Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Autoimmune thyroid disease: new models of cell death in autoimmunity

Key Points

  • Autoimmunity against the thyroid gland generates two opposite pathogenic processes: thyroid hyperplasia in Graves' disease and thyroid destruction in Hashimoto's thyroiditis.

  • Three different mechanisms have been sequentially proposed to be responsible for autoimmune thyrocyte depletion: first, antibody-mediated destruction through immune-complex deposition; second, T-cell-mediated destruction through the release of cytotoxic granules after specific target recognition; and third, death-receptor-mediated induction of apoptosis.

  • The rate of thyrocyte apoptosis dictates the clinical outcome of thyroid autoimmunity. Thyrocyte apoptosis is extremely rare in normal thyroid. It markedly increases during Hashimoto's thyroiditis, but not in Graves' disease. Therefore, regulation of thyrocyte survival is a crucial pathogenic determinant.

  • During Hashimoto's thyroiditis, thyrocytes express death-receptor ligands that might trigger apoptosis of both thyrocytes and infiltrating lymphocytes. So, it is not clear whether lymphocytes kill thyrocytes or vice versa.

  • T-helper lymphocytes produce cytokines that influence both immune and target cells at several levels. The predominance of T-helper type 1 (TH1) or TH2 cytokines might regulate thyrocyte survival through the induction of pro-apoptotic and anti-apoptotic proteins. So, the ability of T-helper cytokines to modify the pattern of apoptotic-related proteins could have a remarkable effect in various immune-mediated conditions.


Autoimmunity to thyroid antigens leads to two distinct pathogenic processes with opposing clinical outcomes: hypothyroidism in Hashimoto's thyroiditis and hyperthyroidism in Graves' disease. The high frequency of these diseases and easy accessibility of the thyroid gland has allowed the identification of key pathogenic mechanisms in organ-specific autoimmune diseases. In early investigations, antibody- and T-cell-mediated death mechanisms were proposed as being responsible for autoimmune thyrocyte depletion. Later, studies on apoptosis have provided new insights into autoimmune target destruction, indicating the involvement of death receptors and cytokine-regulated apoptotic pathways in the pathogenesis of thyroid autoimmunity.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Thyroid autoimmunity produces two opposite pathogenetic processes and clinical outcomes.
Figure 2: Three different mechanisms of thyrocyte depletion in Hashimoto's thyroiditis have been sequentially proposed.
Figure 3: Two independent pathways mediate T-cell cytotoxicity.
Figure 4: Infiltrating T cells might be killed by thyrocytes during Hashimoto's thyroiditis.
Figure 5: Model of thyrocyte fate in thyroid autoimmune diseases.


  1. 1

    Sinha, A. A., Lopez, M. T. & McDevitt, H. O. Autoimmune diseases: the failure of self tolerance. Science 248, 1380–1388 (1990).

    CAS  PubMed  Google Scholar 

  2. 2

    Metcalfe, K. A. et al. Concordance for type 1 diabetes in identical twins is affected by insulin genotype. Diabetes Care 24, 838–842 (2001).

    CAS  PubMed  Google Scholar 

  3. 3

    Brix, T. H., Kyvik, K. O. & Hegedus, L. A population-based study of chronic autoimmune hypothyroidism in Danish twins. J. Clin. Endocrinol. Metab. 85, 536–539 (2000).

    CAS  PubMed  Google Scholar 

  4. 4

    Wesselborg, S., Janssen, O. & Kabelitz, D. Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells. J. Immunol. 150, 4338–4345 (1993).

    CAS  PubMed  Google Scholar 

  5. 5

    Klas, C., Debatin, K. M., Jonker, R. R. & Krammer, P. H. Activation interferes with the APO-1 pathway in mature human T cells. Int. Immunol. 5, 625–630 (1993).The first demonstration that activated T cells become susceptible to CD95-induced apoptosis.

    CAS  PubMed  Google Scholar 

  6. 6

    Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).Identification of a key population of regulatory T cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Suri-Payer, E., Amar, A. Z., Thornton, A. M. & Shevach, E. M. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J. Immunol. 160, 1212–1218 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Wucherpfennig, K. W. & Strominger, J. L. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 80, 695–705 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Olson, J. K., Croxford, J. L., Calenoff, M. A., Dal Canto, M. C. & Miller, S. D. A virus-induced molecular mimicry model of multiple sclerosis. J. Clin. Invest. 108, 311–318 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Bachmaier, K. et al. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403, 211–216 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Robey, E. & Urbain, J. Tolerance and immune regulation. Immunol. Today 12, 175–177 (1991).

    CAS  PubMed  Google Scholar 

  13. 13

    Wucherpfennig, K. W. & Eisenbarth, G. S. Type 1 diabetes. Nature Immunol. 2, 767–768 (2001).

    CAS  Google Scholar 

  14. 14

    Steinman, L. Multiple sclerosis: a two-stage disease. Nature Immunol. 2, 762–764 (2001).

    CAS  Google Scholar 

  15. 15

    Weetman, A. P. & McGregor, A. M. Autoimmune thyroid disease: further developments in our understanding. Endocr. Rev. 15, 788–830 (1994).A comprehensive review on thyroid autoimmunity.

    CAS  Google Scholar 

  16. 16

    Giordano, C. et al. Potential involvement of Fas and its ligand in the pathogenesis of Hashimoto's thyroiditis. Science 275, 960–963 (1997).

    CAS  PubMed  Google Scholar 

  17. 17

    De Maria, R. & Testi, R. Fas–FasL interactions: a common pathogenetic mechanism in organ-specific autoimmunity. Immunol. Today 19, 121–125 (1998).

    CAS  PubMed  Google Scholar 

  18. 18

    Stassi, G. et al. Fas/Fas ligand-driven T cell apoptosis as a consequence of ineffective thyroid immunoprivilege in Hashimoto's thyroiditis. J. Immunol. 162, 263–267 (1999).Unexpected findings indicating that thyrocytes kill infiltrating T cells in Hashimoto's thyroiditis.

    CAS  PubMed  Google Scholar 

  19. 19

    Stassi, G. et al. Control of target cells survival in thyroid autoimmunity by T helper cytokines via regulation of apoptotic proteins. Nature Immunol. 1, 1–6 (2000).A demonstration that production of T-helper cytokines promotes survival or death of thyrocytes during the autoimmune response.

    Google Scholar 

  20. 20

    Davies, T. F., Roti, E., Braverman, L. E. & DeGroot, L. J. Thyroid controversy — stimulating antibodies. J. Clin. Endocrinol. Metab. 83, 3777–3785 (1998).

    CAS  PubMed  Google Scholar 

  21. 21

    Todd, I., Pujol-Borrell, R., Hammond, L. J., Bottazzo, G. F. & Feldmann, M. Interferon-γ induces HLA-DR expression by thyroid epithelium. Clin. Exp. Immunol. 61, 265–273 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Hamilton, F., Black, M., Farquharson, M. A., Stewart, C. & Foulis, A. K. Spatial correlation between thyroid epithelial cells expressing class II MHC molecules and interferon-γ-containing lymphocytes in human thyroid autoimmune disease. Clin. Exp. Immunol. 83, 64–68 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Shimojo, N. et al. Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin receptor and a class II molecule. Proc. Natl Acad. Sci. USA 93, 11074–11079 (1996).The first experimental model of Graves' disease.

    CAS  PubMed  Google Scholar 

  24. 24

    Kita, M. et al. Regulation and transfer of a murine model of thyrotropin receptor antibody mediated Graves' disease. Endocrinology 140, 1392–1398 (1999).

    CAS  PubMed  Google Scholar 

  25. 25

    Costagliola, S. et al. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease. J. Clin. Invest. 105, 803–811 (2000).Description of a new model of Graves' disease that shows lymphocytic infiltration and ophthalmopathy.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

    Dietrich, H. M., Oliveira-dos-Santos, A. J. & Wick, G. Development of spontaneous autoimmune thyroiditis in Obese strain (OS) chickens. Vet. Immunol. Immunopathol. 57, 141–146 (1997).

    CAS  PubMed  Google Scholar 

  27. 27

    Wright, J. R. Jr,, Senhauser, D. A., Yates, A. J., Sharma, H. M. & Thibert, P. Spontaneous thyroiditis in BB Wistar diabetic rats. Vet. Pathol. 20, 522–530 (1983).Description of a spontaneous model of autoimmune thyroiditis in mammals.

    PubMed  Google Scholar 

  28. 28

    Rasooly, L., Burek, C. L. & Rose, N. R. Iodine-induced autoimmune thyroiditis in NOD-H-2h4 mice. Clin. Immunol. Immunopathol. 81, 287–292 (1996).

    CAS  PubMed  Google Scholar 

  29. 29

    Tomazic, V. & Rose, N. R. Autoimmune murine thyroiditis. VIII. Role of different thyroid antigens in the induction of experimental autoimmune thyroiditis. Immunology 30, 63–68 (1976).One of the concluding papers of the initial description of the experimental autoimmune thyroiditis model.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30

    Romball, C. G. & Weigle, W. O. Transfer of experimental autoimmune thyroiditis with T cell clones. J. Immunol. 138, 1092–1098 (1987).Demonstration that thyroid-specific T-cell clones can transfer autoimmune thyroiditis.

    CAS  PubMed  Google Scholar 

  31. 31

    Knight, S. C. et al. Induction of autoimmunity with dendritic cells: studies on thyroiditis in mice. Clin. Immunol. Immunopathol. 48, 277–289 (1988).

    CAS  PubMed  Google Scholar 

  32. 32

    Flynn, J. C., Conaway, D. H., Cobbold, S., Waldmann, H. & Kong, Y. C. Depletion of L3T4+ and Lyt-2+ cells by rat monoclonal antibodies alters the development of adoptively transferred experimental autoimmune thyroiditis. Cell. Immunol. 122, 377–390 (1989).

    CAS  PubMed  Google Scholar 

  33. 33

    Parish, N. M., Roitt, I. M. & Cooke, A. Phenotypic characteristics of cells involved in induced suppression to murine experimental autoimmune thyroiditis. Eur. J. Immunol. 18, 1463–1477 (1988).

    CAS  PubMed  Google Scholar 

  34. 34

    Vladutiu, A. O. Experimental autoimmune thyroiditis in mice chronically treated from birth with anti-IgM antibodies. Cell. Immunol. 121, 49–59 (1989).

    CAS  PubMed  Google Scholar 

  35. 35

    Braley-Mullen, H. et al. Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis. Am. J. Pathol. 152, 1347–1358 (1998).Description of a destructive model of experimental autoimmune thyroiditis.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Kalderon, A. E. & Bogaars, H. A. Immune complex deposits in Graves' disease and Hashimoto's thyroiditis. Am. J. Med. 63, 729–734 (1977).First demonstration of immune-complex deposits in thyroid autoimmunity.

    CAS  PubMed  Google Scholar 

  37. 37

    Weetman, A. P., Cohen, S. B., Oleesky, D. A. & Morgan, B. P. Terminal complement complexes and C1/C1 inhibitor complexes in autoimmune thyroid disease. Clin. Exp. Immunol. 77, 25–30 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Khoury, E. L., Hammond, L., Bottazzo, G. F. & Doniach, D. Presence of the organ-specific 'microsomal' autoantigen on the surface of human thyroid cells in culture: its involvement in complement-mediated cytotoxicity. Clin. Exp. Immunol. 45, 316–328 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Bogner, U., Schleusener, H. & Wall, J. R. Antibody-dependent cell mediated cytotoxicity against human thyroid cells in Hashimoto's thyroiditis but not Graves' disease. J. Clin. Endocrinol. Metab. 59, 734–738 (1984).

    CAS  PubMed  Google Scholar 

  40. 40

    Guo, J., Jaume, J. C., Rapoport, B. & McLachlan, S. M. Recombinant thyroid peroxidase-specific Fab converted to immunoglobulin G (IgG) molecules: evidence for thyroid cell damage by IgG1, but not IgG4, autoantibodies. J. Clin. Endocrinol. Metab. 82, 925–931 (1997).

    CAS  PubMed  Google Scholar 

  41. 41

    Weetman, A. P., Tandon, N. & Morgan, B. P. Antithyroid drugs and release of inflammatory mediators by complement-attacked thyroid cells. Lancet 340, 633–636 (1992).

    CAS  PubMed  Google Scholar 

  42. 42

    Kagi, D. et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265, 528–530 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Lowin, B., Hahne, M., Mattmann, C. & Tschopp, J. Cytolytic T-cell cytotoxicity is mediated through perforin and Fas lytic pathways. Nature 370, 650–652 (1994).References 42 and 43 were the first to show that both perforin and death-receptor pathways mediate T-cell cytotoxicity.

    CAS  Google Scholar 

  44. 44

    Darmon, A. J., Nicholson, D. W. & Bleackley, R. C. Activation of the apoptotic protease CPP32 by cytotoxic T-cell-derived granzyme B. Nature 377, 446–468 (1995).The first demonstration that granzyme B activates the apoptotic caspase cascade.

    CAS  Google Scholar 

  45. 45

    Thornberry, N. A. et al. A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J. Biol. Chem. 272, 17907–17911 (1997).

    CAS  Google Scholar 

  46. 46

    Wu, Z., Podack, E. R., McKenzie, J. M., Olsen, K. J. & Zakarija, M. Perforin expression by thyroid-infiltrating T cells in autoimmune thyroid disease. Clin. Exp. Immunol. 98, 470–477 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Pujol-Borrell, R., Hanafusa, T., Chiovato, L. & Bottazzo, G. F. Lectin-induced expression of DR antigen on human cultured follicular thyroid cells. Nature 304, 71–73 (1983).

    CAS  PubMed  Google Scholar 

  48. 48

    Londei, M., Lamb, J. R., Bottazzo, G. F. & Feldmann, M. Epithelial cells expressing aberrant MHC class II determinants can present antigen to cloned human T cells. Nature 312, 639–641 (1984).References 47 and 48 were the first to show that thyrocytes can express MHC class II molecules and act as antigen-presenting cells.

    CAS  PubMed  Google Scholar 

  49. 49

    Mackenzie, W. A. & Davies, T. F. An intrathyroidal T-cell clone specifically cytotoxic for human thyroid cells. Immunology 61, 101–103 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    MacKenzie, W. A., Schwartz, A. E., Friedman, E. W. & Davies, T. F. Intrathyroidal T cell clones from patients with autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 64, 818–824 (1987).References 49 and 50 describe T-cell clones that are selectively cytotoxic to autologous thyroid cells.

    CAS  PubMed  Google Scholar 

  51. 51

    Sugihara, S., Fujiwara, H., Niimi, H. & Shearer, G. M. Self-thyroid epithelial cell (TEC)-reactive CD8+ T cell lines/clones derived from autoimmune thyroiditis lesions. They recognize self-thyroid antigens directly on TEC to exhibit T helper cell 1-type lymphokine production and cytotoxicity against TEC. J. Immunol. 155, 1619–1628 (1995).

    CAS  PubMed  Google Scholar 

  52. 52

    Hengartner, M. O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).

    CAS  Google Scholar 

  53. 53

    Adams, J. M. & Cory, S. Life-or-death decisions by the Bcl-2 protein family. Trends Biochem. Sci. 26, 61–66 (2001).

    CAS  Google Scholar 

  54. 54

    Arscott, P. L. et al. Fas (APO-1, CD95)-mediated apoptosis in thyroid cells is regulated by a labile protein inhibitor. Endocrinology 138, 5019–5027 (1997).

    CAS  PubMed  Google Scholar 

  55. 55

    Stassi, G. et al. Nitric oxide primes pancreatic β cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J. Exp. Med. 186, 1193–1200 (1997).Describes a new pathway that is responsible for autoimmune β-cell destruction in human diabetes.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Zipp, F., Krammer, P. H. & Weller, M. Immune (dys)regulation in multiple sclerosis: role of the CD95–CD95 ligand system. Immunol. Today 20, 550–554 (1999).

    CAS  PubMed  Google Scholar 

  57. 57

    Borgerson, K. L., Bretz, J. D. & Baker, J. R. Jr. The role of Fas-mediated apoptosis in thyroid autoimmune disease. Autoimmunity 30, 251–264 (1999).

    CAS  PubMed  Google Scholar 

  58. 58

    Leithauser, F. et al. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells. Lab. Invest. 69, 415–429 (1993).An extensive analysis of CD95 expression in human tissues.

    CAS  PubMed  Google Scholar 

  59. 59

    Stokes, T. A. et al. Constitutive expression of FasL in thyrocytes. Science 279, 2015A (1998).

    Google Scholar 

  60. 60

    Stassi, G. & De Maria, R. Response to 'Thyrocytes — not innocent bystanders in autoimmune disease'. Nature Immunol. 2, 183 (2001).

    CAS  Google Scholar 

  61. 61

    Hammond, L. J. et al. Analysis of apoptosis in relation to tissue destruction associated with Hashimoto's autoimmune thyroiditis. J. Pathol. 182, 138–144 (1997).

    CAS  PubMed  Google Scholar 

  62. 62

    Mitsiades, N. et al. Fas/Fas ligand up-regulation and Bcl-2 down-regulation may be significant in the pathogenesis of Hashimoto's thyroiditis. J. Clin. Endocrinol. Metab. 83, 2199–2203 (1998).

    CAS  PubMed  Google Scholar 

  63. 63

    Batteux, F., Tourneur, L., Trebeden, H., Charreire, J. & Chiocchia, G. Gene therapy of experimental autoimmune thyroiditis by in vivo administration of plasmid DNA coding for Fas ligand. J. Immunol. 162, 603–608 (1999).

    CAS  PubMed  Google Scholar 

  64. 64

    Batteux, F., Lores, P., Bucchini, D. & Chiocchia, G. Transgenic expression of Fas ligand on thyroid follicular cells prevents autoimmune thyroiditis. J. Immunol. 164, 1681–1688 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Aust, G. et al. Expression of tumour necrosis factor-α (TNF-α) mRNA and protein in pathological thyroid tissue and carcinoma cell lines. Clin. Exp. Immunol. 105, 148–154 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Bretz, J. D., Arscott, P. L., Myc, A. & Baker, J. R. Jr. Inflammatory cytokine regulation of Fas-mediated apoptosis in thyroid follicular cells. J. Biol. Chem. 274, 25433–25438 (1999).

    CAS  PubMed  Google Scholar 

  67. 67

    Bretz, J. D. et al. TRAIL death pathway expression and induction in thyroid follicular cells. J. Biol. Chem. 274, 23627–23632 (1999).Demonstration of a new potential pathway for thyrocyte apoptosis.

    CAS  PubMed  Google Scholar 

  68. 68

    Bretz, J. D. & Baker, J. R. Jr. Apoptosis and autoimmune thyroid disease: following a TRAIL to thyroid destruction? Clin. Endocrinol. (Oxf.) 55, 1–11 (2001).

    CAS  Google Scholar 

  69. 69

    Kotani, T. et al. Apoptosis in thyroid tissue from patients with Hashimoto's thyroiditis. Autoimmunity 20, 231–236 (1995).

    CAS  PubMed  Google Scholar 

  70. 70

    Myc, A., Arscott, P. L., Bretz, J. D., Thompson, N. W. & Baker, J. R. Jr. Characterization of FAP-1 expression and function in thyroid follicular cells. Endocrinology 140, 5431–5434 (1999).A possible explanation for the refractoriness to CD95-induced apoptosis that is observed in normal thyrocytes.

    CAS  PubMed  Google Scholar 

  71. 71

    Griffith, T. S., Brunner, T., Fletcher, S. M., Green, D. R. & Ferguson, T. A. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 270, 1189–1192 (1995).

    CAS  Google Scholar 

  72. 72

    Stuart, P. M. et al. CD95 ligand (FasL)-induced apoptosis is necessary for corneal allograft survival. J. Clin. Invest. 99, 396–402 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Bennett, M. W. et al. The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma. J. Immunol. 160, 5669–5675 (1998).

    CAS  PubMed  Google Scholar 

  74. 74

    Hahne, M. et al. Melanoma cell expression of Fas(Apo-1/ CD95) ligand: implications for tumor immune escape. Science 274, 1363–1366 (1996).

    CAS  PubMed  Google Scholar 

  75. 75

    O'Connell, J., O'Sullivan, G. C., Collins, J. K. & Shanahan, F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J. Exp. Med. 184, 1075–1082 (1996).

    CAS  PubMed  Google Scholar 

  76. 76

    Allison, J., Georgiou, H. M., Strasser, A. & Vaux, D. L. Transgenic expression of CD95 ligand on islet β-cells induces a granulocytic infiltration but does not confer immune privilege upon islet allografts. Proc. Natl Acad. Sci. USA 94, 3943–3947 (1997).

    CAS  PubMed  Google Scholar 

  77. 77

    Restifo, N. P. Not so Fas: re-evaluating the mechanisms of immune privilege and tumor escape. Nature Med. 6, 493–595 (2000).

    CAS  PubMed  Google Scholar 

  78. 78

    Kang, S. M. et al. Immune response and myoblasts that express Fas ligand. Science 278, 1322–1324 (1997).

    CAS  PubMed  Google Scholar 

  79. 79

    Wei, Y., Chen, K., Sharp, G. C., Yagita, H. & Braley-Mullen, H. Expression and regulation of Fas and Fas ligand on thyrocytes and infiltrating cells during induction and resolution of granulomatous experimental autoimmune thyroiditis. J. Immunol. 167, 6678–6686 (2001).

    CAS  PubMed  Google Scholar 

  80. 80

    Tourneur, L. et al. Transgenic expression of CD95 ligand on thyroid follicular cells confers immune privilege upon thyroid allografts. J. Immunol. 167, 1338–1346 (2001).

    CAS  PubMed  Google Scholar 

  81. 81

    Abbas, A. K., Murphy, K. M. & Sher, A. Functional diversity of helper T lymphocytes. Nature 383, 787–793 (1996).

    CAS  Google Scholar 

  82. 82

    Van der Veen, R. C. & Stohlman, S. A. Encephalitogenic TH1 cells are inhibited by TH2 cells with related peptide specificity: relative roles of interleukin (IL)-4 and IL-10. J. Neuroimmunol. 48, 213–220 (1993).

    CAS  PubMed  Google Scholar 

  83. 83

    Gallichan, W. S., Balasa, B., Davies, J. D. & Sarvetnick, N. Pancreatic IL-4 expression results in islet-reactive TH2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J. Immunol. 163, 1696–1703 (1999).

    CAS  Google Scholar 

  84. 84

    Paschke, R., Schuppert, F., Taton, M. & Velu, T. Intrathyroidal cytokine gene expression profiles in autoimmune thyroiditis. J. Endocrinol. 141, 309–315 (1994).

    CAS  PubMed  Google Scholar 

  85. 85

    Heuer, M., Aust, G., Ode-Hakim, S. & Scherbaum, W. A. Different cytokine mRNA profiles in Graves' disease, Hashimoto's thyroiditis, and nonautoimmune thyroid disorders determined by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Thyroid 6, 97–106 (1996).

    CAS  PubMed  Google Scholar 

  86. 86

    Roura-Mir, C. et al. Single-cell analysis of intrathyroidal lymphocytes shows differential cytokine expression in Hashimoto's and Graves' disease. Eur. J. Immunol. 27, 3290–3302 (1997).The first analysis of cytokine production at a single-cell level in activated T cells that infiltrate the thyroid.

    CAS  PubMed  Google Scholar 

  87. 87

    Lombardi, G. et al. Antigen presentation by interferon-γ-treated thyroid follicular cells inhibits interleukin-2 (IL-2) and supports IL-4 production by B7-dependent human T cells. Eur. J. Immunol. 27, 62–71 (1997).

    CAS  PubMed  Google Scholar 

  88. 88

    Racke, M. K. et al. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J. Exp. Med. 180, 1961–1966 (1994).

    CAS  PubMed  Google Scholar 

  89. 89

    Buer, J. et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J. Exp. Med. 187, 177–183 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

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

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Cunha, F. Q., Moncada, S. & Liew, F. Y. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-γ in murine macrophages. Biochem. Biophys. Res. Commun. 182, 1155–1159 (1992).

    CAS  PubMed  Google Scholar 

  92. 92

    Batteux, F., Trebeden, H., Charreire, J. & Chiocchia, G. Curative treatment of experimental autoimmune thyroiditis by in vivo administration of plasmid DNA coding for interleukin-10. Eur. J. Immunol. 29, 958–963 (1999).

    CAS  PubMed  Google Scholar 

  93. 93

    Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Kawakami, A. et al. Thyroid-stimulating hormone inhibits Fas antigen-mediated apoptosis of human thyrocytes in vitro. Endocrinology 137, 3163–3169 (1996).

    CAS  PubMed  Google Scholar 

  95. 95

    Koga, M. et al. Immunohistochemical analysis of Bcl-2, Bax, and Bak expression in thyroid glands from patients with subacute thyroiditis. J. Clin. Endocrinol. Metab. 84, 2221–2225 (1999).

    CAS  PubMed  Google Scholar 

Download references


G.S. and R.D.M. are supported by the Associazione Italiana per la Ricerca sul Cancro.

Author information



Corresponding author

Correspondence to Ruggero De Maria.

Related links

Related links















cytochrome c











inducible nitric-oxide syntase




thyroid peroxidase


TNFR superfamily




TSH receptor


Graves' disease

Hashimoto's thyroiditis

multiple sclerosis

myasthenia gravis

type 1 diabetes


autoimmune disease



Autoreactive T cells that react strongly with self-ligands are eliminated during development in the thymus by a process that is known as negative selection.


Antigenic peptides that are generated at sub-threshold levels. When cryptic epitopes become visible to the immune system, they might elicit an immune response that is responsible for the autoimmune disease.


Secondary lymphoid follicles that contain reactive B cells which undergo intense proliferation, maturation and death after encountering their specific antigens.


A complex eye disease that is characterized by lymphocyte and chronic inflammatory-cell infiltration in orbital tissues, oedema and proliferation of connective tissue.


Diffuse enlargement of the thyroid gland.


A condition of complete unresponsiveness to antigens that can affect both T and B cells.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stassi, G., De Maria, R. Autoimmune thyroid disease: new models of cell death in autoimmunity. Nat Rev Immunol 2, 195–204 (2002).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing