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Thyroglobulin as Autoantigen: Structure–Function Relationships

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References

  1. Malthiery Y, Marriq C, Berge-Lefranc J, Franc J, Henry M, Lejeune P, Ruf J, Lissitzky S. Thyroglobulin structure and function: recent advances. Biochimie 1989;71:195–210.

    Google Scholar 

  2. Dunn JT. Werner and Ingbar's The Thyroid. 7th ed, Philadelphia: Lippincott-Raven, 1996:85–95.

    Google Scholar 

  3. Shulman S. Thyroid antigens and autoimmunity. Adv Immunol 1971;14:85–185.

    Google Scholar 

  4. Kong YM, Giraldo AA. Autoimmune Disease Models: A Guidebook. San Diego: Academic Press, 1994:123–145.

    Google Scholar 

  5. Malthiery Y, Lissitzky S. Primary structure of human thyroglobulin deduced from the sequence of its 8448-base complimentary DNA. Eur J Biochem 1987;165:491–498.

    Google Scholar 

  6. Mercken L, Simons M, Swillens S, Massaer M, Vassart G. Primary structure of bovine thyroglobulin deduced from the sequence of its 8,431-base complementary DNA. Nature 1985;316:647–651.

    Google Scholar 

  7. Musti AM, Avvedimento EV, Polistina C, Ursini VM, Obici S, Nitsch L, Cocozza S, Di Lauro R. The complete structure of the rat thyroglobulin gene. Proc Natl Acad Sci USA 1986;83:323–327.

    Google Scholar 

  8. Di Lauro R, Obici S, Condliffe D, Ursini VM, Musti A, Moscatelli C, Avvedimento VE. The sequence of 967 amino acids at the carboxyl-end of rat thyroglobulin. Location and surroundings of two thyroxine-forming sites. Eur J Biochem 1985;148:7–11.

    Google Scholar 

  9. van Ommen GB, Sterk A, Mercken LOY, Arnberg AC, Baas F, de Vijlder JJM. Studies on the structures of the normal and abnormal goat thyroglobulin genes. Biochimie 1989;71:211–221.

    Google Scholar 

  10. Durand J, Malthiery Y, Chabaud O, Lissitzky S. C-terminal extremity of ovine thyroglobulin shows strong interspecies homologies. C R SeÂances Soc Biol Fil 1987;181:258–266.

    Google Scholar 

  11. Dunn JT, Anderson PC, Fox JW, Fassler CA, Dunn AD, Hite LA, Moore RC. The sites of hormone formation in rabbit thyroglobulin. J Biol Chem 1987;262:16948–16952.

    Google Scholar 

  12. Roe MT, Anderson PC, Dunn AD, Dunn JT. The hormonogenic sites of turtle thyroglobulin and their homology with those of mammals. Endocrinology 1989;124:1327–1332.

    Google Scholar 

  13. Molina F, Bouanani M, Pau B, Granier C. Characterization of the type-1 repeat from thyroglobulin, a cysteine-rich module found in proteins from different families. Eur J Biochem 1996;240:125–133.

    Google Scholar 

  14. Koch N, Lauer W, Habicht J, Dobberstein B. Primary structure of the gene for the murine Ia antigen-associated invariant chains (Ii). An alternatively spliced exon encodes a cysteine-rich domain highly homologous to a repetitive sequence of thyroglobulin. EMBO J 1987;6:1677–1683.

    Google Scholar 

  15. Schumacher M, Camp S, Maulet Y, Newton M, MachPhee-Quigley K, Taylor SS, Friedman T, Taylor P. Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature 1986;319:407–409.

    Google Scholar 

  16. Swillens S, Ludgate M, Mercken L, Dumont JE, Vassart G. Analysis of sequence and structure homologies between thyroglobulin and acetylcholinesterase: possible functional and clinical significance. Biochem Biophys Res Commun 1986;137: 142–148.

    Google Scholar 

  17. Takagi Y, Omura T, Go M. Evolutionary origin of thyroglobulin by duplication of esterase gene. FEBS Lett 1991;282:17–22.

    Google Scholar 

  18. Mori N, Itoh N, Salvaterra PM. Evolutionary origin of cholinergic macromolecules and thyroglobulin. Proc Natl Acad Sci USA 1987;84:2813–2817.

    Google Scholar 

  19. Herzog V. Secretion of sulfated thyroglobulin. Eur J Cell Biol 1986;39:399–409.

    Google Scholar 

  20. Consiglio E, Acquaviva AM, Formisano S, Liguoro D, Gallo A, Vittorio T, Santisteban P, De Luca M, Shifrin S, Yeh HJC, Kohn LD. Characterization of phosphate residues on thyroglobulin. J Biol Chem 1987;262:10304–10314.

    Google Scholar 

  21. Tsuji T, Yamamoto K, Irimura T, Osawa T. Structure of carbohydrate unit A of porcine thyroglobulin. Biochem J 1981; 195:691–699.

    Google Scholar 

  22. Yamamoto K, Tsuji T, Irimura T, Osawa T. The structure of carbohydrate unit B of porcine thyroglobulin. Biochem J 1981; 195:701–713.

    Google Scholar 

  23. Yang S, Pollock HG, Rawitch AB. Glycosylation in human thyroglobulin: Location of the linked oligosaccharide units and comparison with bovine thyroglobulin. Arch Biochem Biophys 1996;327:61–70.

    Google Scholar 

  24. Mallet B, Lejeune P, Baudry N, Niccoli P, Carayon P, Franc J. N-glycans modulate in vivo and in vitro thyroid hormone synthesis. J Biol Chem 1995;270:29881–29888.

    Google Scholar 

  25. Baudry N, Lejeune P, Niccoli P, Vinet L, Carayon P, Mallet B. Dityrosine bridge formation and thyroid hormone synthesis are tightly linked and are both dependent on N-glycans. FEBS Lett 1996;396:223–226.

    Google Scholar 

  26. Bastiani P, Papandreou MJ, Blanck O, Fenouillet E, Thibalt V, Miquelis R. On the relationship between completion of N-acetyllactosamine units and iodine content of thyroglobulin: a reinvestigation. Endocrinology 1995;136:4204–4209.

    Google Scholar 

  27. Consiglio E, Shifrin S, Yavin Z, Ambesi-Impiombato FS, Rall JE, Salvatore G, Kohn LD. Thyroglobulin interaction with thyroid membranes. Relationship between receptor recognition of N-acetylglucosamine residues and the iodine content of thyroglobulin preparations. J Biol Chem 1981;256:10592–10599.

    Google Scholar 

  28. Bjorkman U, Ekholm R. Effect of tunicamycin on thyroglobulin secretion. Eur J Biochem 1982;585–591.

  29. Mezgrhani H, Mziaut H, Courageot J, Oughideni R, Bastiani P, Miquelis R. Identification of the membrane receptor binding domain of thyroglobulin. Insights into quality control of thyroglobulin biosynthesis. J Biol Chem 1997;272:23340–23346.

    Google Scholar 

  30. Fenouillet E, Fayet E, Hovsepian S, Bahraoui EM, Ronin C. Immunochemical evidence for a role of complex carbohydrate chains in thyroglobulin antigenicity. J Biol Chem 1986;261:15138–15158.

    Google Scholar 

  31. Suzuki K, Lavaroni S, Mori A, Obta M, Saito J, Pietrarelli M, Singer DS, Kimura DS, Kimura S, Katoh R, Kawaoi A, Kohn LD. Autoregulation of thyroid-speci®c gene transcription by thyroglobulin. Proc Natl Acad Sci USA 1998;95:8251–8256.

    Google Scholar 

  32. Marriq C, Lejeune P, Venot N, Vinet L. Hormone formation in the isolated fragment 1–171 of human thyroglobulin involves the couple tyrosine 5 and tyrosine 130. Mol Cell Endocrinol 1991;81:155–164.

    Google Scholar 

  33. Dunn AD, Corsi CM, Myers HE, Dunn JT. Tyrosine 130 is an important outer ring donor for thyroxine formation in thyroglobulin. J Biol Chem 1998;273:25223–25229.

    Google Scholar 

  34. Xiao S, Pollock HG, Taurog A, Rawitch AB. Characterization of hormonogenic sites in a terminal, cyanogen bromide fragment of human thyroglobulin. Arch Biochem Biophys 1995;320:96–105.

    Google Scholar 

  35. den Hartog MT, Sijmons CC, Bakker O, Ris-Stalpers C, de Vijlder JJM. Importance of the content and localization of tyrosine residues for thyroxine formation within the N-terminal part of human thyroglobulin. Eur J Endocrinol 1995;132:611–617.

    Google Scholar 

  36. Lamas L, Anderson PC, Fox JW, Dunn JT. Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J Biol Chem 1989;264:13541–13545.

    Google Scholar 

  37. Rawitch AB, Mercken L, Hamilton JW, Vassart G. The isolation of identical thyroxine-containing amino acid sequences from bovine, ovine and porcine thyroglobulins. Biophys Res Commun 1984;119:335–342.

    Google Scholar 

  38. Rose NR, Saboori AM, Rasooly L, Burek CL. The role of iodine in autoimmune thyroiditis. Crit Rev Immunol 1997;17:511–517.

    Google Scholar 

  39. Champion BR, Rayner DC, Byfield PGH, Page KR, Chan CTJ, Roitt IM. Critical role of iodination for T cell recognition of thyroglobulin in experimental murine thyroid autoimmunity. J Immunol 1987;139:3665–3670.

    Google Scholar 

  40. Champion BR, Page KR, Parish N, Rayner DC, Dawe K, Biswas-Hughes G, Cooke A, Geysen M, Roitt IM. Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells. J Exp Med 1991;174:363–370.

    Google Scholar 

  41. Hutchings PR, Cooke A, Dawe K, Champion BR, Geysen M, Valerio R, Roitt IM. A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis. J Exp Med 1992;175:869–872.

    Google Scholar 

  42. Dawe KI, Hutchings PR, Geysen M, Champion BR, Cooke A, Roitt IM. Unique role of thyroxine in T-cell recognition of a pathogenic peptide in experimental autoimmune thyroiditis. Eur J Immunol 1996;26:768–772.

    Google Scholar 

  43. Kong YM, McCormick DJ, Wan Q, Motte RW, Fuller BE, Giraldo AA, David CS. Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis. Secondary role of iodination. J Immunol 1995;155:5847–5854.

    Google Scholar 

  44. Wan Q, Motte RW, McCormick DJ, Fuller BE, Giraldo AA, David CS, Kong YM. Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis: Role of MHC class II. Clin Immunol Immunopathol 1997;85:187–194.

    Google Scholar 

  45. Wan Q, McCormick DJ, David CS, Kong YM. Thyroglobulin peptides of specific primary hormonogenic sites can generate cytotoxic T cells and serve as target autoantigens in experimental autoimmune thyroiditis. Clin Immunol Immunopathol 1998;86:110–114.

    Google Scholar 

  46. Rasooly L, Rose NR, Saboori AM, Ladenson PW, Burek CL. Iodine is essential for human T cell recognition of human thyroglobulin. Autoimmunity 1998;27:213–219.

    Google Scholar 

  47. Witebsky E, Rose NR. Studies on organ specificity. IV, Production of rabbit thyroid antibodies in the rabbit. J Immunol 1956;76:408–416.

    Google Scholar 

  48. Rose NR, Witebsky E. Studies on organ specificity. V. Changes in the thyroid glands of rabbit following active immunization with rabbit thyroid extracts. J Immunol 1956;76:417–427.

    Google Scholar 

  49. Witebsky E, Rose NR, Terplan K, Paine JR, Egan RW. Chronic thyroiditis and autoimmunization. J Am Med Assoc 1957; 164:1439–1447.

    Google Scholar 

  50. Roitt IM, Doniach D, Campbell PN, Hudson RV. Autoantibodies in Hashimoto's disease. Lancet 1956;2:820–821.

    Google Scholar 

  51. Rose NR, Twarog FJ, Crowle AJ. Murine thyroiditis: importance of adjuvant and mouse strain for the induction of thyroid lesions. J Immunol 1971;106:698–704.

    Google Scholar 

  52. Esquivel PS, Rose NR, Kong YM. Induction of autoimmunity in good and poor responder mice with mouse thyroglobulin and lipopolysaccharide. J Exp Med 1977;145:1250–1263.

    Google Scholar 

  53. ElRehewy M, Kong YM, Giraldo AA, Rose NR. Syngeneic thyroglobulin is immunogenic in good responder mice. Eur J Immunol 1981;11:146–151.

    Google Scholar 

  54. Tomazic V, Rose NR. Autoimmune murine thyroiditis. VIII. Role of different thyroid antigens in the induction of experimental autoimmune thyroiditis. Immunology 1976;30:63–68.

    Google Scholar 

  55. Romball CG, Weigle WO. T cell competence to heterologous and homologous thyroglobulins during the induction of experimental autoimmune thyroiditis. Eur J Immunol 1984;14:887–893.

    Google Scholar 

  56. Clagett JA, Weigle WO. Roles of T and B lymphocytes in the termination of unresponsiveness to autologous thyroglobulin in mice. J Exp Med 1974;139:643–660.

    Google Scholar 

  57. Vladutiu AO, Rose NR. Autoimmune murine thyroiditis: Relation to histocompatibility (H-2) type. Science 1971;174:1137–1139.

    Google Scholar 

  58. Tomazic V, Rose NR, Shreffer DC. Autoimmune murine thyroiditis. IV. Localization of genetic control of the immune response. J Immunol 1974;112:965–969.

    Google Scholar 

  59. Beisel KW, David CS, Giraldo AA, Kong YM, Rose NR. Regulation of experimental autoimmune thyroiditis: Mapping of susceptibility to the I-A subregion of the mouse H-2. Immunogenetics 1982;15:427–430.

    Google Scholar 

  60. Kong YM, David CS, Lomo LC, Fuller BE, Motte RW, Giraldo AA. Role of mouse and human class II transgenes in susceptibility to and protection against mouse autoimmune thyroiditis. Immunogenetics 1997;46:312–317.

    Google Scholar 

  61. Krco CJ, Gores A, David CS, Kong YM. Immunogenetic aspects of human thyroglobulin-reactive T cell lines and hybridomas. J Immunogenetics 1990;17:361–370.

    Google Scholar 

  62. Chronopoulou E, Carayanniotis G. Identification of a thyroiditogenic sequence within the thyroglobulin molecule. J Immunol 1992;149:1039–1044.

    Google Scholar 

  63. Chronopoulou E, Carayanniotis G. H-2E(k) expression influences thyroiditis induction by the thyroglobulin peptide (2495–2511). Immunogenetics 1993;38:150–153.

    Google Scholar 

  64. Rao VP, Balasa B, Carayanniotis G. Mapping of thyroglobulin epitopes: Presentation of a 9mer pathogenic peptide by different mouse MHC class II isotypes. Immunogenetics 1994;40:352–359.

    Google Scholar 

  65. Kong YM, David CS, Giraldo AA, ElRehewy M, Rose NR. Regulation of autoimmune response to mouse thyroglobulin: In¯uence of H-2D-end genes. J Immunol 1979;123:15–18.

    Google Scholar 

  66. Creemers P, Rose NR, Kong YM. Experimental autoimmune thyroiditis: In vitro cytotoxic effects of T lymphocytes on thyroid monolayers. J Exp Med 1983;157:559–571.

    Google Scholar 

  67. Vladutiu AO, Rose NR. Cellular basis of the genetic control of immune responsiveness to murine thyroglobulin in mice. Cell Immunol 1975;17:106–113.

    Google Scholar 

  68. Okayasu I, Kong YM, David CS, Rose NR. In vitro T-lymphocyte proliferative response to mouse thyroglobulin in experimental autoimmune thyroiditis. Cell Immunol 1981;61:32–39.

    Google Scholar 

  69. Braley-Mullen H, Johnson M, Sharp GC, Kyriakos M. Induction of experimental autoimmune thyroiditis in mice with in vitro activated splenic T cells. Cell Immunol 1985;93:132–143.

    Google Scholar 

  70. Simon LL, Justen JM, Giraldo AA, Krco CJ, Kong YM. Activation of cytotoxic T cells and effector cells in experimental autoimmune thyroiditis by shared determinants of mouse and human thyroglobulins. Clin Immunol Immunopathol 1986;39:345–356.

    Google Scholar 

  71. Maron R, Zerubavel R, Friedman A, Cohen IR. T lymphocyte line specific for thyroglobulin produces or vaccinates against autoimmune thyroiditis in mice. J Immunol 1983;131:2316–2322.

    Google Scholar 

  72. Creemers P, Giraldo AA, Rose NR, Kong YM. T-cell subsets in the thyroids of mice developing autoimmune thyroiditis. Cell Immunol 1984;87:692–697.

    Google Scholar 

  73. Flynn JC, Conaway DH, Cobbold S, Waldmann H, Kong YM. Depletion of L3T4. and Lyt-2. cells by rat monoclonal antibodies alters development of adoptively transferred experimental autoimmune thyroiditis. Cell Immunol 1989;122:377–390.

    Google Scholar 

  74. Sercarz EE, Lehmann PV, Ametani A, Benichou G, Miller A, Moudgil K. Dominance and crypticity of T cell antigenic determinants. Annu Rev Immunol 1993;11:729–766.

    Google Scholar 

  75. Kong YM, Giraldo AA, Justen JM, Simon LL, Fuller BE. The Thyroid and Autoimmunity. New York: Elsevier Science Publishers BV, 1986:151–152.

    Google Scholar 

  76. Nabozny GH, Simon LL, Kong YM. Suppression in experimental autoimmune thyroiditis: the role of unique and shared determinants on mouse thyroglobulin in self-tolerance. Cell Immunol 1990;131:140–149.

    Google Scholar 

  77. Champion BR, Page K, Rayner DC, Quartey-Papafio R, Byfield PG, Henderson G. Recognition of thyroglobulin autoantigenic epitopes by murine T and B cells. Immunology 1987;62:255–263.

    Google Scholar 

  78. Gleason SL, Gearhart P, Rose NR, Kuppers RC. Autoantibodies to thyroglobulin are encoded by diverse V-gene segments and recognize restricted epitopes. J Immunol 1990;145:1768–1775.

    Google Scholar 

  79. Kuppers RC, Bresler HS, Burek CL, Gleason SL, Rose NR. Molecular Immunobiology of Self-Reactivity. New York: Marcel Dekker, Inc., 1992:247–284.

    Google Scholar 

  80. Kuppers RC, Hu Q, Rose NR. Mouse thyroglobulin: conservation of sequence homology in C-terminal immunogenic regions of thyroglobulin. Autoimmunity 1996;230:175–180.

    Google Scholar 

  81. Carayanniotis G, Rao VP. Searching for pathogenic epitopes in thyroglobulin: parameters and caveats. Immunol Today 1997;18:83–88.

    Google Scholar 

  82. Hoshioka A, Kohno Y, Katsuki T, Shimojo N, Maruyama N, Inagaki Y, Yokochi T, Tarutani O, Hosoya T, Niimi H. A common T-cell epitope between human thyroglobulin and human thyroid peroxidase is related to murine experimental autoimmune thyroiditis. Immunol Lett 1993;37:235–239.

    Google Scholar 

  83. Margalit H, Spouge JL, Cornette JL, Cease KB, Delisi C, Berzofsky JA. Prediction of immunodominant helper T cell antigenic sites from the primary sequence. J Immunol 1987;138:2213–2229.

    Google Scholar 

  84. Rothbard JB, Taylor WR. A sequence pattern common to T cell epitopes. EMBO J 1988;7:93–100.

    Google Scholar 

  85. Carayanniotis G, Chronopoulou E, Rao VP. Distinct genetic pattern of mouse susceptibility to thyroiditis induced by a novel thyroglobulin peptide. Immunogenetics 1994;39:21–28.

    Google Scholar 

  86. Texier B, Bedin C, Tang H, Camoin L, Laurent-Winter C, Charreire J. Characterization and sequencing of a 40-amino-acid peptide from human thyroglobulin inducing experimental autoimmune thyroiditis. J Immunol 1992;148:3405–3411.

    Google Scholar 

  87. Caturegli P, Vidalain PO, Vali M, Aguilera-Galaviz LA, Rose NR. Cloning and characterization of murine thyroglobulin cDNA. Clin Immunol Immunopathol 1997;85:221–226.

    Google Scholar 

  88. Parma J, Christophe D, Pohl V, Vassart G. Structural organization of the 50 region of the thyroglobulin gene. Evidence for intron loss and ``exonization” during evolution. J Mol Biol 1987;196:769–779.

    Google Scholar 

  89. Molina F, Pau B, Granier C. The type-1 repeats of thyroglobulin regulate thyroglobulin degradation and T3, T4 release in thyrocytes. FEBS Lett 1996;391:229–231.

    Google Scholar 

  90. Yamashita M, Konagaya S. A novel cysteine protease inhibitor of the egg of chum salmon, containing a cysteine-rich thyroglobulin motif. J Biol Chem 1996;271:1282–1284.

    Google Scholar 

  91. Ogrinc T, Dolenc I, Ritonja A, Turk V. Purification of the complex of cathepsin L and MHC class II-associated invariant chain fragment from human kidney. FEBS Lett 1993;336:555–559.

    Google Scholar 

  92. Fowlkes JL, Serra DM, Rosenberg CK, Thrailkill KM. Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) functions as an IGF-reversible inhibitor of IGFBP-4 proteolysis. J Biol Chem 1995;270:27481–27488.

    Google Scholar 

  93. Dunn AD.Werner and Ingbar's The Thyroid. 7th ed, Philadelphia: Lippincott-Raven, 1996:81–84.

    Google Scholar 

  94. Tokuyama T, Yoshinari M, Rawitch AB, Taurog A. Digestion of thyroglobulin with puri®ed thyroid lysosomes: preferential release of iodoamino acids. Endocrinology 1987;121:714–721.

    Google Scholar 

  95. Rousset B, Selmi S, Bornet H, Bourgeat P, Rabilloud R, Munari-Silem Y. Thyroid hormone residues are released from thyroglobulin with only limited alteration of the thyroglobulin structure. J Biol Chem 1989;264:12620–12626.

    Google Scholar 

  96. Brix K, Herzog V. Extrathyroidal release of thyroid hormones from thyroglobulin by J774 mouse macrophages. J Clin Invest 1994;93:1388–1396.

    Google Scholar 

  97. Gleason SL, Gearhart P, Rose NR, Kuppers RC. Autoantibodies to thyroglobulin are encoded by diverse V-gene segments and recognize restricted epitopes. J Immunol 1990;145:1768–1775.

    Google Scholar 

  98. Anderson CL, Rose NR. Induction of thyroiditis in the rabbit by intravenous injection of papain-treated rabbit thyroglobulin. J Immunol 1971;107:1341–1348.

    Google Scholar 

  99. Bresler HS, Burek CL, Rose NR. Autoantigenic determinants on human thyroglobulin. I. Determinant speci®cities of murine monoclonal antibodies. Clin Immunol Immunopathol 1990;54:64–75.

    Google Scholar 

  100. Saboori AM, Rose NR, Burek CL. Amino acid sequence of a tryptic peptide of human thyroglobulin reactive with sera of patients with thyroid diseases. Autoimmunity 1996;22:87–94.

    Google Scholar 

  101. Meister GE, Roberts CGP, Berzofsky JA, De Groot AS. Two novel T cell epitope prediction algorithms based on MHC-binding motifs: Comparison of predicted and published epitopes from Mycobacterium tuberculosis and HIV protein sequences. Vaccine 13: 581–91.

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Vali, M., Rose, N.R. & Caturegli, P. Thyroglobulin as Autoantigen: Structure–Function Relationships. Rev Endocr Metab Disord 1, 69–77 (2000). https://doi.org/10.1023/A:1010016520778

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