Endocrine Pathology

, Volume 9, Issue 3, pp 201–208 | Cite as

Discordant expression of Ii and HLA-DR in thyrocytes: A possible pathogenetic factor in Hashimoto’s thyroiditis

  • Mujun YuEmail author
  • Mingzhen Xu
  • Lou Savas
  • Ashraf Khan
Clinical Research


Hashimoto’s thyroiditis is the archetype of organ-specific autoimmune disease. The key pathogenetic feature is the activation of thyroid-specific T-cells by properly presented endogenous thyroid antigens. There is strong indication that thyrocytes themselves present self-antigens, based on the finding of antigen presenting human leukocyte antigen-DR (HLA-DR) molecules on the thyrocytes in Hashimoto’s thyroiditis. Because class II-associated invariant chain (li) is tightly bound to the antigen-binding groove of the DR molecules in the endoplasmic reticulum and is found to compete with the endogenous peptides for binding with DR, it is speculated that li prevents endogenous peptides from binding to, and being presented by, DR on the cell surface. We hypothesize that in Hashimoto’s thyroiditis, Ii is insufficient, leaving DR molecules open for endogenous peptides. In this article, we test our hypothesis of discordance between DR and li in the thyroid epithelial cells in Hashimoto’s thyroiditis by immunohistochemistry. Formalin-fixed, paraffin-embedded archival tissue from eight cases of Hashimoto’s thyroiditis and four cases of normal thyroid specimen were randomly selected and immunostained with monoclonal antibodies (MAbs) against HLA-DR and li using avidin-biotin-peroxidase method. We found that in all eight cases of Hashimoto’s thyroiditis, li is significantly reduced relative to DR. The results support our hypothesis that presentation of self-antigen may be a result of insufficient li in the thyrocytes in Hashimoto’s thyroiditis.

Key Words

Hashimoto’s thyroiditis HLA-DR invariant chain (li) autoimmune disease autoantigen 


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  1. 1.
    Rapoport, B. Pathophysiology of Hashimoto’s thyroiditis and hypothyroidism. Annu Rev Med 42:91–96, 1991.PubMedGoogle Scholar
  2. 2.
    Rose NR. Pathogenic mechanisms in autoimmune diseases. Clin Immunol Immunopathol 53:S7-S16, 1989.PubMedCrossRefGoogle Scholar
  3. 3.
    Rose NR. Autoimmune diseases: tracing the shared threads. Hosp Pract (Off Ed) 32:147–154, 1997.Google Scholar
  4. 4.
    Tandon N, Weetman AP. T cells and thyroid autoimmunity. J R Coll Physicians Lond 28:10–18, 1994.PubMedGoogle Scholar
  5. 5.
    Volpe R. A perspective on human autoimmune thyroid disease: is there an abnormality of the target cell which predisposes to the disorder? Autoimmunity 13:3–9, 1992.PubMedGoogle Scholar
  6. 6.
    Valtonen VV, Ruutu P, Varis K, Ranki M, Malkamaki M, Makela PH. Serological evidence for the role of bacterial infections in the pathogenesis of thyroid diseases. Acta Med Scand 219:105–111, 1986.PubMedCrossRefGoogle Scholar
  7. 7.
    Tomer Y, Davies TF. Infection, thyroid disease, and autoimmunity. Endocr Rev 14:107–120, 1993.PubMedCrossRefGoogle Scholar
  8. 8.
    Hanafusa T, Pujol-Borrell R, Chiovato L, Russell RC, Doniach D, Bottazzo GF. Aberrant expression of HLA-DR antigen on thyrocytes in Grave’s disease: relevance for autoimmunity. Lancet 2:111–1115, 1983.Google Scholar
  9. 9.
    Kolk DP, Floyd-Smith G. Induction of the murine class-II antigen-associated invariant chain by TNF-alpha is controlled by an NF-kappa B-like element [published erratum appears in Gene 1993 Dec 22; 136(1–2):381]. Gene 126:179–185, 1993.PubMedCrossRefGoogle Scholar
  10. 10.
    Rahmsdorf HJ, Harth N, Eades AM, Litfin M, Steinmetz M, Forni L, Herrlich P. Interferon-gamma, mitomycin C, and cycloheximide as regulatory agents of MHC class II-associated invariant chain expression. J Immunol 136:2293–2299 1986.PubMedGoogle Scholar
  11. 11.
    Pessara U, Koch N. Tumor necrosis factor alpha regulates expression of the major histocompatibility complex class II-associated invariant chain by binding of an NF-kappa B-like factor to a promoter element. Mol Cell Biol 10:4146–4154, 1990.PubMedGoogle Scholar
  12. 12.
    Momburg F, Koch N, Moller P, Moldenhauer G, Butcher GW, Hammerling GJ. Differential expression of Ia and Ia-associated invariant chain in mouse tissues after in vivo treatment with IFN-gamma. J Immunol 136:940–948, 1986.PubMedGoogle Scholar
  13. 13.
    Weetman AP, McGregor AM. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev 15:788–830, 1994.PubMedCrossRefGoogle Scholar
  14. 14.
    Wong GH, Bartlett PF, Clark-Lewis I, Battye F, Schrader JW. Inducible expression of H-2 and Ia antigens on brain cells. Nature 310: 688–691, 1984.PubMedCrossRefGoogle Scholar
  15. 15.
    Sant AJ, Miller J. MHC class II antigen processing: biology of invariant chain. Curr Opin Immunol 6:57–63, 1994.PubMedCrossRefGoogle Scholar
  16. 16.
    Viville S, Neefjes J, Lotteau V, Dierich A, Lemeur M, Ploegh H, Benoist C, Mathis D. Mice lacking the MHC class II-associated invariant chain. Cell 72:635–648, 1993.PubMedCrossRefGoogle Scholar
  17. 17.
    Stockinger B, Pessara U, Lin RH, Habicht J, Grez M, Koch N. A role of Ia-associated invariant chains in antigen processing and presentation. Cell 56:683–689, 1989.PubMedCrossRefGoogle Scholar
  18. 18.
    Williams DB, Watts TH. Molecular chaperones in antigen presentation. Curr Opin Immunol 7:77–84, 1995.PubMedCrossRefGoogle Scholar
  19. 19.
    Bertolino P, Rabourdin-Combe C. The MHC class II-associated invariant chain: a molecule with multiple roles in MHC class II biosynthesis and antigen presentation to CD4+ T cells. Crit Rev Immunol 16:359–379, 1996.PubMedGoogle Scholar
  20. 20.
    Ghosh P, Amaya M, Mellins E, Wiley DC. The structure of an intermediate in class II MHC maturation: CLIP bound to HLA-DR3. Nature 378:457–462, 1995.PubMedCrossRefGoogle Scholar
  21. 21.
    Reyes VE, Lu S, Humphreys RE. Cathepsin B cleavage of Ii from class II MHC alpha- and beta-chains. J Immunol 146:3877–3880, 1991.PubMedGoogle Scholar
  22. 22.
    Sung E, Jones PP. The invariant chain of murine Ia antigens: its glycosylation, abundance and subcellular localization. Mol Immunol 18:899–913, 1981.PubMedCrossRefGoogle Scholar
  23. 23.
    Kvist S, Wiman K, Claesson L, Peterson PA, Dobberstein B. Membrane insertion and oligomeric gomeric assembly of HLA-DR histocompatibility antigens. Cell 29:61–69, 1982.PubMedCrossRefGoogle Scholar
  24. 24.
    Machamer CE, Cresswell P. Biosynthesis and glycosylation of the invariant chain associated with HLA-DR antigens. J Immunol 129: 2564–2569, 1982.PubMedGoogle Scholar
  25. 25.
    De Bernardo E, Davies TF. Antigen presentation in human autoimmune thyroid disease. Exp Cell Biol 54:155–162, 1986.PubMedGoogle Scholar
  26. 26.
    Roche PA, Cresswell P. Invariant chain association with HLA-DR molecules inhibits immunogenic peptide binding. Nature 345:615–618, 1990.PubMedCrossRefGoogle Scholar
  27. 27.
    Ericson ML, Sundstrom M, Sansom DM, Charron DJ. Mutually exclusive binding of peptide and invariant chain to major histocompatibility complex class II antigens. J Biol Chem 269:26,531–26,538, 1994.Google Scholar
  28. 28.
    Hunt DF, Michel H, Dickinson TA, Shabanowitz J, Cox AL, Sakaguchi K, Appella E, Grey HM, Sette A. Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science 256:1817–1820, 1992.PubMedCrossRefGoogle Scholar
  29. 29.
    Rudensky A, Janeway CA Jr. Studies on naturally processed peptides associated with MHC class II molecules. Chem Immunol 57:134–151, 1993.PubMedCrossRefGoogle Scholar
  30. 30.
    Calin-Laurens V, Forquet F, Lombard-Platet S, Bertolino P, Chretien I, Trescol-Biemont MC, Gerlier D, Rabourdin-Combe C. High efficiency of endogenous antigen presentation by MHC class II molecules. Int Immunol 4:1113–1121, 1992.PubMedCrossRefGoogle Scholar
  31. 31.
    Weiss S, Bogen B. MHC class II-restricted presentation of intracellular antigen. Cell 64:767–776, 1991.PubMedCrossRefGoogle Scholar
  32. 32.
    Jacobson S, Sekaly RP, Jacobson CL, McFarland HF, Long EO. HLA class II-restricted presentation of cytoplasmic measles virus antigens to cytotoxic T cells. J Virol 63:1756–1762, 1989.PubMedGoogle Scholar
  33. 33.
    Bodmer H, Viville S, Benoist C, Mathis D. Diversity of endogenous epitopes bound to MHC class II molecules limited by invariant chain. Science 263:1284–1286, 1994.PubMedCrossRefGoogle Scholar
  34. 34.
    Ting JP, Baldwin AS. Regulation of MHC gene expression. Curr Opin Immunol 5:8–16, 1993.PubMedCrossRefGoogle Scholar
  35. 35.
    Benoist C, Mathis D. Regulation of major histocompatibility complex class-II genes: X, Y and other letters of the alphabet. Annu Rev Immunol 8:681–715, 1990.PubMedGoogle Scholar
  36. 36.
    Koch N, Harris AW. Differential expression of the invariant chain in mouse tumor cells: relationship to B lymphoid development. J Immunol 132:12–15, 1984.PubMedGoogle Scholar
  37. 37.
    Tandon N, Metcalfe RA, Barnett D, Weetman AP. Expression of the constimulatory molecule B7/BB1 in autoimmune thyroid disease. QJ Med 87:231–236, 1994.Google Scholar
  38. 38.
    Schultze J, Nadler LM, Gribben JG. B7-mediated costimulation and the immune response. Blood Rev 10:111–127, 1996.PubMedCrossRefGoogle Scholar
  39. 39.
    Kimura H, Davies TF. Thyroid-specific T cells in the normal Wistar rat. II. T cell clones interact with cloned wistar rat thyroid cells and provide direct evidence for autoantigen presentation by thyroid epithelial cells. Clin Immunol Immunopathol 58:195–206, 1991.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1998

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Massachusetts Medical CenterWorcester
  2. 2.Antigen Express Inc.Worcester

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