Mechanisms of Idiotypic Control of the Antibody Repertoire

  • Klaus Rajewsky


The coexistence in the immune system of antibodies and anti-antibodies (idiotypes and antiidiotypes) is the basis of Jerne’s network hypothesis(1) which postulates that idiotypic interactions of antibodies are a main regulatory principle in the immune system. Since Köhler and Milstein developed their hybridization technique for the isolation of cell lines secreting antibodies of predefined specificity,(2)it was possible to isolate antibodies and anti-antibodies from any given inbred mouse strain and to test with these reagents the network hypothesis in a straightforward way. This approach has been used by a number of laboratories and much of that work is discussed throughout this volume and has also recently been reviewed.(3) In the present chapter, I shall summarize the work of this laboratory on this subject and point out the mechanisms of idiotypic control which have emerged from it. The main question asked is whether the idiotypic network controls the functional antibody repertoire. If so, what are the rules of that control, and does the network contribute to the maintenance of a diverse repertoire, to immunological memory and to the guarantee of self tolerance? In the course of the discussion it will become obvious that T cells play a crucial role in idiotypic regulation as has also been suggested by experimental evidence obtained by others.(3) T and B cells might thus communicate via idiotypic interactions and this might lead to the idiotypic similarities of T- and B-cell receptors as they have been observed in many experimental systems.


Antibody Repertoire Antibody Population Idiotypic Network Enhance Mechanism Predefined Specificity 
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  1. 1.
    Jerne, N. K., 1974, Towards a network theory of the immune system, Ann. Immunol. (Inst. Pasteur). 125C:373–389.Google Scholar
  2. 2.
    Köhler, G., and Milstein, C., 1975, Continuous cultures of fused cells secreting antibody of predefined specificity, Nature 256:495–497.PubMedCrossRefGoogle Scholar
  3. 3.
    Rajewsky, K., and Takemori, T., 1983, Genetics, expression, and function of idiotypes, Annu. Rev. Immunol. 1:569–607.PubMedCrossRefGoogle Scholar
  4. 4.
    Imanishi, T., and Makela, O., 1973, Strain differences in the fine specificity of mouse anti-hapten antibodies, Eur. J. Immunol. 3:323–330.PubMedCrossRefGoogle Scholar
  5. 5.
    Imanishi, T., and Makela, O., 1974, Inheritance of antibody specificity. I. Anti-(4-hydroxy-3-nitrophenyl) acetyl of the mouse primary response, J. Exp. Med. 140:1498–1510.PubMedCrossRefGoogle Scholar
  6. 6.
    Jack, R. S., Imanishi-Kari, T., and Rajewsky, K., 1977, Idiotypic analysis of the response of C57BL/6 mice to the (4-hydroxy-3-nitrophenyl)acetyl group, Eur. J. Immunol. 7:559–565.PubMedCrossRefGoogle Scholar
  7. 7.
    Makela, O., and Karjalainen, K., 1977, Inherited immunoglobulin idiotypes of the mouse, Immunol. Rev. 34:119–138.PubMedCrossRefGoogle Scholar
  8. 8.
    Reth, M., Imanishi-Kari, T., Jack, R. S., Cramer, M., Krawinkel, U., Hammerling, G. J., and Rajewsky, K., 1977. The variable portion of T and B cell receptors for antigen: Binding sites for the hapten (4- hydroxy-3-nitrophenyl) acetyl in C57BL/6 mice, in: Regulatory Genetics of the Immune System: ICN- UCLA Symposia on Molecular and Cellular Biology, Volume VI (E. E. Sercarz, L. A. Herzenberg, and C. F. Fox, eds.), Acedemic Press, New York, pp. 139–149.Google Scholar
  9. 9.
    Reth, M., Hammerling, G. J., and Rajewsky, K., 1978, Analysis of the repertoire of anti-NP antibodies in C57BL/6 mice by cell fusion. I. Characterization of antibody families in the primary and hyperimmune response,Eur. f. Immunol. 8:393–400.CrossRefGoogle Scholar
  10. 10.
    Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-Kari, T., Rajewsky, K., and Baltimore, D., 1981, Heavy chain variable region contribution to the NPb family of antibodies: Somatic mutation evident in a λ2a variable region, Cell 24:625–637.PubMedCrossRefGoogle Scholar
  11. 11.
    Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-Kari, T., Rajewsky, K., and Baltimore, D., 1982, Somatic variants of murine immunoglobulin λ light chains, Nature 298:380–382.PubMedCrossRefGoogle Scholar
  12. lla. Dildrop, R., Bovens, J., Siekevitz, M., Beyreuther, K., and Rajewsky, K., 1984, A V-region determinant (idiotope) expressed at high frequency in B lymphocytes is encoded by a large set of antibody structural genes, EMBO f. 3:517–523.Google Scholar
  13. 12.
    Reth, M., Imanishi-Kari, T., and Rajewsky, K., 1979, Analysis of the repertoire of anti-(4-hydroxy-3- nitrophenyl) acetyl (NP) antibodies in C57BL/6 mice by cell fusion. II. Characterization of idiotopes by monoclonal anti-idiotope antibodies, Eur. f. Immunol. 9:1004–1013.CrossRefGoogle Scholar
  14. 13.
    Rajewsky, K., Takemori, T., and Reth, M., 1981, Analysis and regulation of V gene expression by monoclonal antibodies, in:Monoclonal Antibody and T Cell Hybridoma: Perspective and Technical Advances (G. J. Hammerling, U. Hammerling, and J. F. Kearney, eds.), Elsevier/North-Holland, Amsterdam, pp. 399–409.Google Scholar
  15. 14.
    Rajewsky, K., Reth, M., Takemori, T., and Kelsoe, G., 1981, A glimpse into the inner life of the immune system, in: The Immune System (C. M. Steinberg and I. Lefkovits, eds.), Karger, Basel, pp. 1–11.Google Scholar
  16. 15.
    Kelsoe, G., Reth, M., and Rajewsky, K., 1981, Control of idiotope expression by monoclonal anti-idiotope and idiotope-bearing antibody, Eur. J. Immunol. 11:418–423.PubMedCrossRefGoogle Scholar
  17. 16.
    Briiggemann, M., Radbruch, A., and Rajewsky, K., 1982, Immunoglobulin V region variants in hybridoma cells. I. Isolation of a variant with altered idiotypic and antigen-binding specificity, EMBO J. 1:629–634.Google Scholar
  18. 17.
    Takemori, T., Tesch, H., Reth, M., and Rajewsky, K., 1982, The immune response against anti-idiotype antibodies. I. Induction of idiotope-bearing antibodies and analysis of the idiotope repertoire, Eur. f. Immunol. 12:1040–1046.CrossRefGoogle Scholar
  19. 18.
    Reth, M., Kelsoe, G., and Rajewsky, K., 1981, Idiotypic regulation by isologous monoclonal anti-idiotope antibodies,Nature 290:257–259.PubMedCrossRefGoogle Scholar
  20. 18.
    a. Takemori, T., and Rajewsky, K., 1984, Specificity, duration and mechanism of idiotype suppression induced by neonatal injection of monoclonal anti-idiotope antibodies into mice, Eur. J. Immunol, in press.Google Scholar
  21. 19.
    Tesch, H., Takemori, T., and Rajewsky, K., 1983, The immune response against anti-idiotope antibodies. II. The induction of antibodies bearing the target idiotope (Ab3/3) depends on the frequency of the corresponding B cells, Eur. J. Immunol. 13:726–732.PubMedCrossRefGoogle Scholar
  22. 19a.
    Miiller, C. E., and Rajewsky, K., 1984, Idiotope regulation by isotype switch variants of two monoclonal anti-idiotope antibodies, J. Exp. Med. 159:758–772.CrossRefGoogle Scholar
  23. 20.
    Rajewsky, K., Takemori, T., and Miiller, C. E., 1984, Self tolerance through idiotype suppression, in: Progress in Immunology V (Y. Yamamura and T. Tada, eds.), Academic Press Japan, Tokyo, p. 533.Google Scholar
  24. 21.
    Le Guern, C., Ben Aissa, F., Juy, D., Mariame, B., Buttin, G., and Cazenave, P. -A., 1979, Expression and induction of MOPC-46C) idiotopes in different strains of mice,Ann. Immunol. (Inst. Pasteur) 130C:293–302.Google Scholar
  25. 22.
    Urbain, J., Wikler, M., Franssen, J. D., and Colignon, C., 1977, Idiotypic regulation of the immune system by the induction of antibodies against anti-idiotypic antibodies, Proc. Natl. Acad. Sci. USA 74:5126–5130.PubMedCrossRefGoogle Scholar
  26. 23.
    Jerne, N. K., Roland, J., and Cazenave, P. -A., 1982, Recurrent idiotopes and internal images, EMBO J. 1:243–247.PubMedGoogle Scholar
  27. 24.
    Padlan, E. A., Davies, D. R., Pecht, I., Givol, D., and Wright, C., 1976, Model-building studies of antigen-binding sites: The hapten-binding site of MOPC-315, Cold Spring Harbor Symp. Quant. Biol. 42:627–637.Google Scholar
  28. 25.
    Dwek, R. A., Wain-Hobson, S., Dower, S., Gettins, P., Sutton, B., Perkins, S. J., and Givol, D., 1977, Structure of an antibody combining site by magnetic resonance, Nature (London) 266:31–37.CrossRefGoogle Scholar
  29. 26.
    Reth, M., Bothwell, A. L. M., and Rajewsky, K., 1981, Structural properties of the hapten binding site and Idiotopes in the NPb antibody family, in: Immunoglobulin idiotypes: ICN-UCLA Symposia on Molecular and Cellular Biology, Volume XX (C. A. Janeway, Jr., E. E. Sercarz, and H. Wigzell, eds.), Academic Press, New York, pp. 169–178.Google Scholar
  30. 27.
    Weigert, M., and Riblet, R., 1976, Genetic control of antibody variable regions in the mouse,Cold Spring Harbor Symp. Quant. Biol. 41:837–846.CrossRefGoogle Scholar
  31. 28.
    Tesch, H., Smith, F. I., Mtiller-Hermes, W. J. P., and Rajewsky, K., 1984, Heterogeneous and monoclonal helper T cells induce similar anti-NP antibody populations in the primary adoptive response. I. Isotype distribution, Eur. J. Immunol. 14:188–194.PubMedCrossRefGoogle Scholar
  32. 29.
    Smith, F. I., Tesch, H., and Rajewsky, K., 1984, Heterogeneous and monoclonal helper T cells induce similar anti-(4-hydroxy-3-nitrophenyl)acetyl (NP) antibody populations in the primary adoptive response, Eur. J. Immunol. 14:195–200.PubMedCrossRefGoogle Scholar
  33. 30.
    Loh, D. Y., Bothwell, A. L. M., White-Scharf, M. E., Imanishi-Kari, T., and Baltimore, D., 1983, Molecular basis of mouse strain-specific anti-hapten response, Cell 33:85–93.PubMedCrossRefGoogle Scholar
  34. 31.
    Rocca-Serra, J., Tonnelle, C., and Fougereau, M., 1983, Two monoclonal antibodies against antigens using the same V H germ-line gene, Nature 304:353–355.PubMedCrossRefGoogle Scholar
  35. 32.
    Nishikawa, S., Takemori, T., and Rajewsky, K., 1983, The expression of a set of antibody variable regions in LPS reactive B cells at various stages of ontogeny and its control by anti-idiotypic antibody, Eur. J. Immunol. 13:318–325.PubMedCrossRefGoogle Scholar
  36. 33.
    Eichmann, K., 1974, Idiotype suppression. I. Influence of the dose and of the effector functions of antiidiotypic antibody on the production of an idiotype,Eur. J. Immunol. 4:296–302.PubMedCrossRefGoogle Scholar
  37. 34.
    Eichmann, K., and Rajewsky, K., 1975, Induction of T and B cell immunity by anti-idiotypic antibody, Eur. J. Immunol. 5:661–666.PubMedCrossRefGoogle Scholar
  38. 35.
    Kelsoe, G., Reth, M., and Rajewsky, K., 1980, Control of idiotope expression by monoclonal anti-idiotope antibodies,Immunol. Rev. 52:75–88.PubMedCrossRefGoogle Scholar
  39. 36.
    Kelsoe, G., Takemori, T., Reth, M., and Rajewsky, K., 1981, Generation of specific regulatory T cells with monoclonal anti-idiotope antibody: Induction of suppressor T cells, in: B Lymphocytes in the Immune Response: Functional, Developmental and Interactive Properties (N. R. Klinman, D. E. Mosier, I. Sher, and E. S. Vitetta, eds.), Elsevier/North-Holland, Amsterdam, pp. 423–430.Google Scholar
  40. 36a.
    Takemori, T., and Rajewsky, K., 1984, Mechanism of neonatally induced idiotype suppression and its relevance for the acquisition of self tolerance, Immunol. Rev. 79:103–117.PubMedCrossRefGoogle Scholar
  41. 37.
    Eichmann, K., 1975, Idiotype suppression. II. Amplification of a suppressor T cell with anti-idiotypic activity, Eur. J. Immunol. 5:511–515.PubMedCrossRefGoogle Scholar
  42. 38.
    Cerney, J., Cronkhite, R., and Heusser, C., 1983, Antibody response of mice following neonatal treatment with a monoclonal anti-receptor antibody: Evidence for B cell tolerance and T suppressor cells specific for different idiotopic determinants, Eur. J. Immunol. 13:244–248.CrossRefGoogle Scholar
  43. 39.
    Berek, C., 1983, Antibodies specific for different T15 idiotopes induce neonatal suppression of the T15 idiotype, Eur. J. Immunol. 13:766–772.PubMedCrossRefGoogle Scholar
  44. 40.
    Hiinig, T., 1983, The role of accessory cells in polyclonal T cell activation. II. Induction of interleukin 2 responsiveness requires cell-cell contact,Eur. J. Immunol. 13:596–601.CrossRefGoogle Scholar
  45. 41.
    Unanue, E. R., 1981, The regulatory role of macrophages in antigenic stimulation. Part two: Symbiotic relationship between lymphocytes and macrophages,Adv. Immunol. 31:1–136.PubMedCrossRefGoogle Scholar
  46. 42.
    Chestnut, R. W., and Grey, H. M., 1981, Studies on the capacity of B cells to serve as antigen-presenting cells, J. Immunol. 126:1075–1079.Google Scholar
  47. 43.
    Cerny, J., and Caulfield, M. J., 1981, Stimulation of specific antibody-forming cells in antigen-primed nude mice by the adoptive transfer of syngeneic anti-idiotypic T cells, J. Immunol. 126:2262–2266.PubMedGoogle Scholar
  48. 44.
    Richter, R. H., 1975, A network theory of the immune system, Eur. J. Immunol. 5:350–354.PubMedCrossRefGoogle Scholar
  49. 45.
    Rajewsky, K., 1983, Symmetry and asymmetry in idiotypic interactions, Ann. Immunol. (Inst. Pasteur) 134D:133–141.CrossRefGoogle Scholar
  50. 46.
    Wikler, M., Demeur, C., Dewasme, G., and Urbain, J., 1980, Immunoregulatory role of maternal idiotypes: Ontogeny of immune networks,J. Exp. Med. 152:1024–1035.PubMedCrossRefGoogle Scholar
  51. 47.
    Rubinstein, L. J., Yeh, M., and Bona, C. A., 1982, Idiotype-anti-idiotype network. II. Activation of silent clones by treatment at birth with idiotypes is associated with the expansion of idiotype-specific helper T cells,J.Exp. Med. 156:506–521.PubMedCrossRefGoogle Scholar
  52. 48.
    Ivars, F., Holmberg, D., Forni, L., Cazenave, P. -A., and Coutinho, A., 1982, Antigen-independent IgM- induced antibody responses: Requirement for “recurrent” idiotypes, Eur. J. Immunol. 12:146–151.PubMedCrossRefGoogle Scholar
  53. 49.
    Ortiz-Ortiz, L., Weigle, W. O., and Parks, D. L., 1982, Deregulation of idiotype expression: Induction of tolerance in an anti-idiotypic response, J. Exp. Med. 156:898–911.PubMedCrossRefGoogle Scholar
  54. 50.
    Jormalainen, S., and Makela, O., 1971, Anti-hapten antibodies in normal sera, Eur. J. Immunol. 1:471–478.PubMedCrossRefGoogle Scholar
  55. 51.
    Sprent, J., 1973, Circulating T and B lymphocytes of the mouse. II. Life span, Cell Immunol. 7:40–59.PubMedCrossRefGoogle Scholar
  56. 52.
    Eichmann, K., Falk, I., and Rajewsky, K., 1978, Recognition of idiotypes in lymphocyte interactions. II. Antigen-independent cooperation between T and B lymphocytes that possess similar and complementary idiotypes, Eur. J. Immunol. 8:853–857.PubMedCrossRefGoogle Scholar
  57. 53.
    Gearhart, P.-J., 1982, Generation of immunoglobulin variable gene diversity, Immunol. Today 3:107–112.CrossRefGoogle Scholar
  58. 54.
    Rajewsky, K., and Eichmann, K., 1977, Antigen receptors of T helper cells, Contemp. Top. Immunobiol. 7:69–112.PubMedGoogle Scholar
  59. 55.
    Binz, H., and Wigzell, H., 1977, Antigen-binding idiotypic T-lymphocyte receptors,Contemp. Top. Immunobiol. 7:113–177.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Klaus Rajewsky
    • 1
  1. 1.Institute for GeneticsUniversity of CologneCologne 41Federal Republic of Germany

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