Generation and Regulation of B Cell Autoreactivity Arising in the Periphery

  • Philip Kuo
  • Daniel Michael
  • Boaz Tadmor
  • Betty Diamond
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 406)


Recent work on the role of environmental antigens in activating autoreactivity underscores a potentially confounding complication to current models of peripheral tolerance. Cross-reactive B cells that bind both autoantigen and foreign antigen are capable of mediating tissue damage, yet may be subject to positive selection as a consequence of interaction with antigen and T cell help. This discussion will review our work with cross-reactive antibodies and suggest a hypothesis to explain their generation and subsequent regulation.


Somatic Mutation Germinal Center Keyhole Limpet Hemocyanin Foreign Antigen Cell Repertoire 
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  1. 1.
    Blackwell, T.K. and Alt, F.W. Mechanism and developmental program of immunoglobulin gene rearrangement in mammals. Ann. Rev. Genetics 23: 605, 1989.CrossRefGoogle Scholar
  2. 2.
    Goodnow, C.C. Transgenic mice and analysis of B cell tolerance. Annu. Rev. Immunol. 10: 489, 1992.CrossRefGoogle Scholar
  3. 3.
    MacLennan, I.C. Autoimmunity. Deletion of autoreactive B cells. Curr. Biol. 5 (2): 103–6, 1995.Google Scholar
  4. 4.
    Nemazee, D., Russell, D., Arnold, B., Haemmerling, G., Allison, J., Miller, J.F., Morahan, G. and Buerki, K. Clonal deletion of autospecific B lymphocytes. Immunol Rev. 122: 117–32, 1991.PubMedCrossRefGoogle Scholar
  5. 5.
    Radic, M., Erikson, J., Litwin, S. and Weigert, M. B lymphocytes may escape tolerance by revising their Ag receptors. J. Exp. Med. 177: 1165, 1993.CrossRefGoogle Scholar
  6. 6.
    Tiegs, S., Russell, D. and Nemazee, D. Receptor editing in self reactive bone marrow B cells. J. Exp. Med. 177: 1009, 1993.CrossRefGoogle Scholar
  7. 7.
    Gay, D., Saunders, T., Camper, S. and Weigert, M., Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177: 999, 1993.PubMedCrossRefGoogle Scholar
  8. 8.
    Goodnow, C.C., Crosbie, T., Adelstein, S., Lavoie, T.B., Smith-Gill, S. J., Brink, R.A. Pritchard-Briscoe, H., Witherspoon, J.S., Lobley, R.H., Raphael K., Trent, R.J. and Basten, A. Altered immunoglobulin expression and functional silencing of self reactive B lymphocytes in transgenic mice. Nature 334: 676, 1988.PubMedCrossRefGoogle Scholar
  9. 9.
    Nemazee, D.A. and Burki, K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature. 337: 562, 1989.PubMedCrossRefGoogle Scholar
  10. 10.
    Hartley, S.B., Crosbie, J., Brink, R.A., Kantor, A.B., Basten, A. and Goodnow, C.C. Elimination from peripheral lymph tissue of self reactive B lymphocytes recognizing membrane bound Ag. Nature 353: 765, 1991.PubMedCrossRefGoogle Scholar
  11. 11.
    Erikson, J., Radic, M.Z., Camper, S.A., Hardy, R.R., Carmack, C. and Weigert, M. Expression of anti-DNA immunoglobulin transgene in non-autoimmune mice. Nature. 349: 331, 1991.PubMedCrossRefGoogle Scholar
  12. 12.
    Bretscher, P. and Cohen M. A theory of self-nonself discrimination. Science 169: 1042, 1970.PubMedCrossRefGoogle Scholar
  13. 13.
    Bretscher, P. The two signal model of lymphocyte activation twenty-one years later. Immunol. Today 13: 74, 1992.PubMedCrossRefGoogle Scholar
  14. 14.
    Offen, D., Spatz, L., Escowitz, H., Factor, S. and Diamond, B. Induction of tolerance to an IgG autoantibody. Proc. Natl. Acad. Sci. 89: 8332, 1992.PubMedCrossRefGoogle Scholar
  15. 15.
    Russell, D.M., Dembic, Z., Morahan, G., Miller, J.F., Burki, K. and Nemazee, D. Peripheral deletion of self-reactive B cells. Nature. 354: 308, 1991.PubMedCrossRefGoogle Scholar
  16. 16.
    Oettinger, M.A., Schatz, D.G., Gorka, C. and Baltimore, D. RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science. 248: 1517, 1990.PubMedCrossRefGoogle Scholar
  17. 17.
    Gray, D. Regulation of immunological memory. Curr Opin Immunol. 6: 425, 1994.PubMedCrossRefGoogle Scholar
  18. 18.
    Thorbecke, G.J., Amin, A.R. and Tsiagbe, V.K. Biology of germinal centers in lymphoid tissue. FASEB J. 8: 832, 1994.PubMedGoogle Scholar
  19. 19.
    Apel, M. and Berek, C. Somatic mutations in antibodies expressed by germinal center B cells early after primary immunization. Int. Immunol. 2: 813, 1990.Google Scholar
  20. 20.
    Jacob, J., Kelsoe, Rajewsky, K. and Weiss, U. Intraclonal generation of antibody mutants in germinal centers. Nature 354: 389, 1991.PubMedCrossRefGoogle Scholar
  21. 21.
    Betz, A.G., Neuberger, M.S. and Milstein, C. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol. Today 14: 405, 1993.PubMedCrossRefGoogle Scholar
  22. 22.
    Betz, A.G., Rada, C., Pannel, R., Milstein, C. and Neuberger, M.S. Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc. Nat. Acad. Sci. USA 90: 2385, 1993.PubMedCrossRefGoogle Scholar
  23. 23.
    Reynaud, C.A., Anquez, V., Duhan, A. and Weill, J.L. A single rearrangement event generates most of the chicken immunoglobulin light chain diversity. Cell 40: 283, 1985PubMedCrossRefGoogle Scholar
  24. 24.
    Reynaud, L.A., Garcia, C., Hein, W.R. and Weill, J.L. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 80: 115, 1995.PubMedCrossRefGoogle Scholar
  25. 25.
    Diamond, B., Katz, J.B., Paul, E., Aranow, C., Lustgarten, D. and Scharff, M.D. The role of somatic mutation in the pathogenic anti-DNA response. Ann. Rev. Immunol. 10: 731, 1992.CrossRefGoogle Scholar
  26. 26.
    Manheimer-Lory, A., Monhian, R., Splaver, A., Gaynor, B. and Diamond, B. Analysis of the VkI family: Germline genes and expressed antibodies. Autoimmunity 20: 259, 1995.PubMedCrossRefGoogle Scholar
  27. 27.
    Manheimer-Lory, A., Irigoyen, M., Gaynor, B., Monhian, R., Splaver, A. and Diamond, B. Analysis of VKI and VKII light chain genes in the expressed B cell repertoire. Annals of the N.Y. Acad. Sci. 764: 301, 1995.CrossRefGoogle Scholar
  28. 28.
    Manheimer-Lory, A., Katz, J.B., Pillinger, M., Ghossein, C., Smith, A. and Diamond, B. Molecular characteristics of antibodies bearing an anti-DNA associated idiotype. J. Exp. Med. 174: 1639, 1991.PubMedCrossRefGoogle Scholar
  29. 29.
    Paul, E. and Diamond, B. Characterization of two human anti-DNA antibodies bearing the pathogenic idiotype 8.12. Autoimmunity 16: 13, 1993.PubMedCrossRefGoogle Scholar
  30. 30.
    Radic, M.Z. and Weigert, M. Genetic and structural evidence for Ag selection of anti-DNA antibodies. Ann. Rev. Immunol. 12: 487. 1994.CrossRefGoogle Scholar
  31. 31.
    Shlomchik, M., Mascelli, M., Shan, H., Radic, M.F., Pisetsky, D., Marshak-Rothstein, A. and Weigert, M. Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation. J. Exp. Med. 171: 765, 1990.CrossRefGoogle Scholar
  32. 32.
    Marion, T.N., Tillman, D.M., Jou, N.T. and Hill, R.J. Selection of immunoglobulin variable regions in autoimmunity to DNA. Immunol Rev. 128: 123, 1992.PubMedCrossRefGoogle Scholar
  33. 33.
    Shlomchik, M.J., Aucoin, A.H., Pisetsky, D.S. and Weigert, M.G. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc. Natl. Acad. Sci. USA. 84: 9150, 1987.PubMedCrossRefGoogle Scholar
  34. 34.
    Shoenfeld, Y., Vilner, Y., Coates, A.R.M, Rauch, J., Lavie, G., Shaul, D. and Pinkhas, J. Monoclonal anti-tuberculosis antibodies react with DNA and monoclonal anti-DNA antibodies react with Mycobacterium tuberculosis. Clin Exp Immunol. 66: 255, 1986.PubMedGoogle Scholar
  35. 35.
    Carroll, P., Stafford, D., Schwartz, A. and Stollar, B.D. Murine monoclonal anti-DNA autoantibodies bind to endogenous bacteria. J Immunol. 135: 1086, 1985.PubMedGoogle Scholar
  36. 36.
    Vashishtha, A. and Fischetti, V.A. Surface-exposed conserved region of the streptococcal M protein induces antibodies cross-reactive with denatured forms of myosin. J. Immunol. 150: 4693, 1993.PubMedGoogle Scholar
  37. 37.
    Cunningham, M.W., Antone, S.M. Gulizia, J.M., McManus, B.M., Fischetti, V.A. and Gauntt, C.J. Cytotoxic and viral neutralizing antibodies cross-react with streptococcal M protein, enteroviruses and human cardiac myosin. Immunology 89: 1320, 1992.Google Scholar
  38. 38.
    Adderson, E.E., Shackelford, P.G., Quinn, A., Wilson, P.M., Cunningham, M.W., Insel, R.A. and Carroll, W.L. Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide. Nucleotide sequences of monospecific anti-Haemophilus antibodies and polyspecific antibodies cross-reacting with self antigens. J. Clin. Invest. 91: 3734, 1993.CrossRefGoogle Scholar
  39. 39.
    El-Roiey, A., Sela, O., Isenberg, D.A., Feldman, R., Collaco, B.C., Kennedy, R. and Shoenfeld, Y. The sera of patients with Klebsiella infections contain a common anti-DNA (16/6Id) and polynucleotide activity. Clin. Exp. Immunol. 67: 507, 1987.PubMedGoogle Scholar
  40. 40.
    Grayzel, A., Solomon, A., Aranow, C. and Diamond, B. Antibodies elicited by pneumococcal antigens bear an anti-DNA associated idiotype. J Clin. Invest. 87: 842, 1991.PubMedCrossRefGoogle Scholar
  41. 41.
    Monestier, M., Bonin, B., Migliorini, P., Dang, H., Datta, S., Kuppers, R., Rose, N., Maurer, P., Talal, N. and Bona, C. Autoantibodies of various specificities encoded by genes from the VHJ558 family bind to foreign antigens and share idiotypes of antibodies specific for self and foreign antigens. J Exp Med. 166: 1109, 1987.PubMedCrossRefGoogle Scholar
  42. 42.
    Limpanasithikul, W., Ray, S. and Diamond, B. Cross reactive antibodies have both protective and pathogenic potential. J. Immunol. 155: 967, 1995.PubMedGoogle Scholar
  43. 43.
    Diamond, B. and Scharff, M.D. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc. Natl. Acad. Sci. USA 81: 5841, 1984.PubMedCrossRefGoogle Scholar
  44. 44.
    Clarke, S.H., Staudt, L.M., Kavaler, J., Schwartz, D., Gerhard, W. and Weigert, M. Inter-and intraclonal diversity in the antibody response to influenza hemagglutinin. J. Exp. Med. 161: 687, 1985.PubMedCrossRefGoogle Scholar
  45. 45.
    Dipasquale, B. and Youle, R.J. Programmed cell death in heterokaryons. Am. J. Pathology 141: 1471, 1992.Google Scholar
  46. 46.
    Nakayama, K., Negishi, I., Kuida, K., Shinkai, Y., Louie, M.D., Fields, L.E., Lucas, P.J., Stewart, V., Alt, F.W. and Loh, D.Y. Disappearance of the lymphoid system in bcl-2 homozygous mutant chimeric mice. Science 261: 1584, 1993.PubMedCrossRefGoogle Scholar
  47. 47.
    McDonnell, T.J. and Korsmeyer, S.J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14; 18). Nature 349: 254, 1991PubMedCrossRefGoogle Scholar
  48. 48.
    Strasser, A., Whittingham, S., Vaux, D.L., Bath, M.L., Adamas, J.M. and Cory, S., and Harris, A.W. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88: 8661, 1991.PubMedCrossRefGoogle Scholar
  49. 49.
    Strasser, A., Harris, A.W. and Cory, S. The role of bc1–2 in lymphoid differentiation and neoplastic transformation. Curr Top in Micro and Imm. 182: 299, 1992.CrossRefGoogle Scholar
  50. 50.
    Hockenbery, D.M., Zutter, M., Hickey, W., Nahm, M. and Korsmeyer, S.J. Bcl-2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc. Natl. Acad. Sci. USA 88: 6961, 1991.PubMedCrossRefGoogle Scholar
  51. 51.
    Liu, Y.J., Mason, D.Y., Johnson, G.D., Abbott, S., Gregory, C.D., Hardie, D.L., Gordon, H.J. and MacLennan, I.C. Germinal center cells express bc1–2 protein after activation by signals which prevent their entry into apoptosis. Eur. J. Immunol. 21: 1905, 1991.Google Scholar
  52. 52.
    Boise, L.H., Gonzalez-Garcia, M., Postema, C.E., Ding, L., Lindstein, T., Turka, L.A., Mao, X., Nunez, G. and Thompson, C.B. bel-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74: 597, 1993.PubMedCrossRefGoogle Scholar
  53. 53.
    Nunez, G., Merino, R., Grillot, D. and Gonzalez-Garcia, M. Bcl-2 and Bcl-x: regulatory switches for lymphoid death and survival. Immunol. Today 15: 582, 1994.PubMedCrossRefGoogle Scholar
  54. 54.
    Ohta K., Iwai K., Kasahara Y., Taniguchi N., Krajewski S., Reed J.C. and Miyawaki T. Immunoblot analysis of cellular expression of Bcl-2 family proteins, Bcl-2, Bax, Bcl-X and Mc1–1 in human peripheral blood and lymphoid tissues. Int. Immunol. 7: 1817, 1995.PubMedCrossRefGoogle Scholar
  55. 55.
    Ray, S. and Diamond, B. Generation of a novel fusion partner to sample the repertoire of splenic B cells destined for apoptosis. Proc. Natl. Acad. Sci. USA 91: 5548, 1994.PubMedCrossRefGoogle Scholar
  56. 56.
    Ray S., Putterman C. and Diamond B. Pathogenic autoantibodies are routinely generated during the response to foreign antigen: a paradigm for autoimmune disease. Proc. Natl. Acad. Sci. USA (In press).Google Scholar
  57. 57.
    Crews, S., Griffin, J., Huang, H., Calame, K. and Hood, L. A single VH gene encodes the immunological response to PC. Cell 25: 59, 1981.PubMedCrossRefGoogle Scholar
  58. 58.
    George, J., Penner, S.J., Weber, J., Berry, J. and Claflin, J.L. Influence of membrane Ig receptor density and affinity on B cell signaling by antigen. Implications for affinity maturation. J. Immunol. 151: 5955, 1993.PubMedGoogle Scholar
  59. 59.
    Hartley, S.B., Cooke, M.P., Fulcher, D.A., Harris, A.W., Cory, S., Basten, A. and Goodnow, C.C. Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death. Cell 72: 325, 1993.PubMedCrossRefGoogle Scholar
  60. 60.
    Pulendran, B., KIannourakis, G., Nouri, S., Smith, K.G.C. and Nossal, G.J.V. Soluble antigen can cause enhanced apoptosis of germinal-center B cells. Nature 375: 331, 1995.PubMedCrossRefGoogle Scholar
  61. 61.
    Shokat, K.M. and Goodnow, C.C. Antigen-induced B-cell death and elimination during germinal-center immune responses. Nature 375: 334, 1995.PubMedCrossRefGoogle Scholar
  62. 62.
    Linton, P., Rudie, A. and Klinman, N.R. Tolerance susceptibility of newly generating memory B cells. J. Immunol. 146: 4099, 1991.PubMedGoogle Scholar
  63. 63.
    Johnson, J.G. and Jemmerson, J.G. Tolerance induction in resting memory B cells specific for a protein antigen. J. Immunol. 148: 2682, 1992.PubMedGoogle Scholar
  64. 64.
    Unni, K.K., Holley, K.E., McDuffie, F.C. and Titus, J.L. Comparative study of NZB mice under germ free and conventional conditions. J. Rheumatol. 2: 36, 1975.PubMedGoogle Scholar
  65. 65.
    Taurog, J.D., Richardson, J.A., Croft, J.T., Simmons, W.A., Zhou, M., Fernandez-Sueiro, J.L., Balish, E. and Hammer, R.E. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J. Exp. Med. 180: 2359, 1994.PubMedCrossRefGoogle Scholar
  66. 66.
    Fieser, T.M., Gershwin, M.E., Steinberg, A.D., Dixon, F.J. and Theofilopoulos, A.N. Abrogation of murine lupus by the xid gene is associated with reduced responsiveness of B cells to T-cell-helper signals. Cellular Immunol. 87: 708, 1984.CrossRefGoogle Scholar
  67. 67.
    Arnett, F.C. The genetic basis of lupus erythematosus. In: Dubois’ Lupus Erythematosus, 4e. Wallace, D.J. and Hahn, B.H. eds. pp. 13–36. Philadelphia, Lea and Febiger, 1993.Google Scholar
  68. 68.
    Naparstek, Y., Andre-Schwartz, J., Manser, T., Wysocki, L.J., Breitman, L., Stollar, B.D., Gefter, M. and Schwartz, R.S. A single germline VH gene segment of normal A/J mice encodes autoantibodies characteristics of systemic lupus erythematosus. J. Exp. Med. 164: 614, 1986.PubMedCrossRefGoogle Scholar
  69. 69.
    Casson, L.P. and Manser, T. Random mutagenesis of two complementarity determining region amino acids yields an unexpectedly high frequency of antibodies with increased affinity for both cognate antigen and autoantigen J. Exp. Med. 182: 743, 1995.PubMedCrossRefGoogle Scholar
  70. 70.
    Lagresie, C., Bella C., Daniel, P.T., Kramer, P.H. and Defrance, T. Regulation of germinal center B cell differentiation. Role of the human APO-1/FAS (CD95) molecule. J. Immunol. 154: 5746, 1995.Google Scholar
  71. 71.
    Watanabe D., Suda T. and Nagata S. Expression of Fas in B cells of the mouse germinal center and Fas-dependent killing of activated B cells. Int Immunol. 12: 1949, 1995.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Philip Kuo
    • 1
  • Daniel Michael
    • 1
  • Boaz Tadmor
    • 1
  • Betty Diamond
    • 1
  1. 1.Albert Einstein College of MedicineBronxUSA

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