• Craig P. Chappell
  • Joseph Dauner
  • Joshy Jacob*
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 633)

1 Introduction

The adaptive immune response to pathogenic infection or immunization can provide the host with lifelong protection from repeat encounters, a phenomenon known as immunological memory. Immune protection is attributed in large part to the generation of antigen (Ag)-specific T and B lymphocytes during the initial infection that respond with greater rapidity and vigor upon subsequent exposure to the same or crossreactive pathogen.1A critical component of this protection is the humoral system, which serves to maintain persistent levels of both circulating serum antibody (Ab) and memory B cells capable of responding to secondary infection. The differentiation of resting memory B cells into antibody-forming cells (AFCs) is widely attributed to the rapid increase in serum Ab levels seen upon secondary infection. Importantly, memory B cell receptors (BCRs) and immune serum often possess an increased affinity for Ag compared to naive B cells, which allows for a qualitatively...


Germinal Center Somatic Hypermutation Affinity Maturation Germinal Center Reaction Germinal Center Formation 
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.


  1. 1.
    1. Gray, D. Immunological memory. Annu Rev Immunol 11, 49–77 (1993)CrossRefGoogle Scholar
  2. 2.
    2. Jacob, J., Kassir, R. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. J Exp Med 173, 1165–1175 (1991)CrossRefGoogle Scholar
  3. 3.
    3. Jacob, J. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers.J Exp Med 176, 679–687 (1992)CrossRefGoogle Scholar
  4. 4.
    4. Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389–392 (1991)CrossRefGoogle Scholar
  5. 5.
    5. Cozine, C.L., Wolniak, K.L. & Waldschmidt, T.J. The primary germinal center response in mice. Curr Opin Immunol 17, 298–302 (2005)CrossRefGoogle Scholar
  6. 6.
    6. Wolniak, K.L., Shinall, S.M. & Waldschmidt, T.J. The germinal center response. Crit Rev Immunol 24, 39–65 (2004)CrossRefGoogle Scholar
  7. 7.
    7. McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Antigen-specific memory B cell development. Annu Rev Immunol 23, 487–513 (2005)CrossRefGoogle Scholar
  8. 8.
    8. Fang, Y., Xu, C., Fu, Y.X., Holers, V.M. & Molina, H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J Immunol 160, 5273–5279 (1998)Google Scholar
  9. 9.
    9. Humphrey, J.H., Grennan, D. & Sundaram, V. The origin of follicular dendritic cells in the mouse and the mechanism of trapping of immune complexes on them. Eur J Immunol 14, 859–864 (1984)CrossRefGoogle Scholar
  10. 10.
    10. Qin, D. . Evidence for an important interaction between a complement-derived CD21 ligand on follicular dendritic cells and CD21 on B cells in the initiation of IgG responses. J Immunol 161, 4549–4554 (1998)Google Scholar
  11. 11.
    11. Tew, J.G., Wu, J., Fakher, M., Szakal, A.K. & Qin, D. Follicular dendritic cells: beyond the necessity of T-cell help. Trends Immunol 22, 361–367 (2001)CrossRefGoogle Scholar
  12. 12.
    12. Cutrona, G. The propensity to apoptosis of centrocytes and centroblasts correlates with elevated levels of intracellular myc protein. Eur J Immunol 27, 234–238 (1997)CrossRefGoogle Scholar
  13. 13.
    13. Inada, K. c-Fos induces apoptosis in germinal center B cells. J Immunol 161, 3853–3861 (1998)Google Scholar
  14. 14.
    14. Liu, Y.J. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol 21, 1905–1910 (1991)CrossRefGoogle Scholar
  15. 15.
    15. Martinez-Valdez, H. Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med 183, 971–977 (1996)CrossRefGoogle Scholar
  16. 16.
    16. Shokat, K.M. & Goodnow, C.C. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375, 334–338 (1995)CrossRefGoogle Scholar
  17. 17.
    17. Tuscano, J.M. Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center. Blood 88, 1359–1364 (1996)Google Scholar
  18. 18.
    18. Wang, Z., Karras, J.G., Howard, R.G. & Rothstein, T.L. Induction of bcl-x by CD40 engagement rescues sIg-induced apoptosis in murine B cells. J Immunol 155, 3722–3725 (1995)Google Scholar
  19. 19.
    19. Takahashi, Y., Ohta, H. & Takemori, T. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14, 181–192 (2001)CrossRefGoogle Scholar
  20. 20.
    20. Lebecque, S., de Bouteiller, O., Arpin, C., Banchereau, J. & Liu, Y.J. Germinal center founder cells display propensity for apoptosis before onset of somatic mutation. J Exp Med 185, 563–571 (1997)CrossRefGoogle Scholar
  21. 21.
    21. Cleary, A.M., Fortune, S.M., Yellin, M.J., Chess, L. & Lederman, S. Opposing roles of CD95 (Fas/APO-1) and CD40 in the death and rescue of human low density tonsillar B cells. J Immunol 155, 3329–3337 (1995)Google Scholar
  22. 22.
    22. Laman, J.D., Claassen, E. & Noelle, R.J. Functions of CD40 and its ligand, gp39 (CD40L). Crit Rev Immunol 16, 59–108 (1996)Google Scholar
  23. 23.
    23. Choe, J., Kim, H.S., Zhang, X., Armitage, R.J. & Choi, Y.S. Cellular and molecular factors that regulate the differentiation and apoptosis of germinal center B cells. Anti-Ig down-regulates Fas expression of CD40 ligand-stimulated germinal center B cells and inhibits Fas-mediated apoptosis. J Immunol 157, 1006–1016 (1996)Google Scholar
  24. 24.
    24. Slifka, M.K., Antia, R., Whitmire, J.K. & Ahmed, R. Humoral immunity due to long-lived plasma cells. Immunity 8, 363–372 (1998)CrossRefGoogle Scholar
  25. 25.
    25. Toyama, H. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17, 329–339 (2002)CrossRefGoogle Scholar
  26. 26.
    26. Inamine, A. Two waves of memory B-cell generation in the primary immune response. Int Immunol 17, 581–589 (2005)CrossRefGoogle Scholar
  27. 27.
    27. McHeyzer-Williams, M.G., McLean, M.J., Lalor, P.A. & Nossal, G.J. Antigen-driven B cell differentiation in vivo. J Exp Med 178, 295–307 (1993)CrossRefGoogle Scholar
  28. 28.
    28. Anderson, S.M., Tomayko, M.M., Ahuja, A., Haberman, A.M. & Shlomchik, M.J. New markers for murine memory B cells that define mutated and unmutated subsets. J Exp Med 204, 2103–2114 (2007)CrossRefGoogle Scholar
  29. 29.
    29. Smith, K.G., Light, A., Nossal, G.J. & Tarlinton, D.M. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J 16, 2996–3006 (1997)CrossRefGoogle Scholar
  30. 30.
    30. Paus, D. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203, 1081–1091 (2006)CrossRefGoogle Scholar
  31. 31.
    31. Shih, T.A., Meffre, E., Roederer, M. & Nussenzweig, M.C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nat Immunol 3, 570–575 (2002)CrossRefGoogle Scholar
  32. 32.
    32. Takahashi, Y., Dutta, P.R., Cerasoli, D.M. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. V. Affinity maturation develops in two stages of clonal selection. J Exp Med 187, 885–895 (1998)CrossRefGoogle Scholar
  33. 33.
    33. Lu, Y.F., Singh, M. & Cerny, J. Canonical germinal center B cells may not dominate the memory response to antigenic challenge. Int Immunol 13, 643–655 (2001)CrossRefGoogle Scholar
  34. 34.
    34. William, J., Euler, C., Christensen, S. & Shlomchik, M.J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066–2070 (2002)CrossRefGoogle Scholar
  35. 35.
    35. Rossbacher, J., Haberman, A.M., Neschen, S., Khalil, A. & Shlomchik, M.J. Antibody-independent B cell-intrinsic and -extrinsic roles for CD21/35. Eur J Immunol 36, 2384–2393 (2006)CrossRefGoogle Scholar
  36. 36.
    36. Anderson, S.M., Hannum, L.G. & Shlomchik, M.J. Memory B cell survival and function in the absence of secreted antibody and immune complexes on follicular dendritic cells. J Immunol 176, 4515–4519 (2006)Google Scholar
  37. 37.
    37. Hannum, L.G., Haberman, A.M., Anderson, S.M. & Shlomchik, M.J. Germinal center initiation, variable gene region hypermutation, and mutant B cell selection without detectable immune complexes on follicular dendritic cells. J Exp Med 192, 931–942 (2000)CrossRefGoogle Scholar
  38. 38.
    38. Weiss, U. & Rajewsky, K. The repertoire of somatic antibody mutants accumulating in the memory compartment after primary immunization is restricted through affinity maturation and mirrors that expressed in the secondary response. J Exp Med 172, 1681–1689 (1990)CrossRefGoogle Scholar
  39. 39.
    39. Berek, C., Griffiths, G.M. & Milstein, C. Molecular events during maturation of the immune response to oxazolone. Nature 316, 412–418 (1985)CrossRefGoogle Scholar
  40. 40.
    40. Berek, C. & Milstein, C. Mutation drift and repertoire shift in the maturation of the immune response. Immunol Rev 96, 23–41 (1987)CrossRefGoogle Scholar
  41. 41.
    41. Griffiths, G.M., Berek, C., Kaartinen, M. & Milstein, C. Somatic mutation and the maturation of immune response to 2-phenyl oxazolone. Nature 312, 271–275 (1984)CrossRefGoogle Scholar
  42. 42.
    42. Blier, P.R. & Bothwell, A.L. The immune response to the hapten NP in C57BL/6 mice: insights into the structure of the B-cell repertoire. Immunol Rev 105, 27–43 (1988)CrossRefGoogle Scholar
  43. 43.
    43. Blier, P.R. & Bothwell, A. A limited number of B cell lineages generates the heterogeneity of a secondary immune response. J Immunol 139, 3996–4006 (1987)Google Scholar
  44. 44.
    44. Cumano, A. & Rajewsky, K. Structure of primary anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibodies in normal and idiotypically suppressed C57BL/6 mice. Eur J Immunol 15, 512–520 (1985)CrossRefGoogle Scholar
  45. 45.
    45. Jacob, J., Przylepa, J., Miller, C. & Kelsoe, G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells. J Exp Med 178, 1293–1307 (1993)CrossRefGoogle Scholar
  46. 46.
    46. Siekevitz, M., Kocks, C., Rajewsky, K. & Dildrop, R. Analysis of somatic mutation and class switching in naive and memory B cells generating adoptive primary and secondary responses. Cell 48, 757–770 (1987)CrossRefGoogle Scholar
  47. 47.
    47. Smith, F.I., Cumano, A., Licht, A., Pecht, I. & Rajewsky, K. Low affinity of kappa chain bearing (4-hydroxy-3-nitrophenyl)acetyl (NP)-specific antibodies in the primary antibody repertoire of C57BL/6 mice may explain lambda chain dominance in primary anti-NP responses. Mol Immunol 22, 1209–1216 (1985)CrossRefGoogle Scholar
  48. 48.
    48. Chappell, C.P. & Jacob, J. Identification of memory B cells using a novel transgenic mouse model. J Immunol 176, 4706–4715 (2006)Google Scholar
  49. 49.
    49. Terres, G. & Wolins, W. Enhanced sensitization in mice by simultaneous injection of antigen and specific rabbit antiserum. Proc Soc Exp Biol Med 102, 632–635 (1959)Google Scholar
  50. 50.
    50. Terres, G. & Wolins, W. Enhanced immunological sensitization of mice by the simultaneous injection of antigen and specific antiserum. I. Effect of varying the amount of antigen used relative to the antiserum. J Immunol 86, 361–368 (1961)Google Scholar
  51. 51.
    51. Terres, G. & Stoner, R.D. Specificity of enhanced immunological sensitization of mice following injections of antigens and specific antisera. Proc Soc Exp Biol Med 109, 88–91 (1962)Google Scholar
  52. 52.
    52. Collisson, E.W., Andersson, B. & Lamon, E.W. Modulation of hapten-specific antibody responses with anticarrier antibody. I. Differential effects of IgM and IgG anticarrier on primary direct and indirect hapten-specific plaque-forming cells. Proc Soc Exp Biol Med 162, 194–198 (1979)Google Scholar
  53. 53.
    53. Heyman, B. & Wigzell, H. Specific IgM enhances and IgG inhibits the induction of immunological memory in mice. Scand J Immunol 21, 255–266 (1985)CrossRefGoogle Scholar
  54. 54.
    54. Laissue, J., Cottier, H., Hess, M.W. & Stoner, R.D. Early and enhanced germinal center formation and antibody responses in mice after primary stimulation with antigen–isologous antibody complexes as compared with antigen alone. J Immunol 107, 822–831 (1971)Google Scholar
  55. 55.
    55. Klaus, G.G. The generation of memory cells. II. Generation of B memory cells with preformed antigen–antibody complexes. Immunology 34, 643–652 (1978)Google Scholar
  56. 56.
    56. Klaus, G.G. Generation of memory cells. III. Antibody class requirements for the generation of B-memory cells by antigen–antibody complexes. Immunology 37, 345–351 (1979)Google Scholar
  57. 57.
    57. Klaus, G.G. & Humphrey, J.H. The generation of memory cells. I. The role of C3 in the generation of B memory cells. Immunology 33, 31–40 (1977)Google Scholar
  58. 58.
    58. Kunkl, A. & Klaus, G.G. The generation of memory cells. IV. Immunization with antigen-antibody complexes accelerates the development of B-memory cells, the formation of germinal centres and the maturation of antibody affinity in the secondary response. Immunology 43, 371–378 (1981)Google Scholar
  59. 59.
    59. Kunkl, A. & Klaus, G.G. The generation of memory cells. V. Preferential priming of IgG1 B memory cells by immunization with antigen IgG2 antibody complexes. Immunology 44, 163–168 (1981)Google Scholar
  60. 60.
    60. Stoner, R.D., Terres, G. & Hess, M.W. Early and enhanced antioxin responses elicited with complexes of tetanus toxoid and specific mouse and human antibodies. J Infect Dis 131, 230–238 (1975)Google Scholar
  61. 61.
    61. Terres, G., Habicht, G.S. & Stoner, R.D. Carrier-specific enhancement of the immune response using antigen–antibody complexes. J Immunol 112, 804–811 (1974)Google Scholar
  62. 62.
    62. Terres, G., Morrison, S.L., Habicht, G.S. & Stoner, R.D. Appearance of an early “primed state” in mice following the concomitant injections of antigen and specific antiserum. J Immunol 108, 1473–1481 (1972)Google Scholar
  63. 63.
    63. Coulie, P.G. & Van Snick, J. Enhancement of IgG anti-carrier responses by IgG2 anti-hapten antibodies in mice. Eur J Immunol 15, 793–798 (1985)CrossRefGoogle Scholar
  64. 64.
    64. Henry, C. & Jerne, N.K. Competition of 19S and 7S antigen receptors in the regulation of the primary immune response. J Exp Med 128, 133–152 (1968)CrossRefGoogle Scholar
  65. 65.
    65. Quintana, I.Z., Silveira, A.V. & Moller, G. Regulation of the antibody response to sheep erythrocytes by monoclonal IgG antibodies. Eur J Immunol 17, 1343–1349 (1987)CrossRefGoogle Scholar
  66. 66.
    66. Cerottini, J.C., McConahey, P.J. & Dixon, F.J. Specificity of the immunosuppression caused by passive administration of antibody. J Immunol 103, 268–275 (1969)Google Scholar
  67. 67.
    67. Karlsson, M.C., Wernersson, S., Diaz de Stahl, T., Gustavsson, S. & Heyman, B. Efficient IgG-mediated suppression of primary antibody responses in Fcgamma receptor-deficient mice. Proc Natl Acad Sci USA 96, 2244–2249 (1999)CrossRefGoogle Scholar
  68. 68.
    68. Krieger, N.J., Pesce, A. & Michael, J.G. Immunoregulation of the anti-bovine serum albumin response by polyclonal and monoclonal antibodies. Cell Immunol 80, 279–287 (1983)CrossRefGoogle Scholar
  69. 69.
    69. Strannegard, O. & Belin, L. Suppression of reagin synthesis in rabbits by passively administered antibody. Immunology 18, 775–785 (1970)Google Scholar
  70. 70.
    70. Wernersson, S. IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain-deficient mice and increased in Fc gamma RII-deficient mice. J Immunol 163, 618–622 (1999)Google Scholar
  71. 71.
    71. Wiersma, E.J. Enhancement of the antibody response to protein antigens by specific IgG under different experimental conditions. Scand J Immunol 36, 193–200 (1992)CrossRefGoogle Scholar
  72. 72.
    72. Wiersma, E.J., Nose, M. & Heyman, B. Evidence of IgG-mediated enhancement of the antibody response in vivo without complement activation via the classical pathway. Eur J Immunol 20, 2585–2589 (1990)CrossRefGoogle Scholar
  73. 73.
    73. Enriquez-Rincon, F. & Klaus, G.G. Differing effects of monoclonal anti-hapten antibodies on humoral responses to soluble or particulate antigens. Immunology 52, 129–136 (1984)Google Scholar
  74. 74.
    74. Applequist, S.E., Dahlstrom, J., Jiang, N., Molina, H. & Heyman, B. Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes. J Immunol 165, 2398–2403 (2000)Google Scholar
  75. 75.
    75. Heyman, B., Pilstrom, L. & Shulman, M.J. Complement activation is required for IgM-mediated enhancement of the antibody response. J Exp Med 167, 1999–2004 (1988)CrossRefGoogle Scholar
  76. 76.
    76. Ravetch, J.V. & Kinet, J.P. Fc receptors. Annu Rev Immunol 9, 457–492 (1991)Google Scholar
  77. 77.
    77. Ahearn, J.M. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity 4, 251–262 (1996)CrossRefGoogle Scholar
  78. 78.
    78. Fischer, M.B. Dependence of germinal center B cells on expression of CD21/CD35 for survival. Science 280, 582–585 (1998)CrossRefGoogle Scholar
  79. 79.
    79. Diaz de Stahl, T. & Heyman, B. IgG2a-mediated enhancement of antibody responses is dependent on FcRgamma+ bone marrow-derived cells. Scand J Immunol 54, 495–500 (2001)CrossRefGoogle Scholar
  80. 80.
    80. Nie, X., Basu, S. & Cerny, J. Immunization with immune complex alters the repertoire of antigen-reactive B cells in the germinal centers. Eur J Immunol 27, 3517–3525 (1997)CrossRefGoogle Scholar
  81. 81.
    81. Song, H., Nie, X., Basu, S., Singh, M. & Cerny, J. Regulation of VH gene repertoire and somatic mutation in germinal centre B cells by passively administered antibody. Immunology 98, 258–266 (1999)CrossRefGoogle Scholar
  82. 82.
    82. Rada, C., Gupta, S.K., Gherardi, E. & Milstein, C. Mutation and selection during the secondary response to 2-phenyl oxazolone. Proc Natl Acad Sci USA 88, 5508–5512 (1991)CrossRefGoogle Scholar
  83. 83.
    83. Hebeis, B.J. Activation of virus-specific memory B cells in the absence of T cell help. J Exp Med 199, 593–602 (2004)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Craig P. Chappell
    • 1
  • Joseph Dauner
  • Joshy Jacob*
  1. 1.Department of Microbiology and ImmunologyEmory UniversityAtlantaUSA

Personalised recommendations