Epitope spreading in immune-mediated diseases: implications for immunotherapy


Evidence continues to accumulate supporting the hypothesis that tissue damage during an immune response can lead to the priming of self-reactive T and/or B lymphocytes, regardless of the specificity of the initial insult. This review will focus primarily on epitope spreading at the T-cell level. Understanding the cellular and molecular basis of epitope spreading in various chronic immune-mediated human diseases and their animal models is crucial to understanding the pathogenesis of these diseases and to the ultimate goal of designing antigen-specific treatments.

Key Points

  • Epitope spreading is defined as the diversification of epitope specificity from the initial focused, dominant epitope-specific immune response, directed against a self or foreign protein, to subdominant and/or cryptic epitopes on that protein (intramolecular spreading) or other proteins (intermolecular spreading).

  • The immune response consists of an initial magnification phase, which can either be deleterious as in autoimmune disease or beneficial as in vaccinations, and a later downregulatory phase to return the immune system to homeostasis. Epitope spreading may be an important component of both phases.

  • Human studies strongly suggest that epitope spreading has a role in ongoing disease, although epitope spreading is very difficult to verify in human disease. Animal models have therefore been useful, as the peptide specificity of the initial immune response can be manipulated, genetically identical animals used, and the immune response over time in different lymphoid organs and in the target tissue can be assessed.

  • Studies in two models of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalitogenic virus-induced demyelinating disease (TMEV-IDD) have shown conclusively that epitope spreading plays a pathological role in ongoing disease and that blocking this process by inducing tolerance to spread myelin epitopes or blocking costimulation of T cells (necessary for epitope spreading) blocks (EAE) or inhibits (TMEV-IDD) ongoing clinical disease.

  • Early tolerance to glutamic acid decarboxylase (GAD) in the non-obese diabetic (NOD) mouse model of diabetes has been shown to block epitope spreading and disease progression. Several human studies have observed epitope spreading in beta cell-specific humoral responses from birth to disease onset in offspring of diabetic parents.

  • Convincing evidence for the pathological role of epitope spreading is also seen in experimental autoimmune myasthenia gravis (EAMG) and adjuvant arthritis. Epitope spreading might also play a role in chronic graft rejection.

  • Treatment of human autoimmune diseases must take into consideration the dynamic nature of both the magnification and downregulatory phases of the immune response. With knowledge of the initial immune target, early antigen-specific treatments can block continued tissue damage, epitope spreading and clinical disease.

  • Induction of anti-inflammatory T helper (TH)2 responses via epitope spreading may be an important intrinsic immunoregulatory mechanism geared to limit tissue destruction and promote re-establishment of tissue-specific immune tolerance.

  • Early induction of a TH2 response to one specific β-cell autoantigen (βCAA) accelerated epitope spreading of TH2 responses to other βCAAs and can prevent the development of diabetes in the NOD mice.

  • Tumour vaccination studies suggest that epitope spreading may increase the efficiency of peptide vaccination.

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Figure 1: Epitope spreading in autoimmune and virus-induced tissue immunopathology.
Figure 2: Hierarchical pattern of intramolecular and intermolecular epitope spreading in PLP139–151-induced relapsing EAE and Theiler's virus-induced demyelinating disease (TMEV-IDD).
Figure 3: Mechanisms of infection-induced autoimmunity.


  1. 1

    Lehmann, P. V., Forsthuber, T., Miller, A. & Sercarz, E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature 358, 155–157 (1992).The first description of epitope spreading in an autoimmune disease.

  2. 2

    Lehmann, P. V., Sercarz, E. E., Forsthuber, T., Dayan, C. M. & Gammon, G. Determinant spreading and the dynamics of the autoimmune T-cell repertoire. Immunol. Today 14, 203–208 (1993).

  3. 3

    Lehmann, P. V., Targoni, O. S. & Forsthuber, T. G. Shifting T-cell activation thresholds in autoimmunity and determinant spreading. Immunol. Rev. 164, 53–61 (1998).

  4. 4

    Steinman, L. Despite epitope spreading in the pathogenesis of autoimmune disease, highly restricted approaches to immune therapy may still succeed [with a hedge on this bet]. J. Autoimmun. 14, 278–282 (2000).

  5. 5

    Yu, M., Johnson, J. M. & Tuohy, V. K. A predictable sequential determinant spreading cascade invariably accompanies progression of experimental autoimmune encephalomyelitis: a basis for peptide-specific therapy after onset of clinical disease. J. Exp. Med. 183, 1777–1788 (1996).

  6. 6

    Vanderlugt, C. L. et al. The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunol. Rev. 164, 63–72 (1998).

  7. 7

    Kumar, V. Determinant spreading during experimental autoimmune encephalomyelitis: is it potentiating, protecting or participating in the disease? Immunol. Rev. 164, 73–80 (1998).

  8. 8

    Tuohy, V. K. et al. The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis. Immunol. Rev. 164, 93–100 (1998).

  9. 9

    McRae, B. L., Vanderlugt, C. L., Dal Canto, M. C. & Miller, S. D. Functional evidence for epitope spreading in the relapsing pathology of experimental autoimmune encephalomyelitis. J. Exp. Med. 182, 75–85 (1995).The first demonstration that epitope spreading has pathological significance in ongoing autoimmunity.

  10. 10

    Vanderlugt, C. L. et al. Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis. J. Immunol. 164, 670–678 (2000).A demonstration that ongoing autoimmunity and epitope spreading can be specifically inhibited by peptide-specific tolerance or blockade of CD80/86–CD28 co-stimulation.

  11. 11

    Kennedy, M. K. et al. Inhibition of murine relapsing experimental autoimmune encephalomyelitis by immune tolerance to proteolipid protein and its encephalitogenic peptides. J. Immunol. 144, 909–915 (1990).

  12. 12

    Anderson, A. C. et al. High frequency of autoreactive myelin proteolipid protein-specific T cells in the periphery of naive mice: mechanisms of selection of the self-reactive repertoire. J. Exp. Med. 191, 761–770 (2000).

  13. 13

    Miller, S. D. et al. Blockade of CD28/B7-1 interaction prevents epitope spreading and clinical relapses of murine EAE. Immunity 3, 739–745 (1995).

  14. 14

    Howard, L. M. et al. Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. J. Clin. Invest. 103, 281–290 (1999).Evidence that blockade of CD40/CD154 co-stimulation can ameliorate ongoing autoimmunity and epitope spreading.

  15. 15

    Karandikar, N. J., Eagar, T. A., Vanderlugt, C. L., Bluestone, J. A. & Miller, S. D. CTLA-4 downregulates epitope spreading and mediates remission in autoimmune disease. J. Neuroimmunol. 109, 173–180 (2000).

  16. 16

    Karandikar, N. J., Vanderlugt, C. L., Bluestone, J. A. & Miller, S. D. Targeting the B7/CD28:CTLA-4 costimulatory system in CNS autoimmune disease. J. Neuroimmunol. 89, 10–18 (1998).

  17. 17

    Tuohy, V. K., Yu, M., Yin, L., Kawczak, J. A. & Kinkel, P. R. Regression and spreading of self-recognition during the development of autoimmune demyelinating disease. J. Autoimmun. 13, 11–20 (1999).

  18. 18

    Rudick, R. A. Disease-modifying drugs for relapsing-remitting multiple sclerosis and future directions for multiple sclerosis therapeutics. Arch. Neurol. 56, 1079–1084 (1999).

  19. 19

    Arnason, B. G. Immunologic therapy of multiple sclerosis. Annu. Rev. Med. 50, 291–302 (1999).

  20. 20

    Tuohy, V. K. et al. Modulation of the IL-10/IL-12 cytokine circuit by interferon-β inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis. J. Neuroimmunol. 111, 55–63 (2000).

  21. 21

    Fiorentino, D. F., Zlotnik, A., Mosman, T. R., Howard, M. H. & O'Garra, A. IL-10 inhibits cytokine production by activated macrophages. J. Immunol. 147, 3815–3822 (1991).

  22. 22

    Fiorentino, D. F. et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by TH1 cells. J. Immunol. 146, 3444–3451 (1991).

  23. 23

    De Waal Malefyt, R., Abrams, J., Bennett, B., Figdor, C. G. & De Vries, J. E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 174, 1209–1220 (1991).

  24. 24

    Ding, L. & Shevach, E. M. IL-10 inhibits mitogen-induced T cell proliferation by selectively inhibiting macrophage costimulatory function. J. Immunol. 148, 3133–3139 (1992).

  25. 25

    McFarland, H. I. et al. Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis. J. Immunol. 162, 2384–2390 (1999).

  26. 26

    Tuohy, V. K., Yu, M., Weinstock-Guttman, B. & Kinkel, R. P. Diversity and plasticity of self recognition during the development of multiple sclerosis. J. Clin. Invest. 99, 1682–1690 (1997).An initial demonstration of spreading and focusing of responses to PLP epitopes during the progression of multiple sclerosis.

  27. 27

    Tuohy, V. K., Yu, M., Yin, L., Kawczak, J. A. & Kinkel, R. P. Spontaneous regression of primary autoreactivity during chronic progression of experimental autoimmune encephalomyelitis and multiple sclerosis. J. Exp. Med. 189, 1033–1042 (1999).

  28. 28

    Goebels, N. et al. Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: epitope spreading versus clonal persistence. Brain 123, 508–518 (2000).

  29. 29

    Kurtzke, J. F. Epidemiologic evidence for multiple sclerosis as an infection. Clin. Microbiol. Rev. 6, 382–427 (1993).

  30. 30

    Olson, J. K., Croxford, J. L. & Miller, S. D. Virus-induced autoimmunity: potential role of viruses in initiation, perpetuation, and progression of T cell-mediated autoimmune diseases. Viral Immunol. 14, 227–250 (2001).

  31. 31

    Karpus, W. J., Pope, J. G., Peterson, J. D., Dal Canto, M. C. & Miller, S. D. Inhibition of Theiler's virus-mediated demyelination by peripheral immune tolerance induction. J. Immunol. 155, 947–957 (1995).

  32. 32

    Miller, S. D. et al. Persistent infection with Theiler's virus leads to CNS autoimmunity via epitope spreading. Nature Med. 3, 1133–1136 (1997).The first description that a persistent virus infection can lead to autoimmunity via epitope spreading.

  33. 33

    Katz-Levy, Y. et al. Temporal development of autoreactive TH1 responses and endogenous antigen presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice. J. Immunol. 165, 5304–5314 (2000).

  34. 34

    Katz-Levy, Y. et al. Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler's virus-infected mice. J. Clin. Invest. 104, 599–610 (1999).Evidence of endogenous presentation of self epitopes by resident APCs in the target tissue of the disease.

  35. 35

    Borrow, P. et al. Investigation of the role of delayed-type-hypersensitivity responses to myelin in the pathogenesis of Theiler's virus-induced demyelinating disease. Immunology 93, 478–484 (1998).

  36. 36

    Neville, K. L., Padilla, J. & Miller, S. D. Myelin-specific tolerance attenuates the progression of a virus-induced demyelinating disease: implications for the treatment of MS. J. Neuroimmunol. (In the press).

  37. 37

    Eisenbarth, G. S. Type I diabetes mellitus. A chronic autoimmune disease. N. Engl. J. Med. 314, 1360–1368 (1986).

  38. 38

    Delovitch, T. L. & Singh, B. The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7, 727–738 (1997).

  39. 39

    Kaufman, D. L. et al. Spontaneous loss of T cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366, 69–72 (1993).

  40. 40

    Zechel, M. A., Elliott, J. F., Atkinson, M. A. & Singh, B. Characterization of novel T-cell epitopes on 65 kDa and 67 kDa glutamic acid decarboxylase relevant in autoimmune responses in NOD mice. J. Autoimmun. 11, 83–95 (1998).

  41. 41

    Zechel, M. A., Chaturvedi, P. & Singh, B. Characterization of immunodominant peptide determinants of IDDM-associated autoantigens in the NOD mouse. Res. Immunol. 148, 338–348 (1997).

  42. 42

    Tian, J., Lehmann, P. V. & Kaufman, D. L. Determinant spreading of T helper cell 2 (TH2) responses to pancreatic islet autoantigens. J. Exp. Med. 186, 2039–2043 (1997).Evidence of protective epitope spreading.

  43. 43

    Zechel, M. A., Krawetz, M. D. & Singh, B. Epitope dominance: evidence for reciprocal determinant spreading to glutamic acid decarboxylase in non-obese diabetic mice. Immunol. Rev. 164, 111–118 (1998).

  44. 44

    Tian, J. et al. Infectious TH1 and TH2 autoimmunity in diabetes-prone mice. Immunol. Rev. 164, 119–127 (1998).

  45. 45

    Durinovic-Bello, I. Autoimmune diabetes: the role of T cells, MHC molecules and autoantigens. Autoimmunity 27, 159–177 (1998).

  46. 46

    Bonifacio, E., Scirpoli, M., Kredel, K., Fuchtenbusch, M. & Ziegler, A. G. Early autoantibody responses in prediabetes are IgG1 dominated and suggest antigen-specific regulation. J. Immunol. 163, 525–532 (1999).

  47. 47

    Bonifacio, E., Lampasona, V., Bernasconi, L. & Ziegler, A. G. Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes. Diabetes 49, 202–208 (2000).

  48. 48

    Sohnlein, P. et al. Epitope spreading and a varying but not disease-specific GAD65 antibody response in type I diabetes. The Childhood Diabetes in Finland Study Group. Diabetologia 43, 210–217 (2000).

  49. 49

    Braghi, S. et al. Modulation of humoral islet autoimmunity by pancreas allotransplantation influences allograft outcome in patients with type 1 diabetes. Diabetes 49, 218–224 (2000).

  50. 50

    Vincent, A. et al. Determinant spreading and immune responses to acetylcholine receptors in myasthenia gravis. Immunol. Rev. 164, 157–168 (1998).

  51. 51

    Vincent, A., Jacobson, L. & Shillito, P. Response to human acetylcholine receptor α 138–199: determinant spreading initiates autoimmunity to self-antigen in rabbits. Immunol. Lett. 39, 269–275 (1994).

  52. 52

    Curnow, J., Corlett, L., Willcox, N. & Vincent, A. Presentation by myoblasts of an epitope from endogenous acetylcholine receptor indicates a potential role in the spreading of the immune response. J. Neuroimmunol. 115, 127–134 (2001).

  53. 53

    Wang, H. B. et al. Anti-CTLA-4 antibody treatment triggers determinant spreading and enhances murine myasthenia gravis. J. Immunol. 166, 6430–6436 (2001).

  54. 54

    Yamamoto, A. M. et al. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch. Neurol. 58, 885–890 (2001).

  55. 55

    Van Eden, W. et al. Heat-shock protein T-cell epitopes trigger a spreading regulatory control in a diversified arthritogenic T-cell response. Immunol. Rev. 164, 169–174 (1998).

  56. 56

    Sonderstrup, G. & McDevitt, H. Identification of autoantigen epitopes in MHC class II transgenic mice. Immunol. Rev. 164, 129–138 (1998).

  57. 57

    Moudgil, K. D. et al. Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J. Exp. Med. 185, 1307–1316 (1997).

  58. 58

    Moudgil, K. D. Diversification of response to hsp65 during the course of autoimmune arthritis is regulatory rather than pathogenic. Immunol. Rev. 164, 175–184 (1998).

  59. 59

    Prakken, A. B. et al. Autoreactivity to human heat-shock protein 60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis. Arthritis Rheum. 39, 1826–1832 (1996).

  60. 60

    Prakken, A. B. et al. T-cell reactivity to human HSP60 in oligo-articular juvenile chronic arthritis is associated with a favorable prognosis and the generation of regulatory cytokines in the inflamed joint. Immunol. Lett. 57, 139–142 (1997).

  61. 61

    deGraeff-Meeder, E. R. et al. Juvenile chronic arthritis: T cell reactivity to human HSP60 in patients with a favorable course of arthritis. J. Clin. Invest. 95, 934–940 (1995).

  62. 62

    Alam, A. et al. Persistence of dominant T cell clones in synovial tissues during rheumatoid arthritis. J. Immunol. 156, 3480–3485 (1996).

  63. 63

    Bradley, J. A. Indirect T cell recognition in allograft rejection. Int. Rev. Immunol. 13, 245–255 (1996).

  64. 64

    Suciu-Foca, N., Harris, P. E. & Cortesini, R. Intramolecular and intermolecular spreading during the course of organ allograft rejection. Immunol. Rev. 164, 241–246 (1998).

  65. 65

    Ciubotariu, R. et al. Persistent allopeptide reactivity and epitope spreading in chronic rejection of organ allografts. J. Clin. Invest 101, 398–405 (1998).Evidence of epitope spreading in allograft rejection.

  66. 66

    Di Rosa, F. & Barnaba, V. Persisting viruses and chronic inflammation: understanding their relation to autoimmunity. Immunol. Rev. 164, 17–27 (1998).

  67. 67

    Dorries, R. The role of T-cell-mediated mechanisms in virus infections of the nervous system. Curr. Top. Microbiol. Immunol. 253, 219–245 (2001).

  68. 68

    Xu, L., Villain, M., Galin, F. S., Araga, S. & Blalock, J. E. Prevention and reversal of experimental autoimmune myasthenia gravis by a monoclonal antibody against acetylcholine receptor-specific T cells. Cell Immunol. 208, 107–114 (2001).

  69. 69

    Leadbetter, E. A. et al. Experimental autoimmune encephalomyelitis induced with a combination of myelin basic protein and myelin oligodendrocyte glycoprotein is ameliorated by administration of a single myelin basic protein peptide. J. Immunol. 161, 504–512 (1998).

  70. 70

    Al-Sabbagh, A., Nelson, P. A., Akselband, Y., Sobel, R. A. & Weiner, H. L. Antigen-driven peripheral immune tolerance: suppression of experimental autoimmmune encephalomyelitis and collagen-induced arthritis by aerosol administration of myelin basic protein or type II collagen. Cell. Immunol. 171, 111–119 (1996).

  71. 71

    Anderton, S. M. & Wraith, D. C. Hierarchy in the ability of T cell epitopes to induce peripheral tolerance to antigens from myelin. Eur. J. Immunol. 28, 1251–1261 (1998).

  72. 72

    Nicholson, L. B., Murtaza, A., Hafler, B. P., Sette, A. & Kuchroo, V. K. A T cell receptor antagonist peptide induces T cells that mediate bystander suppression and prevent autoimmune encephalomyelitis induced with multiple myelin antigens. Proc. Natl Acad. Sci. USA 94, 9279–9284 (1997).

  73. 73

    Bielekova, B. et al. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83–99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nature Med. 6, 1167–1175 (2000).

  74. 74

    Pakala, S. V., Kurrer, M. O. & Katz, J. D. T helper 2 (TH2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice. J. Exp. Med. 186, 299–306 (1997).

  75. 75

    Lafaille, J. J. et al. Myelin basic protein-specific T helper 2 (TH2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. J. Exp. Med. 186, 307–312 (1997).

  76. 76

    Yang, L., DuTemple, B., Gorczynski, R. M., Levy, G. & Zhang, L. Evidence for epitope spreading and active suppression in skin graft tolerance after donor-specific transfusion. Transplantation 67, 1404–1410 (1999).

  77. 77

    Waldmann, H. & Cobbold, S. Regulating the immune response to transplants: a role for CD4+ regulatory cells? Immunity 14, 399–406 (2001).

  78. 78

    el Shami, K. et al. MHC class I-restricted epitope spreading in the context of tumor rejection following vaccination with a single immunodominant CTL epitope. Eur. J. Immunol. 29, 3295–3301 (1999).Evidence of MHC-class-I–restricted epitope spreading in tumour immunity.

  79. 79

    Markiewicz, M. A., Fallarino, F., Ashikari, A. & Gajewski, T. F. Epitope spreading upon P815 tumor rejection triggered by vaccination with the single class I MHC-restricted peptide P1A. Int. Immunol. 13, 625–632 (2001).

  80. 80

    Disis, M. L., Grabstein, K. H., Sleath, P. R. & Cheever, M. A. Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin. Cancer Res. 5, 1289–1297 (1999).

  81. 81

    Brossart, P. et al. Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96, 3102–3108 (2000).

  82. 82

    Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

  83. 83

    Hurwitz, A. A., Yu, T. F., Leach, D. R. & Allison, J. P. CTLA-4 blockade synergizes with tumor-derived granulocyte–macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc. Natl Acad. Sci. USA 95, 10067–10071 (1998).

  84. 84

    Olson, J. K., Croxford, J. L., Calenoff, M., Dal Canto, M. C. & Miller, S. D. A virus-induced molecular mimicry model of multiple sclerosis. J. Clin. Invest. 108, 311–318 (2001).Evidence that epitope spreading can be initiated after induction of autoimmunity via molecular mimicry.

  85. 85

    Mokhtarian, F., Shi, Y., Zhu, P. F. & Grob, D. Immune responses, and autoimmune outcome, during virus infection of the central nervous system. Cell. Immunol. 157, 195–210 (1994).

  86. 86

    Mokhtarian, F., Zhang, Z., Shi, Y., Gonzales, E. & Sobel, R. A. Molecular mimicry between a viral peptide and a myelin oligodendrocyte glycoprotein peptide induces autoimmune demyelinating disease in mice. J. Neuroimmunol. 95, 43–54 (1999).

  87. 87

    Lawson, C. M. Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis. Cell Mol. Life Sci. 57, 552–560 (2000).

  88. 88

    Fairweather, D., Kaya, Z., Shellam, G. R., Lawson, C. M. & Rose, N. R. From infection to autoimmunity. J. Autoimmun. 16, 175–186 (2001).

  89. 89

    Horwitz, M. S. et al. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nature Med. 4, 781–786 (1998).

  90. 90

    Zhao, Z.-S., Granucci, F., Yeh, L., Schaffer, P. A. & Cantor, H. Molecular mimicry by herpes simplex virus-type 1: Autoimmune disease after viral infection. Science 279, 1344–1347 (1998).

  91. 91

    Deshpande, S. P. et al. Herpes simplex virus-induced keratitis: evaluation of the role of molecular mimicry in lesion pathogenesis. J. Virol. 75, 3077–3088 (2001).

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Correspondence to Stephen D. Miller.

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type-1 diabetes

multiple sclerosis

myasthenia gravis

rheumatoid arthritis



A cryptic epitope is defined as a hidden or sequestered epitope that is processed and presented more efficiently as a result of an inflammatory immune response initiated by either a dominant epitope, as in a response to an infectious agent, or revealed as a result of the diversification of the response secondary to self tissue damage, as in an autoimmune response.


CD4+ T cells have been divided into at least two distinct types. TH1 cells produce IFN-γ, lymphotoxin and TNF-α, and mediate macrophage inflammatory responses such as delayed-type hypersensitivity (DTH). Demyelination in multiple sclerosis models is thought to be due to TH1 cells. TH2 cells produce IL-4, IL-10 and/or TGF-β, and can downregulate TH1 responses.


Spreading from one epitope to another on the same molecule, for example, from PLP139–151 to PLP178–191.


Spreading of the specificity of an immune response from an epitope on one molecule to one on a different molecule is termed intermolecular epitope spreading. An example would be the spread in EAE induced with PLP139–151, an epitope on proteolipid protein, to an epitope on myelin basic protein, such as MBP84–104.


(IMDS). IMDS is a group of distinct clinical disorders often associated with eventual progression toward clinically definite multiple sclerosis.


Polymerase chain reaction-based method of identifying pseudoclonal TCR usage by analyzing Vβ family gene usage. In independent reactions, Vβ–Cβ products across the CDR3 region are amplified from cDNA, tagged with a fluorochrome, and resolved on a polyacrylamide gel electrophoresis gel. Expanded pseudoclonal Vβ–Cβ products of a single length are distinguished from other Vβ–Cβ products by size differences introduced at the coding junction.


Inflammation surrounding the insulin-producing β-cells in the pancreas. Diabetes occurs when β-cells can no longer produce adequate amounts of insulin.


Heat-shock proteins are expressed in all cells, including microbes, when they are stressed; for example, when they experience high temperatures. These proteins can then become targeted by an immune response.


Used to trigger an immune response to proteins or peptides emulsified in the adjuvant; it consists of freeze-dried Mycobacterium, emulsifying agents and mineral oil.


Production of anti-inflammatory cytokines (e.g. IL-4, IL-10, TGF-β) by an antigen-specific regulatory T cell, which suppress immune responses to additional epitopes in a non-specific manner.

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