Pathogenesis of Autoimmune Disease



The term autoimmunity signifies the presence of specific memory-type immune reactions that are directed against one or more self-epitopes. Under most conditions, autoimmunity is determined in terms of immunoglobulins that react with either unknown or well-defined human antigens. Today it is supposed that the production of these autoantibodies requires prior activation of potentially autoreactive B cells by memory T cells. These T cells not only have to recognize a closely related peptide structure. Importantly, these T cells can stimulate B cells only when primed by activated antigen presenting cells.


Major Histocompatibility Complex Bullous Pemphigoid Major Histocompatibility Complex Molecule Peripheral Tolerance Inflammatory Autoimmune Disease 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Abrams JR, Kelley SL, Hayes E, Kikuchi T, Brown MJ, Kang S, Lebwohl MG, Guzzo CA, Jegasothy BV, Linsley PS, Krueger JG (2000) Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells. J Exp Med 192: 681–694PubMedCrossRefGoogle Scholar
  2. Ackermann L, Harvima IT (1998) Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis. Arch Dermatol Res 290: 353–359PubMedCrossRefGoogle Scholar
  3. Adorini L, Sinigaglia F (1997) Pathogenesis and immunotherapy of autoimmune diseases. Immunol Today 18: 209–211PubMedCrossRefGoogle Scholar
  4. Akdis CA, Joss A, Akdis M, Faith A, Blaser K (2000) A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding. Faseb J 14: 1666–1668PubMedGoogle Scholar
  5. Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392: 86–89PubMedCrossRefGoogle Scholar
  6. Alferink J, Tafuri A, Vestweber D, Hallmann R, Hammerling GJ, Arnold B (1998) Control of neonatal tolerance to tissue antigens by peripheral T cell trafficking. Science 282: 1338–1341PubMedCrossRefGoogle Scholar
  7. Amagai M, Klaus-Kovtun V, Stanley JR (1991) Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67: 869–877PubMedCrossRefGoogle Scholar
  8. Amagai M, Hashimoto T, Shimizu N, Nishikawa T (1994) Absorption of pathogenic antoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg 3) produced by baculovirus. J Clin Invest 94: 59–67PubMedCrossRefGoogle Scholar
  9. Arnold B, Schonrich G, Hammerling GJ (1993) Multiple levels of peripheral tolerance. Immunol. Today 14: 12–14Google Scholar
  10. Austin LM, Ozawa M, Kikuchi T, Walters IB, Krueger JG (1999) The majority of epidermal T cells in Psoriasis vulgaris lesions can produce type 1 cytokines, interferon-gamma, interleukin-2, and tumor necrosis factor-alpha, defining TC1 (cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in circulating blood T cells in psoriatic patients. J Invest Dermatol 113: 752–759PubMedCrossRefGoogle Scholar
  11. Bachmaier K, Neu N, de la Maza LM, Pal S, Hessel A, Penninger JM (1999) Chlamydia in- fections and heart disease linked through antigenic mimicry. Science 283: 1335–1339PubMedCrossRefGoogle Scholar
  12. Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S (1994) The CD40 antigen and its ligand. Annu Rev Immunol 12: 881–922PubMedCrossRefGoogle Scholar
  13. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392: 245–252PubMedCrossRefGoogle Scholar
  14. Bendelac A, Carnaud C, Boitard C, Bach JF (1987) Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt2+ T cells. J Exp Med 166: 823–832PubMedCrossRefGoogle Scholar
  15. Berg PA, Klein R, Röcken M (1997) Cytokines in primary biliary cirrhosis. Semin Liver Dis 17: 115–123PubMedCrossRefGoogle Scholar
  16. Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, Kollias G, Kunkel SL, Hultner L, Röcken M (2000) Mast Cells Control Neutrophil Recruitment during T Cell-mediated Delayed-type Hypersensitivity Reactions through Tumor Necrosis Factor and Macrophage Inflammatory Protein 2. J Exp Med 192: 1441–1452PubMedCrossRefGoogle Scholar
  17. Biedermann T, Mailhammer R, Mai A, Sander C, Ogilvie A, Brombacher F, Maier K, Levine AD, Röcken M (2001) Reversal of established delayed type hypersensitivity reactions following therapy with II.-4 or antigen-specific Th2 cells. Eur J Immunol 31: 1582–1591PubMedCrossRefGoogle Scholar
  18. Biedermann T, Röcken M (2001) T cells. In Immune Mechanisms in cutaneous disease, 2nd Edition, DA Norris, ed. New York: Marcel Dekker, Inc., in pressGoogle Scholar
  19. Bischoff SC, Lorentz A, Schwengberg S, Weier G, Raab R, Manns MP (1999) Mast cells are an important cellular source of tumour necrosis factor alpha in human intestinal tissue. Gut 44: 643–652PubMedCrossRefGoogle Scholar
  20. Blackman M, Kappler J, Marrack P (1990) The role of the T cell receptor in positive and negative selection of developing T cells. Science 248: 1335–1341PubMedCrossRefGoogle Scholar
  21. Bonomo A, Matzinger P (1993) Thymus epithelium induces tissue-specific tolerance. J Exp Med 177: 1153–1164PubMedCrossRefGoogle Scholar
  22. Bouneaud C, Kourilsky P, Bousso P (2000) Impact of Negative Selection on the T Cell Repertoire Reactive to a Self-Peptide. A Large Fraction of T Cell Clones Escapes Clonal Deletion. Immunity 13: 829–840Google Scholar
  23. Büdinger L, Borradori L, Yee C, Eming R, Ferencik S, Grosse-Wilde H, Merk HF, Yancey K, Hertl M (1998) Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls. J Clin Invest 102: 2082–2089PubMedCrossRefGoogle Scholar
  24. Chen R, Diaz L, Giudice G, Liu Z (2000) The role of C5a in mast cell activation during subepidermal blistering in experimetnal bullous pemphigoid. J Invest Dermatol 114 (A): 762Google Scholar
  25. Christophers E (1996) The immunopathology of psoriasis. Int Arch Allergy Immunol 110: 199–206PubMedCrossRefGoogle Scholar
  26. Chuang TY, Stitle L, Brashear R, Lewis C (1999) Hepatitis C virus and lichen planus: A case-control study of 340 patients. J Am Acad Dermatol 41: 787–789PubMedCrossRefGoogle Scholar
  27. Degitz K, Röcken M (1997) Lichen ruber planus nach Hepatitis-B-Impfung. In: Plewig G and Przybilla B (eds) Fortschritte der praktischen Dermatologie and Venerologie ( 1996 ) Springer, Berlin Heidelberg New York, 426–427CrossRefGoogle Scholar
  28. Ehl S, Hombach J, Aichele P, Rulicke T, Odermatt B, Hengartner H, Zinkernagel R, Pircher H (1998) Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+ T cells to cause immunopathology. J Exp Med 187: 763–774PubMedCrossRefGoogle Scholar
  29. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397–440PubMedCrossRefGoogle Scholar
  30. Gautam AM, Lock CB, Smilek DE, Pearson CI, Steinman L, McDevitt HO (1994) Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity. Proc Natl Acad Sci USA 91: 767–771PubMedCrossRefGoogle Scholar
  31. Gelbmann CM, Mestermann S, Gross V, Kollinger M, Scholmerich J, Falk W (1999) Strictures in Crohns disease are characterised by an accumulation of mast cells colocalised with laminin but not with fibronectin or vitronectin. Gut 45: 210–217PubMedCrossRefGoogle Scholar
  32. Gerlach JT, Diepolder HM, Jung MC, Gruener NH, Schraut WW, Zachoval R, Hoffmann R, Schirren CA, Santantonio T, Pape GR (1999) Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 117: 933–941PubMedCrossRefGoogle Scholar
  33. Goldman M, Druet P, Gleichmann E (1991) TH2 cells in systemic autoimmunity: insights from allogeneic diseases and chemically-induced autoimmunity. Immunol Today 12: 223–227PubMedCrossRefGoogle Scholar
  34. Goodnow CC, Brink R, Adams E (1991) Breakdown of self-tolerance in anergic B lymphocytes. Nature 352: 532–536PubMedCrossRefGoogle Scholar
  35. Green EA, Flavell RA (2000) The temporal importance of TNFalpha expression in the development of diabetes. Immunity 12: 459–469PubMedCrossRefGoogle Scholar
  36. Groux H, Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389: 737–742PubMedCrossRefGoogle Scholar
  37. Harrison LC, Honeyman MC, DeAizpurua HJ, Schmidli RS, Colman PG, Tait BD, Cram DS (1993) Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 341: 1365–1369PubMedCrossRefGoogle Scholar
  38. Hertl M, Karr RW, Amagai M, Katz SI (1998) Heterogeneous MHC II restriction pattern of autoreactive desmoglein 3 specific T cell responses in pemphigus vulgaris patients and normals. J Invest Dermatol 110: 388–392PubMedCrossRefGoogle Scholar
  39. Hertl M (2000) Humoral and cellular autoimmunity in autoimmune bullous skin disorders. Int Arch Allergy Immunol 122: 91–100PubMedCrossRefGoogle Scholar
  40. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192: 1213–1222PubMedCrossRefGoogle Scholar
  41. Kalinski P, Hilkens CM, Wierenga EA, Kapsenberg ML (1999) T-cell priming by type-1 and type-2 polarized dendritic cells: the concept of a third signal. Immunol. Today 20: 561–567Google Scholar
  42. Katz JD, Benoist C, Mathis D (1995) T helper cell subsets in insulin-dependent diabetes. Science 268: 1185–1188PubMedCrossRefGoogle Scholar
  43. Kisielow P, Teh HS, Bluthmann H, von Boehmer H (1988) Positive selection of antigen-specific T cells in thymus by restricting MHC molecules. Nature 335: 730–733PubMedCrossRefGoogle Scholar
  44. Kisielow P, von Boehmer H (1995) Development and selection of T cells: facts and puzzles. Adv Immunol 58: 87–209PubMedCrossRefGoogle Scholar
  45. Kolb H, Kolb-Bachofen V, Roep BO (1995) Autoimmune versus inflammatory type I diabetes: a controversy? Immunol Today 16: 170–172PubMedCrossRefGoogle Scholar
  46. Kretz-Rommel A, Rubin RL (2000) Disruption of positive selection of thymocytes causes autoimmunity. Nat Med 6: 298–305PubMedCrossRefGoogle Scholar
  47. Lanzavecchia A (1985) Antigen-specific interaction between T and B cells. Nature 314: 533–539CrossRefGoogle Scholar
  48. Limmer A, Sacher T, Alferink J, Kretschmar M, Schonrich G, Nichterlein T, Arnold B, Hammerling GJ (1998) Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment. Eur J Immunol 28: 2395–2406PubMedCrossRefGoogle Scholar
  49. Liu Z, Giudice GJ, Swartz SJ, Fairley JA, Till GO, Troy JL, Diaz LA (1995) The role of complement in experimental bullous pemphigoid. J Clin Invest 95: 1539–1544PubMedCrossRefGoogle Scholar
  50. Liu Z, Shipley JM, Vu TH, Zhou X, Diaz LA, Werb Z, Senior RM (1998) Gelatinase B-defi- cient mice are resistant to experimental bullous pemphigoid. J Exp Med 188: 475–482PubMedCrossRefGoogle Scholar
  51. Liu Z, Shapiro SD, Zhou X, Twining SS, Senior RM, Giudice GJ, Fairley JA, Diaz LA (2000) A critical role for neutrophil elastase in experimental bullous pemphigoid. J Clin Invest 105: 113–123PubMedCrossRefGoogle Scholar
  52. Louis JA, Chiller JM, Weigle WO (1973) The ability of bacterial lipopolysaccharide to modulate the induction of unresponsiveness to a state of immunity. Cellular parameters. J Exp Med 138: 1481–1495Google Scholar
  53. Martin R, McFarland HF, McFarlin DE (1992) Immunological aspects of demyelinating diseases. Annu Rev Immunol 10: 153–187PubMedCrossRefGoogle Scholar
  54. Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12: 991–1045PubMedCrossRefGoogle Scholar
  55. Matzinger P, Anderson CC (2001) Immunity or tolerance: Opposite outcomes of microchimerism from skin grafts. Nat Med 7: 80–87Google Scholar
  56. Mease PJ, Goffe BS, Metz J, VanderStoep A, Finck B, Burge DJ (2000) Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 356: 385–390PubMedCrossRefGoogle Scholar
  57. Mican JM, Metcalfe DD (1990) Arthritis and mast cell activation. J Allergy Clin Immunol 86: 677–683PubMedCrossRefGoogle Scholar
  58. Mokhtarian F, McFarlin DE, Raine CS (1984) Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature 309: 356–358PubMedCrossRefGoogle Scholar
  59. Moradpour D, Blum HE (1999) Current and evolving therapies for hepatitis C. Eur J Gastroenterol Hepatol 11: 1199–1202PubMedCrossRefGoogle Scholar
  60. Moser M, Murphy KM (2000) Dendritic cell regulation of TH1-TH2 development. Nat Immunol 1: 199–205PubMedCrossRefGoogle Scholar
  61. Moskophidis D, Lechner F, Pircher H, Zinkernagel RM (1993) Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature 362: 758–761PubMedCrossRefGoogle Scholar
  62. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7: 145–173PubMedCrossRefGoogle Scholar
  63. Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17: 138–146PubMedCrossRefGoogle Scholar
  64. Naucler CS, Larsson S, Moller E (1996) A novel mechanism for virus-induced autoimmunity in humans. Immunol Rev 152: 175–192PubMedCrossRefGoogle Scholar
  65. Ohashi PS, Oehen S, Buerki K, Pircher H, Ohashi CT, Odermatt B, Malissen B, Zinkernagel RM, Hengartner H (1991) Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65: 305–317PubMedCrossRefGoogle Scholar
  66. Oldstone MB, Nerenberg M, Southern P, Price J, Lewicki H (1991) Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell 65: 319–331PubMedCrossRefGoogle Scholar
  67. Powrie F (1995) T cells in inflammatory bowel disease: protective and pathogenic roles. Immunity 3: 171–174PubMedCrossRefGoogle Scholar
  68. Prinz JC (1999) Which T cells cause psoriasis? Clin Exp Dermatol 24: 291–295PubMedCrossRefGoogle Scholar
  69. Racke MK, Bonomo A, Scott DE, Cannella B, Levine A, Raine CS, Shevach EM, Rocken M (1994) Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med 180: 1961–1966PubMedCrossRefGoogle Scholar
  70. Rocha B, von Boehmer H (1991) Peripheral selection of the T cell repertoire. Science 251: 1225–1228PubMedCrossRefGoogle Scholar
  71. Röcken M, Saurat, JH, Hauser C (1992a) A common precursor for CD4+ T cells producing IL-2 or IL-4. J Immunol 148: 1031–1036PubMedGoogle Scholar
  72. Röcken M, Urban JF, Shevach EM (1992b) Infection breaks T-cell tolerance. Nature 359: 79–82PubMedCrossRefGoogle Scholar
  73. Röcken M, Urban J, Shevach EM (1994) Antigen-specific activation, tolerization, and reactivation of the interleukin 4 pathway in vivo. J Exp Med 179: 1885–1893PubMedCrossRefGoogle Scholar
  74. Röcken M, Shevach EM (1996) Immune deviation - the third dimension of nondeletional T cell tolerance. Immunol Rev 149: 175–194PubMedCrossRefGoogle Scholar
  75. Röcken M, Racke M, Shevach EM (1996) IL-4-induced immune deviation as antigen-specific therapy for inflammatory autoimmune disease. Immunol Today 17: 225–231PubMedCrossRefGoogle Scholar
  76. Rothe MJ, Nowak M, Kerdel FA (1990) The mast cell in health and disease. J Am Acad Dermatol 23: 615–624PubMedCrossRefGoogle Scholar
  77. Rubin RL (1997) Dubois Lupus Erythematosus, 5th Edition, Wallace DJ and Hahn BH (eds) Williams & Wilkens, Baltimore, 871–901Google Scholar
  78. Schonrich G, Kalinke U, Momburg F, Malissen M, Schmitt-Verhulst AM, Malissen B, Hammerling GJ, Arnold B (1991) Down-regulation of T cell receptors on self-reactive T cells as a novel mechanism for extrathymic tolerance induction. Cell 65: 293–304PubMedCrossRefGoogle Scholar
  79. Schuler G, Steinman RM (1997) Dendritic cells as adjuvants for immune-mediated resistance to tumors. J Exp Med 186: 1183–1187PubMedCrossRefGoogle Scholar
  80. Schuler G, Thurner B, Romani N (1997) Dendritic cells: from ignored cells to major players in T-cell-mediated immunity. Int Arch Allergy Immunol 112: 317–322PubMedCrossRefGoogle Scholar
  81. Schwartz RH (1998) Immunological tolerance. In Fundamental Immunology, 4th Edition, Paul WE (ed) Lippincott-Raven, Philadelphia, New York, 701–740Google Scholar
  82. Sinha AA, Lopez MT, McDevitt HO (1990) Autoimmune diseases: the failure of self tolerance. Science 248: 1380–1388PubMedCrossRefGoogle Scholar
  83. Stenger S, Modlin RL (1999) T cell mediated immunity to Mycobacterium tuberculosis. Curr Opin Microbiol 2: 89–93PubMedCrossRefGoogle Scholar
  84. Stockinger B (1999) T lymphocyte tolerance: from thymic deletion to peripheral control mechanisms. Adv Immunol 71: 229–265PubMedCrossRefGoogle Scholar
  85. Strober W, Ehrhardt RO (1993) Chronic intestinal inflammation: an unexpected outcome in cytokine or T cell receptor mutant mice. Cell 75: 203–205PubMedCrossRefGoogle Scholar
  86. Tessari G, Barba A, Schena D (1996) Lichen ruber planus following the administration of human anti-hepatitis B virus immunoglobulins [letter]. Acta Derm Venereol 76: 154PubMedGoogle Scholar
  87. Vollmer S, Menssen A, Trommler P, Schendel D, Prinz JC (1994) T lymphocytes derived from skin lesions of patients with psoriasis vulgaris express a novel cytokine pattern that is distinct from that of T helper type 1 and T helper type 2 cells. Eur J Immunol 24: 2377–2382PubMedCrossRefGoogle Scholar
  88. von Herrath MG, Guerder S, Lewicki H, Flavell RA, Oldstone MB (1995) Coexpression of B7-1 and viral (“self”) transgenes in pancreatic beta cells can break peripheral ignorance and lead to spontaneous autoimmune diabetes. Immunity 3: 727–738CrossRefGoogle Scholar
  89. Webb S, Morris C, Sprent J (1990) Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell 63: 1249–1256PubMedCrossRefGoogle Scholar
  90. Weber S, Traunecker A, Oliver” F, Gerhard W, Karjalainen K (1992) Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor. Nature 356: 793–796PubMedCrossRefGoogle Scholar
  91. Weinberg AD, English M, Swain SL (1990) Distinct regulation of lymphokine production is found in fresh versus in vitro primed mucine helper T cells J Immunol 144: 1800–1807Google Scholar
  92. Wucherpfennig KW, Strominger JL (1995) Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80: 695–705PubMedCrossRefGoogle Scholar
  93. Zhang J, Hafler D, Hohlfeld R, Miller A, eds (1998) Immunotherapy in neuroimmunologic diseases. Martin Dunitz Ltd, LondonGoogle Scholar
  94. Zimmermann S, Egeter O, Hausmann S, Lipford GB, Röcken M, Wagner H, Heeg K (1998) CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal mucine leishmaniasis. J Immunol 160: 3627–3630PubMedGoogle Scholar
  95. Zinkernagel RM (1996) Immunology taught by viruses. Science 271: 173–178PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2001

Authors and Affiliations

There are no affiliations available

Personalised recommendations