–176Google Scholar
  93. 93.
    Melchers F, Haasner D, Grawunder U, Kalberer C, Karasuyama H, Winkler T, Rolink A (1994) Roles of IgH and L chains and of surrogate H and L chains in the development of cells of the B lymphocyte lineage. Ann Rev Immunol 12:209–225Google Scholar
  94. 94.
    Melchers F, Strasser A, Bauer SR, Kudo A, Thalmann P, Rolink A (1989) Cellular stages and molecular steps of murine B cell development. Cold Spring Harb Symp Quant Biol LIV:183–189Google Scholar
  95. 95.
    Melchers F, ten Boekel E, Seidl T, Kong XC, Yamagami T, Onishi K, Shimizu T, Rolink AG, Andersson J (2000) Repertoire selection by pre-B-cell receptors and B-cell receptors, and genetic control of B-cell development from immature to mature B cells. Immunol Rev 175:33–46PubMedGoogle Scholar
  96. 96.
    Miller C, Kelsoe G (1995) Ig VH hypermutation is absent in the germinal centers of aged mice. J Immunol 155(7):3377–3384PubMedGoogle Scholar
  97. 97.
    97. Miller JP, Allman D (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171(5):2326–2330PubMedGoogle Scholar
  98. 98.
    Miller JP, Allman D (2005) Linking age-related defects in B lymphopoiesis to the aging of hematopoietic stem cells. Semin Immunol 17(5):321–329PubMedGoogle Scholar
  99. 99.
    Miller JP, Cancro MP (2007) B cells and aging: balancing the homeostatic equation. Exp Gerontol 42(5):396–399PubMedGoogle Scholar
  100. 100.
    Miller JP, Stadanlick JE, Cancro MP (2006) Space, selection, and surveillance: setting boundaries with BLyS. J Immunol 176(11):6405–6410PubMedGoogle Scholar
  101. 101.
    Mishto M, Santoro A, Bellavista E, Bonafe M, Monti D, Franceschi C (2003) Immunoproteasomes and immunosenescence. Ageing Res Rev 2(4):419–432PubMedGoogle Scholar
  102. 102.
    Mocchegiani E, Malavolta M (2004) NK and NKT cell functions in immunosenescence. Aging Cell 3(4):177–184PubMedGoogle Scholar
  103. 103.
    Monroe JG, Allman D (2004) Keeping track of pro-B cells: a new model for the effects of IL-7 during B cell development. Eur J Immunol 34(10):2642–2646PubMedGoogle Scholar
  104. 104.
    Montecino-Rodriguez E, Dorshkind K (2006) New perspectives in B-1 B cell development and function. Trends Immunol 27(9):428–433PubMedGoogle Scholar
  105. 105.
    Montecino-Rodriguez E, Leathers H, Dorshkind K (2006) Identification of a B-1 B cellspecified progenitor. Nat Immunol 7(3):293–301PubMedGoogle Scholar
  106. 106.
    Morrison AM, Nutt SL, Thevenin C, Rolink A, Busslinger M (1998) Loss- and gain-offunction mutations reveal an important role of BSAP (Pax-5) at the start and end of B cell differentiation. Semin Immunol 10(2):133–142PubMedGoogle Scholar
  107. 107.
    Mostoslavsky R, Alt FW, Bassing CH (2003) Chromatin dynamics and locus accessibility in the immune system. Nat Immunol 4(7):603–606PubMedGoogle Scholar
  108. 108.
    Murre C (2005) Helix-loop-helix proteins and lymphocyte development. Nat Immunol 6(11):1079–1086PubMedGoogle Scholar
  109. 109.
    Nemazee D, Russell D, Arnold B, Haemmerling G, Allison J, Miller JFAP, Morahan G, Buerki K (1991) Clonal deletion of autospecific B lymphocytes. Immunol Rev 122:117–132PubMedGoogle Scholar
  110. 110.
    Nemazee D, Weigert M (2000) Revising B cell receptors. J Exp Med 191(11):1813–1817PubMedGoogle Scholar
  111. 111.
    Ng SY, Yoshida T, Georgopoulos K (2007) Ikaros and chromatin regulation in early hematopoiesis. Curr Opin Immunol 19(2):116–122PubMedGoogle Scholar
  112. 112.
    Nicoletti C, Borghesi-Nicoletti C, Yang XH, Schulze DH, Cerny J (1991) Repertoire diversity of antibody response to bacterial antigens in aged mice. II. Phosphorylcholine-antibody in young and aged mice differ in both VH/VL gene repertoire and in specificity. J Immunol 147(8):2750–2755PubMedGoogle Scholar
  113. 113.
    Nicoletti C, Cerny J (1991) The repertoire diversity and magnitude of antibody responses to bacterial antigens in aged mice: I. Age-associated changes in antibody responses differ according to the mouse strain. Cell Immunol 133(1):72–83PubMedGoogle Scholar
  114. 114.
    Nicoletti C, Yang X, Cerny J (1993) Repertoire diversity of antibody response to bacterial antigens in aged mice. III. Phosphorylcholine antibody from young and aged mice differ in structure and protective activity against infection with Streptococcus pneumoniae. J Immunol 150(2):543–549PubMedGoogle Scholar
  115. 115.
    Nossal G, Pike B (1975) Evidence for the clonal abortion theory of B-lymphocyte tolerance. J Exp Med 141:904–917PubMedGoogle Scholar
  116. 116.
    Nossal GJV. 1983. Cellular mechanisms of immunologic tolerance. Ann Rev Immunol 1:33–62Google Scholar
  117. 117.
    Nutt SL, Rolink AG, Busslinger M (1999) The molecular basis of B-cell lineage commitment. Cold Spring Harb Symp Quant Biol 64:51–59PubMedGoogle Scholar
  118. 118.
    O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin LL, Mantchev GT, Bram RJ, Noelle RJ (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199(1):91–98PubMedGoogle Scholar
  119. 119.
    O’Riordan M, Grosschedl R (1999) Coordinate regulation of B cell differentiation by the transcription factors EBF and E2A. Immunity 11(1):21–31PubMedGoogle Scholar
  120. 120.
    Osmond D (1991) Proliferation kinetics and the lifespan of B cells in central and peripheral lymphoid organs. Curr Opin Immunol 3:179–185PubMedGoogle Scholar
  121. 121.
    Osmond DG (1990) B cell development in the bone marrow. Seminars in Immunology 2:173PubMedGoogle Scholar
  122. 122.
    Osmond DG, Park Y-H (1987) B lymphocyte progenitors in mouse bone marrow. Int Rev Immunol 2:241–261PubMedGoogle Scholar
  123. 123.
    Osmond DG, Rolink A, Melchers F (1998) Murine B lymphopoiesis: towards a unified model. Immunol Today 19(2):65–68PubMedGoogle Scholar
  124. 124.
    Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R (2006) Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203(4):1081–1091PubMedGoogle Scholar
  125. 125.
    Pawelec G (2003) Immunosenescence and human longevity. Biogerontology 4(3):167–170PubMedGoogle Scholar
  126. 126.
    Pawelec G, Koch S, Griesemann H, Rehbein A, Hahnel K, Gouttefangeas C (2006) Immunosenescence, suppression and tumour progression. Cancer Immunol Immunother 55(8):981–986Google Scholar
  127. 127.
    Pawelec G, Wagner W, Adibzadeh M, Engel A (1999) T cell immunosenescence in vitro and in vivo. Exp Gerontol 34(3):419–429PubMedGoogle Scholar
  128. 128.
    Pelanda R, Schwers S, Sonoda E, Torres RM, Nemazee D, Rajewsky K (1997) Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity 7(6):765–775PubMedGoogle Scholar
  129. 129.
    Prak EL, Trounstine M, Huszar D, Weigert M (1994) Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance. J Exp Med 180(5):1805–1815PubMedGoogle Scholar
  130. 130.
    Prak EL, Weigert M (1995) Light chain replacement: a new model for antibody gene rearrangement. J Exp Med 182(2):541–548PubMedGoogle Scholar
  131. 131.
    Quinn WJ 3rd, Scholz JL, Cancro MP (2005) Dwindling competition with constant demand: can homeostatic adjustments explain age-associated changes in peripheral B cell selection? Semin Immunol 17(5):362–369PubMedGoogle Scholar
  132. 132.
    Radbruch A, Muehlinghaus G, Luger EO, Inamine A, Smith KG, Dorner T, Hiepe F (2006) Competence and competition: the challenge of becoming a long-lived plasma cell. Nat Rev Immunol 6(10):741–750PubMedGoogle Scholar
  133. 133.
    Reth M (1991) Regulation of B-cell development by pre-B-cell receptors. Curr Biol 1(3):198–199PubMedGoogle Scholar
  134. 134.
    Reth M, Petrac E, Wiese P, Lobel L, Alt FW (1987) Activation of V kappa gene rearrangement in pre-B cells follows the expression of membrane-bound immunoglobulin heavy chains. EMBO J 6(11):3299–3305PubMedGoogle Scholar
  135. 135.
    Riley RL, Kruger MG, Elia J (1991) B cell precursors are decreased in senescent BALB/c mice, but retain normal mitotic activity in vivo and in vitro. Clin Immunol Immunopathol 59(2):301–313PubMedGoogle Scholar
  136. 136.
    Riley SC, Froscher BG, Linton PJ, Zharhary D, Marcu K, Klinman NR (1989) Altered VH gene segment utilization in the response to phosphorylcholine by aged mice. J Immunol 143(11):3798–3805PubMedGoogle Scholar
  137. 137.
    Rogerson BJ, Harris DP, Swain SL, Burgess DO (2003) Germinal center B cells in Peyer’s patches of aged mice exhibit a normal activation phenotype and highly mutated IgM genes. Mech Ageing Dev 124(2):155–165PubMedGoogle Scholar
  138. 138.
    Rolnik A, Melchers F (1991) Molecular and cellular orgins of B lymphocyte diversity. Cell 66:1081–1094Google Scholar
  139. 139.
    Schatz DG, Oettinger MA, Schlissel MS (1992) V(D)J recombination: molecular biology and regulation. Annu Rev Immunol 10:359–383PubMedGoogle Scholar
  140. 140.
    Schebesta M, Heavey B, Busslinger M (2002) Transcriptional control of B-cell development. Curr Opin Immunol 14(2):216–223PubMedGoogle Scholar
  141. 141.
    Schittek B, Rajewsky K (1990) Maintenance of B-cell memory by long-lived cells generated from proliferating precursors. Nature 346(6286):749–751PubMedGoogle Scholar
  142. 142.
    Schlissel MS (2003) Regulating antigen-receptor gene assembly. Nat Rev Immunol 3(11):890–899PubMedGoogle Scholar
  143. 143.
    Schlissel MS (2004) Regulation of activation and recombination of the murine Igkappa locus. Immunol Rev 200:215–223PubMedGoogle Scholar
  144. 144.
    Schlissel MS, Stanhope-Baker P (1997) Accessibility and the developmental regulation of V(D)J recombination. Semin Immunol 9(3):161–170PubMedGoogle Scholar
  145. 145.
    Shahaf G, Allman D, Cancro MP, Mehr R (2004) Screening of alternative models for transitional B cell maturation. Int Immunol 16(8):1081–1090PubMedGoogle Scholar
  146. 146.
    Sherwood EM, Blomberg BB, Xu W, Warner CA, Riley RL (1998) Senescent BALB/c mice exhibit decreased expression of lambda5 surrogate light chains and reduced development within the pre-B cell compartment. J Immunol 161(9):4472–4475PubMedGoogle Scholar
  147. 147.
    Sherwood EM, Xu W, King AM, Blomberg BB, Riley RL (2000) The reduced expression of surrogate light chains in B cell precursors from senescent BALB/c mice is associated with decreased E2A proteins. Mech Ageing Dev 118(1–2):45–59PubMedGoogle Scholar
  148. 148.
    Shih TA, Roederer M, Nussenzweig MC (2002) Role of antigen receptor affinity in T cellindependent antibody responses in vivo. Nat Immunol 3(4):399–406PubMedGoogle Scholar
  149. 149.
    Singh H, DeKoter RP, Walsh JC (1999) PU.1, a shared transcriptional regulator of lymphoid and myeloid cell fates. Cold Spring Harb Symp Quant Biol 64:13–20PubMedGoogle Scholar
  150. 150.
    Singh H, Medina KL, Pongubala JM (2005) Contingent gene regulatory networks and B cell fate specification. Proc Natl Acad Sci U S A 102(14):4949–4953PubMedGoogle Scholar
  151. 151.
    Singh H, Pongubala JM (2006) Gene regulatory networks and the determination of lymphoid cell fates. Curr Opin Immunol 18(2):116–120PubMedGoogle Scholar
  152. 152.
    Song H, Price PW, Cerny J (1997) Age-related changes in antibody repertoire: contribution from T cells. Immunol Rev 160:55–62PubMedGoogle Scholar
  153. 153.
    Srivastava B, Lindsley RC, Nikbakht N, Allman D (2005) Models for peripheral B cell development and homeostasis. Semin Immunol 17(3):175–182PubMedGoogle Scholar
  154. 154.
    Stadanlick JE, Cancro MP (2006) Unraveling the warp and weft of B cell fate. Immunity 25(3):395–396PubMedGoogle Scholar
  155. 155.
    Stephan RP, Lill-Elghanian DA, Witte PL (1997) Development of B cells in aged mice: decline in the ability of pro-B cells to respond to IL-7 but not to other growth factors. J Immunol 158(4):1598–1609PubMedGoogle Scholar
  156. 156.
    Stephan RP, Reilly CR, Witte PL (1998) Impaired ability of bone marrow stromal cells to support B-lymphopoiesis with age. Blood 91(1):75–88PubMedGoogle Scholar
  157. 157.
    Stephan RP, Sanders VM, Witte PL (1996) Stage-specific alterations in murine B lymphopoiesis with age. Int Immunol 8(4):509–518PubMedGoogle Scholar
  158. 158.
    Stout RD, Suttles J (2005) Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol Rev 205:60–71PubMedGoogle Scholar
  159. 159.
    Szabo P, Shen S, Telford W, Weksler ME (2003) Impaired rearrangement of IgH V to DJ segments in bone marrow Pro-B cells from old mice. Cell Immunol 222(1):78–87PubMedGoogle Scholar
  160. 160.
    Szabo P, Shen S, Weksler ME (1999). Age-associated defects in B lymphocyte development. Exp Gerontol 34(3):431–434PubMedGoogle Scholar
  161. 161.
    Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, Brink R (2004) Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 20(6):785–798PubMedGoogle Scholar
  162. 162.
    Tiegs SL, Russell DM, Nemazee D (1993) Receptor editing in self-reactive bone marrow B cells. J Exp Med 177(4):1009–1020PubMedGoogle Scholar
  163. 163.
    Treml LS, Crowley JE, Cancro MP (2006) BLyS receptor signatures resolve homeostatically independent compartments among naive and antigen-experienced B cells. Semin Immunol 18(5):297–304PubMedGoogle Scholar
  164. 164.
    Tsubata T, Reth M (1990) The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface. J Exp Med 172(3):973–976PubMedGoogle Scholar
  165. 165.
    Tsubata T, Tsubata R, Reth M (1992) Crosslinking of the cell surface immunoglobulin (musurrogate light chains complex) on pre-B cells induces activation of V gene rearrangements at the immunoglobulin kappa locus. Int Immunol 4(6):637–641PubMedGoogle Scholar
  166. 166.
    Van Der Put E, Frasca D, King AM, Blomberg BB, Riley RL (2004) Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. J Immunol 173(2):818–827PubMedGoogle Scholar
  167. 167.
    Van Der Put E, Sherwood EM, Blomberg BB, Riley RL (2003) Aged mice exhibit distinct B cell precursor phenotypes differing in activation, proliferation and apoptosis. Exp Gerontol 38(10):1137–1147PubMedGoogle Scholar
  168. 168.
    von Bulow GU, van Deursen JM, Bram RJ (2001) Regulation of the T-independent humoral response by TACI. Immunity 14(5):573–582Google Scholar
  169. 169.
    Wang H, Clarke SH (2004) Positive selection focuses the VH12 B-cell repertoire towards a single B1 specificity with survival function. Immunol Rev 197:51–59PubMedGoogle Scholar
  170. 170.
    Weksler MC, Innes JD, Goldstein G (1978) Immunological studies of aging. IV. The contribution of thymic involution to the immune deficiencies of aging mice and reversal with thymopoietin 32–36. J Exp Med 148(4):996–1006PubMedGoogle Scholar
  171. 171.
    Weksler ME (2000) Changes in the B-cell repertoire with age. Vaccine 18(16):1624–1628Google Scholar
  172. 172.
    Weksler ME, Szabo P (2000) The effect of age on the B-cell repertoire. J Clin Immunol 20(4):240–249PubMedGoogle Scholar
  173. 173.
    Weller S, Braun MC, Tan BK, Rosenwald A, Cordier C, Conley ME, Plebani A, Kumararatne DS, Bonnet D, Tournilhac O et al (2004) Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104(12):3647–3654PubMedGoogle Scholar
  174. 174.
    William J, Euler C, Christensen S, Shlomchik MJ (2002) Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297(5589):2066–2070PubMedGoogle Scholar
  175. 175.
    Williams GT, Jolly CJ, Kohler J, Neuberger MS (2000) The contribution of somatic hypermutation to the diversity of serum immunoglobulin: dramatic increase with age. Immunity 13(3):409–417PubMedGoogle Scholar
  176. 176.
    Wortis HH, Berland R (2001) Cutting edge commentary: origins of B-1 cells. J Immunol 166(4):2163–2166PubMedGoogle Scholar
  177. 177.
    Xiang Z, Cutler AJ, Brownlie RJ, Fairfax K, Lawlor KE, Severinson E, Walker EU, Manz RA, Tarlinton DM, Smith KG (2007) FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol 8(4):419–429PubMedGoogle Scholar
  178. 178.
    Yang X, Stedra J, Cerny J (1996) Relative contribution of T and B cells to hypermutation and selection of the antibody repertoire in germinal centers of aged mice. J Exp Med 183(3):959–970PubMedGoogle Scholar
  179. 179.
    Zediak VP, Maillard I, Bhandoola A (2007) Multiple prethymic defects underlie age-related loss of T progenitor competence. Blood 110(4):1161–1167PubMedGoogle Scholar
  180. 180.
    Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD (2006) Transcription factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to-DJ(H) rearrangement of immunoglobulin genes. Nat Immunol 7(6):616–624PubMedGoogle Scholar
  181. 181.
    Zharhary D (1986) T cell involvement in the decrease of antigen-responsive B cells in aged mice. Eur J Immunol 16(9):1175–1178PubMedGoogle Scholar
  182. 182.
    Zharhary D, Klinman NR (1983) Antigen responsiveness of the mature and generative B cell populations of aged mice. J Exp Med 157(4):1300–1308PubMedGoogle Scholar
  183. 183.
    Zharhary D, Klinman NR (1984) B cell repertoire diversity to PR8 influenza virus does not decrease with age. J Immunol 133(5):2285–2287PubMedGoogle Scholar
  184. 184.
    Zharhary D, Klinman NR (1986) The frequency and fine specificity of B cells responsive to (4-hydroxy-3-nitrophenyl)acetyl in aged mice. Cell Immunol 100(2):452–461PubMedGoogle Scholar
  185. 185.
    Zharhary D, Klinman NR (1986) A selective increase in the generation of phosphorylcholine- specific B cells associated with aging. J Immunol 136(2):368–370PubMedGoogle Scholar
  186. 186.
    Zharhary D, Segev Y, Gershon H (1977) The affinity and spectrum of cross reactivity of antibody production in senescent mice: the IgM response. Mech Ageing Dev 6(5):385–392PubMedGoogle Scholar
  187. 187.
    Zheng B, Han S, Takahashi Y, Kelsoe G (1997) Immunosenescence and germinal center reaction. Immunol Rev 160:63–77PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Jean L. Scholz
    • 1
  • William J. QuinnIII
    • 1
  • Michael P. Cancro
    • 1
  1. 1.Department of Pathology and Laboratory MedicineUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

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