Summary
The autoimmune process that results in Type 1 (insulin-dependent) diabetes mellitus may be viewed as a failure to develop or maintain tolerance to self-antigens expressed in the islets of Langerhans. During T-cell development in the thymus, cells that are reactive with self antigens encountered there may undergo clonal deletion or, as more recently described, clonal anergy which effectively removes these cells from the pool of mature antigen reactive T cells. For antigens not found in the thymus, tolerance to self antigens is more complex and may depend on site of antigen expression, ambient concentrations of lymphokines, and availability of antigen-presenting cells that can deliver co-stimulatory signals. Transgenic mice in which the majority of T cells express T-cell receptors against “self” antigens or in which expression of antigens is targeted to peripheral tissues have proven useful for studies of tolerance in both T- and B-cell compartments. In general, T-cell reactivity against foreign antigen expressed on Beta cells does not occur because of the failure to activate T cells reactive with the antigen, termed clonal ignorance. This may be broken with, for example, viral infection or cytokines. In one transgenic model, dendritic cells that surround the islets of Langerhans have been shown to be responsible for presentation of islet antigens to the immune system. B-cell tolerance can also involve mechanisms of clonal deletion or clonal anergy similar to that occurring with T cells. In addition, a mechanism for changing the affinity of the B-cell antigen receptor termed “receptor editing” has been described, which may play an important role in diversifying the B-cell repertoire while removing self-reactive cells. Tolerance to antigens may also be induciblc. For example, monoclonal antibodies against T-cell epitopes may induce antigen-specific tolerance that is transferable to other animals, and MHC blocking peptides which can inhibit T-cell responses that are restricted by disease associated MHC molecules. In conclusion, although several possible triggers and mechanisms of autoimmune diabetes can be envisioned, none can be excluded by existing data. However, advances in understanding mechanisms of tolerance to islet and other self antigens suggest potentially useful therapeutic approaches to arresting the autoimmune response.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Rocha B, von Boehmer H (1991) Peripheral selection of the T cell repertoire. Science 251: 1225–1228
Swat W, Ignatowicz L, von Boehmer H, Kisielow P (1991) Clonal deletion of immature CD4+8+ thymocytes in suspension culture by extrathymic antigen-presenting cells. Nature 351: 150–153
Schonrich G, Mongurs R, Hammerling GJ, Arnold B (1992) Anergy induced by thymic medullary epithelium. Eur J Immunol (in press)
Miller JFAP, Morahan G, Allison J, Hoffmann M (1991) A transgenic approach to the study of peripheral T cell tolerance. Immunol Rev 122: 103–116
Morahan G, Hoffmann M, Miller JFAP (1991) A non-deletional mechanism of peripheral tolerance in T cell receptor transgenic mice. Proc Nat Acad Sci USA 88: 11421–11425
Allison J, Malcolm L, Chosich N, Miller JFAP (1992) Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of IL-2 in islet Beta cells. Eur J Immunol (in press)
Miller JFAP, Morahan G (1992) Peripheral T cell tolerance. Ann Rev Immunol 10:51–70
Schonrich G, Kalinki U, Momburg R et al. (1991) Downregulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 65:293–305
Haemmerling GJ, Schonrich G, Momburg R et al. (1991) Non-deletional mechanisms of peripheral and central tolerance: studies with transgenic mice with tissue specific expression of a foreign MHC class I antigen. Immunol Rev 122: 47–67
Schonrich G, Momburg R, Malissen M et al. (1992) Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen. Intern Immunol (in press)
Lo D, Freedman J, Hesse S, Brinster RL, Sherman L (1991) Peripheral tolerance in transgenic mice: tolerance to class II MHC and non-MHC transgene antigens. Immunol Rev 122: 87–102
Lo D, Freedman J, Hesse S, Palmiter RD, Brinster RL, Sherman L (1992) Peripheral tolerance to an islet cell specific hemagglutinin transgene affects both CD4+ and CD8+ T cells. Eur J Immunol (in press)
Ohashi PS, Oehen S, Burki K et al. (1991) Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 68: 305–317
Zinkemagel RM, Pincher HP, Ohashi P et al. (1991) T and B cell tolerance and responses to viral antigens in transgenic mice: implications for the pathogenesis of autoimmune versus immunopathological disease. Immunol Rev 122: 133–171
von Boehmer H, Kirberg J, Rocha B (1991) An unusual lineage α/β T cells that contains autoreactive cells. J Exp Med 174: 1001–1008
Nemazee D, Russell D, Dembic Z, Bürki K (1991) Peripheral deletion of self-reactive B-cells. Nature 354: 308–311
Nemazee D, Russell D, Arnold B et al. (1991) Clonal deletion of autospecific B lymphocytes. Immunol Rev 122: 117–132
Nemazee D, Bürki K (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337: 562–566
Nemazee DA, Bürki K (1989) Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc Natl Acad Sci USA 86: 8039–8043
Goodnow CC, Brink R, Adams E (1991) Breakdown of self-tolerance in anergic B lymphocytes. Nature 352: 532–536
Hartley SB, Crosbie J, Brink R, Kantor AB, Basten A, Goodnow CC (1991) Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane bound antigens. Nature 353: 765–769
Goodnow CC (1992) Transgenic mice and analysis of B cell tolerance. Ann Rev Immunol 10: 489–518
Mason DY, Jones M, Goodnow CC (1992) Development and follicular localisation of tolerant B lymphocytes in lysozyme/antilysozyme IgM/IgD-transgenic mice. Intern Immunol 4: 163–175
Karvelas M, Nossal GJV, (1992) Memory cell generation abelated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments. Proc Nat'l Acad Sci (USA) 89:3150–3154
Nossal GJV (1992) The molecular and cellular basis of affinity maturation in the antibody response. Cell 68: 1–2
Adorini L (ed) (1990) The molecular basis of antigen-presentation to T lymphocytes: novel possibilities for immunointervention. Intern Rev Immunol 6: 1–88
Guery JC, Sette A, Leighton J, Dragomir A, Adorini L (1992) Selective immunosuppression by administration of major histocompatibility complex (MHC) class II binding peptides: evidence for in vivo MHC blockade preventing T cell activation. J Exp Med 175:1345–1352
Adorini L, Barnaba V, Bona C et al. (1990) New perspectives on immunointervention in autoimmune diseases. Immunol Today 11: 383–386
Cobbold SP, Martin G, Waldmann H (1990) The induction of skin graph tolerance in major histocompatibility complex-mismatched in prime recipients: prime T-cells can be tolerized in the periphery with anti-CD4 and anti-CD8 antibodies. Eur J Immun 20: 2747–2955
Qia S, Wise M, Cobbold SP et al. (1990) Induction of tolerance in peripheral T cells with monoclonal antibodies. Eur Immun 20: 2737–2748
MacLennan IC, Liu YJ, Oldfield S et al. (1990) The evolution of Beta-cell clones. Curr Top Microbiol Immun 159: 37–63
Sarvetnick N, Shizuru J, Liggitt D et al. (1990) Loss of pancreatic islet tolerance induced by Beta-cell expression of interferon-gamma. Nature 346: 844–847
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nossal, G.J.V., Herold, K.C. & Goodnow, C.C. Autoimmune tolerance and Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 35 (Suppl 2), S49–S59 (1992). https://doi.org/10.1007/BF00586279
Issue Date:
DOI: https://doi.org/10.1007/BF00586279