Peripheral Tolerance and Organ Specific Autoimmunity

  • Harald von Boehmer
  • Elmar Jaeckel
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 490)


Concepts of specific immunotolerance were first introduced after the clonal selection theory gained acceptance. In early days Burnet and Lederberg formulated the simple concept that there was a fundamental difference between immature and mature, antigen-receptor bearing lymphocytes such that binding of antigen by the former would result in cell death, while binding to the latter would result in gain of effector function. At that time it was not known that immunocytes developed in distinct anatomical sites and thus would perhaps not encounter all self antigens as if they were circulating in the organism like mature lymphocytes. Even then this concept would fail to deal with proteins expressed only in adulthood. Nevertheless, this was the first theory of recessive tolerance that gained experimental support and by now is an established fact. A variant of that theme is the recently discovered receptor-deletion whereby immature B but not T cells change their receptors when confronted with antigen, perhaps because the antigen keeps the rearrangement process ongoing whereby already productive genes are deleted and new ones are being generated. Thus we have clonal or cellular deletion as well as receptor editing of immature lymphocytes as possible mechanism that affect immature lymphocytes whereby unresponsiveness is achieved without prior activation to effector function i.e. cytokine secretion, cytolytic activity or antibody production.


Molecular Mimicry Oral Tolerance Nonobese Diabetic Mouse Activation Induce Cell Death Receptor Editing 
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  1. 1.
    F.M.A. Burnet, A modification of Jerne’s theory of antibody production using the concept of clonal selection.Australian Journal of Science 20,67–69 (1957).Google Scholar
  2. 2.
    F.M.A. Burnet, The clonal selection theory.London Cambridge University Press(1959).Google Scholar
  3. 3.
    J. Lederberg, Genes and antibodies: Do antigens bear instructions for antibody specificity or they select cell lines that arise by mutation?Science 129,1649(1959).PubMedCrossRefGoogle Scholar
  4. 4.
    D. Gay, T. Saunders, S. Camper, M. Weigert, Receptor editing: an approach by autoreactive B cells to escape tolerance.JExp Med 177,999–1008 (1993).CrossRefGoogle Scholar
  5. 5.
    S.L. Tiegs, D.M. Russell, D. Nemazee, Receptor editing in self-reactive bone marrow B cells.J Exp Med 177,1009–1020 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    R.K. Gershon, K. Kondo, Infectious immunological tolerance.Immunology 21,903–914 (1971).PubMedGoogle Scholar
  7. 7.
    E.M. Shevach, A. Thornton, E. Suri-Payer, T lymphocyte-mediated control of autoimmunity.Novartis Found Symp 215,200–211 (1998).PubMedGoogle Scholar
  8. 8.
    R.K. Gershon, K. Kondo, Cell interactions in the induction of tolerance: the role of thymic lymphocytes.Immunology 18,723–737 (1970).PubMedGoogle Scholar
  9. 9.
    S. Sakaguchi, K. Fukuma, K. Kuribayashi, T. Masuda, Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease.JExp Med 161,72–87 (1985).CrossRefGoogle Scholar
  10. 10.
    D. Fowell, A.J. McKnight, F. Powrie, R. Dyke, D. Mason, Subsets of CD4+ T cells and their roles in the induction and prevention of autoimmunity.Immunol Rev 123,37–64 (1991).PubMedCrossRefGoogle Scholar
  11. 11.
    A. Miller, A. al-Sabbagh, L.M. Santos, M.P. Das, H.L. Weiner, Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression.J Immunol 1517307–7315 (1993).PubMedGoogle Scholar
  12. 12.
    A. Miller, O. Lider, H.L. Weiner, Antigen-driven bystander suppression after oral administration of antigens.JExp Med 174,791–798 (1991).CrossRefGoogle Scholar
  13. 13.
    Y. Chen, V.K. Kuchroo, J. Inobe, D.A. Hafler, H.L. Weiner, Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.Science 265,1237–1240 (1994).PubMedCrossRefGoogle Scholar
  14. 14.
    F. Powrie, J. Carlino, M.W. Leach, S. Mauze, R.L. Coffman, A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.JExp Med 183,2669–2674 (1996).CrossRefGoogle Scholar
  15. 15.
    A.M. Thornton, E.M. Shevach, CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.JExp Med 188,287–296 (1998).CrossRefGoogle Scholar
  16. 16.
    B. Rocha, H. von Boehmer, Peripheral selection of the T cell repertoire.Science 251,1225–1228 (1991).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Lanoue, C. Bona, H. von Boehmer, A. Sarukhan, Conditions that induce tolerance in mature CD4+ T cells.JExp Med 185,405–414 (1997).CrossRefGoogle Scholar
  18. 18.
    B. Rocha, A. Grandien, A.A. Freitas, Anergy and exhaustion are independent mechanisms of peripheral T cell tolerance.J Exp Med 181,993–1003 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    S. Webb, C. Morris, J. Sprent, Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity.Cell 63,1249–1256 (1990).PubMedCrossRefGoogle Scholar
  20. 20.
    C. Kurts, H. Kosaka, F.R. Carbone, J.F. Miller, W.R. Heath, Class I-restricted cross-presentation of exogenous self-antigens leads to deletion of autoreactive CD8(+) T cells.JExp Med 186,239–245 (1997).CrossRefGoogle Scholar
  21. 21.
    J. Buer, A. Lanoue, A. Franzke, C. Garcia, H. von Boehmer, A. Sarukhan, Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo.JExp Med 187,177–183 (1998).CrossRefGoogle Scholar
  22. 22.
    C. Tanchot, S. Guillaume, J. Delon, C. Bourgeois, A. Franzke, A. Sarukhan, A. Trautmann, B. Rocha, Modifications of CD8+ T cell function during in vivo memory or tolerance induction.Immunity 8,581–590 (1998).PubMedCrossRefGoogle Scholar
  23. 23.
    B. Rocha, C. Tanchot, H. von Boehmer, Clonal anergy blocks in vivo growth of mature T cells and can be reversed in the absence of antigen.JExp Med 177,1517–1521 (1993).CrossRefGoogle Scholar
  24. 24.
    K.W. Wucherpfennig, J.L. Strominger, Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein.Cell 80,695–705 (1995).PubMedCrossRefGoogle Scholar
  25. 25.
    P.S. Ohashi, S. Oehen, K. Buerki, H. Pircher, C.T. Ohashi, B. Odermatt, B. Malissen, R.M. Zinkernagel, H. Hengartner, Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice.Cell 65,305–317 (1991).PubMedCrossRefGoogle Scholar
  26. 26.
    M.B. Oldstone, M. Nerenberg, P. Southern, J. Price, H. Lewicki, Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response.Cell 65,319–331 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    S.R. Nahill, R.M. Welsh, High frequency of cross-reactive cytotoxic T lymphocytes elicited during the virus-induced polyclonal cytotoxic T lymphocyte response.J Exp Med 177,317–327 (1993).PubMedCrossRefGoogle Scholar
  28. 28.
    J.W. Kappler, N. Roehm, P. Marrack, T cell tolerance by clonal elimination in the thymus.Cell 49,273–280 (1987).PubMedCrossRefGoogle Scholar
  29. 29.
    H. von Boehmer, P. Kisielow, Self-nonself discrimination by T cells.Science 248,1369–1373 (1990).CrossRefGoogle Scholar
  30. 30.
    P. Kisielow, H. Bluthmann, U.D. Staerz, M. Steinmetz, H. von Boehmer, Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes.Nature 333,742–746 (1988).PubMedCrossRefGoogle Scholar
  31. 31.
    S.B. Hartley, J. Crosbie, R. Brink, A.B. Kantor, A. Basten, C.C. Goodnow, Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens.Nature 353,765–769 (1991).PubMedCrossRefGoogle Scholar
  32. 32.
    M. Lenardo, K.M. Chan, F. Hornung, H. McFarland, R. Siegel, J. Wang, L. Zheng, Mature T lymphocyte apoptosis--immune regulation in a dynamic and unpredictable antigenic environment.Annu Rev Immunol 17,221–253 (1999).PubMedCrossRefGoogle Scholar
  33. 33.
    G.G. Singer, A.K. Abbas, The fas antigen is involved in peripheral but not thymic deletion of T lymphocytes in T cell receptor transgenic mice.Immunity 1,365–371 (1994).PubMedCrossRefGoogle Scholar
  34. 34.
    L. Klein, M. Klugmann, K.A. Nave, B. Kyewski, Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cellsNat Med 6,56–61 (2000).PubMedCrossRefGoogle Scholar
  35. 35.
    L. Klein, T. Klein, U. Ruther, B. Kyewski, CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium.JExp Med188,5–16 (1998).CrossRefGoogle Scholar
  36. 36.
    C. Jolicoeur, D. Hanahan, K.M. Smith, T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus.Proc Natl Acad Sci USA 91,6707–6711 (1994).PubMedCrossRefGoogle Scholar
  37. 37.
    L. Klein and B. Kyewski, Self-antigen presentation by thymic stromal cells: A subtle division of labor. Curr Opin Immunol (2000).in pressGoogle Scholar
  38. 38.
    J. Kirberg, L. Bruno, H. von Boehmer, CD4+8-help prevents rapid deletion of CD8+ cells after a transient response to antigen.Eur J Immunol 23,1963–1967 (1993).PubMedCrossRefGoogle Scholar
  39. 39.
    H. von Boehmer, J. Kirberg, L. Bruno, A. Lanoue and A. Sarukhan, Tolerance induction in mature CD8+and CD4+T cells. In (Eds. J. Banchereau, B. Dodet, R. Schwartz and E. Trannoy) pp. 5–20, Elsevier, Paris 1996.Google Scholar
  40. 40.
    C. Kurts, F.R. Carbone, M. Barnden, E. Blanas, J. Allison, W.R. Heath, J.F. Miller, CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.JExp Med 186,2057–2062 (1997).CrossRefGoogle Scholar
  41. 41.
    L.T. Nguyen, K. McKall-Faienza, A. Zakarian, D.E. Speiser, T.W. Mak, P.S. Ohashi, TNF receptor 1 (TNFR1) and CD95 are not required for T cell deletion after virus infection but contribute to peptide-induced deletion under limited conditions.Eur J Immunol 30,683–688 (2000).PubMedCrossRefGoogle Scholar
  42. 42.
    A. Reich, H. Korner, J.D. Sedgwick, H. Pircher, Immune down-regulation and peripheral deletion of CD8 T cells does not require TNF receptor-ligand interactions nor CD95 (Fas, APO-1).Eur JImmunol 30,678–682 (2000).CrossRefGoogle Scholar
  43. 43.
    J.G. Chai, I. Bartok, P. Chandler, S. Vendetti, A. Antoniou, J. Dyson, R. Lechler, Anergic T cells act as suppressor cells in vitro and in vivo.Eur J Immunol 29,686–692 (1999).PubMedCrossRefGoogle Scholar
  44. 44.
    H.L. Weiner, Oral tolerance: immune mechanisms and treatment of autoimmune diseases.Immunol Today 18,335–343 (1997).PubMedCrossRefGoogle Scholar
  45. 45.
    Y. Chen, V.K. Kuchroo, J. Inobe, D.A. Haler, H.L. Weiner, Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.Science 265,1237–1240 (1994).PubMedCrossRefGoogle Scholar
  46. 46.
    Y. Chen, J. Inobe, R. Marks, P. Gonnella, V.K. Kuchroo, H.L. Weiner, Peripheral deletion of antigen-reactive T cells in oral tolerance.Nature 376,177–180 (1995).PubMedCrossRefGoogle Scholar
  47. 47.
    E. Blanas, F.R. Carbone, J. Allison, J.F. Miller, W.R. Heath, Induction of autoimmune diabetes by oral administration of autoantigen.Science 274,1707–1709 (1996).PubMedCrossRefGoogle Scholar
  48. 48.
    E. Suri-Payer, A.Z. Amar, R. McHugh, K. Natarajan, D.H. Margulies, E.M. Shevach, Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of antiH/K ATPase-reactive T cells.Eur JImmunol 29,669–677 (1999).CrossRefGoogle Scholar
  49. 49.
    T.L. Delovitch, B. Singh, The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD.Immunity 7,727–738 (1997).PubMedCrossRefGoogle Scholar
  50. 50.
    R. Tisch, H. McDevitt, Insulin-dependent diabetes mellitus.Cell 85,291–297 (1996).PubMedCrossRefGoogle Scholar
  51. 51.
    J.F. Bach, D. Mathis, The NOD mouse.Res Immunol 148,285–286 (1997).CrossRefGoogle Scholar
  52. 52.
    J.D. Katz, B. Wang, K. Haskins, C. Benoist, D. Mathis, Following a diabetogenic T cell from genesis through pathogenesis.Cell74,1089–1100 (1993).PubMedCrossRefGoogle Scholar
  53. 53.
    C. Kurts, W.R. Heath, F.R. Carbone, J. Allison, J.F. Miller, H. Kosaka, Constitutive class I-restricted exogenous presentation of self antigens in vivo.JExp Med184,923–930 (1996).CrossRefGoogle Scholar
  54. 54.
    D. Lo, C.R. Reilly, B. Scott, R. Liblau, H.O. McDevitt, L.C. Burkly, Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes.EurJlmmunol 23,1693–1698 (1993).Google Scholar
  55. 55.
    B. Scott, R. Liblau, S. Degermann, L.A. Marconi, L. Ogata, A.J. Caton, H.O. McDevitt, D. Lo, A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity.Immunity 1,73–83 (1994).PubMedCrossRefGoogle Scholar
  56. 56.
    S. Degermann, C. Reilly, B. Scott, L. Ogata, H. von Boehmer, D. Lo, On the various manifestations of spontaneous autoimmune diabetes in rodent models.Eur J Immunol 24,3155–3160 (1994).PubMedCrossRefGoogle Scholar
  57. 57.
    D. Kagi, B. Odermatt, P. Seiler, R.M. Zinkernagel, T.W. Mak, H. Hengartner, Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice.J Exp Med 186,989–997 (1997).PubMedCrossRefGoogle Scholar
  58. 58.
    S. Degermann, C. Reilly, B. Scott, L. Ogata, H. von Boehmer, D. Lo, On the various manifestations of spontaneous autoimmune diabetes in rodent models.Eur J Immunol 24,3155–3160 (1994).PubMedCrossRefGoogle Scholar
  59. 59.
    A. Sarukhan, A. Lanoue, A. Franzke, N. Brousse, J. Buer, H. von Boehmer, Changes in function of antigen-specific lymphocytes correlating with progression towards diabetes in a transgenic model.EMBOJ 17,71–80 (1998).CrossRefGoogle Scholar
  60. 60.
    A. Sarukhan, O. Lechner, H. von Boehmer, Autoimmune insulitis and diabetes in the absence of antigen-specific contact between T cells and islet beta-cells.Eur J Immunol 29,3410–3416 (1999).PubMedCrossRefGoogle Scholar
  61. 61.
    D.M. LaFace, A.B. Peck, Reciprocal allogeneic bone marrow transplantation between NOD mice and diabetes-nonsusceptible mice associated with transfer and prevention of autoimmune diabetes.Diabetes 38,894–901 (1989).PubMedCrossRefGoogle Scholar
  62. 62.
    U. Walter, A. Franzke, A. Sarukhan, C. Zober, H. von Boehmer, J. Buer and O. Lechner, Monitoring gene expression of TNFR family members by beta-cells during development of autoimmune diabetes. Eur J Immunol (2000).in pressGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Harald von Boehmer
    • 1
  • Elmar Jaeckel
    • 1
  1. 1.Department of Cancer Immunology & AIDSHarvard Medical School Dana-Farber Cancer InstituteBostonUSA

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