��

��. ��:

19-Sep-2000

�� , 16(4), ��-�� 1999, 337-351

��

��
��, ��, �� -��, ��

�. ��,¹ �. ��²
¹�� , �� Pasteur
²�' �� , �� "��"

� �� , �� 30 ��. � �� , � �� -�� , �� . �� Graves, � �� Hashimoto, �� (postpartum thyroiditis)� �� -�� . �� (thyroglobulin, TG), � �� (thyroid peroxidase, TPO, �� ) �� (thyroid stimulating hormone receptor, TSH-R). �� TSH-R �� Graves, �� -�� -�G, �� , �� Hashimoto �� . ��, �� , �� -�� (��) �� , �� , �� . � �� . � �� - �� -��, �� . ��, �� . ��, �� HLA-DR �� HLA-DQ (HLA �� ). ��, �� , � �� Graves �� DR3, � �� Hashi moto �� HLA-DR4, DR5 �� DQ7, �� HLA-DR5 �� DQ7. �� (�� ). �� , ��, �� . �� , �� -��. �� , �� .

�� : �� , �� -��, �� , �� .

1. ��

�� Graves, � �� Hashimoto, �� (postpartum thyroiditis)� �� -�� , �� : �� (TG), �� (��), �� , �� (TSH-R). � �� . �� , �� . �� , �� , �� . � �� (�� ) �� , �� , �� . �� - � ��-��. �� , �� -��. ��, �� (�-��) �� -�� (�-��) �� .

�� , �� , �� -��.

2. �� 

2.1. ��

� �� (TG) �� 660.000 (2�2748 �� ), � �� , �� ¹ (��. 1, ��. 1). � �� , �� , �� . �� , �� , � �� (�₄) �� (�₃). �� . �� TG �� 80.² �� , �� TG �� 8. �� , �� 300.000 �� 37 ��.² � �� TG �� mRNA �� cDNA. �� mRNA �� , �� TG �� , �� TG �� (�� .�.). �� mRNA �� 2748 �� 2750. � �� TG �� 77,3%.²

2.1.1. �� TG. �� , �� . �� TG (��-TG) �� , �� , � �� (RIA) � �� (ELISA) ��.

� �� ³ (��. 2). �� -TG �� Hashimoto, �� . �� -TG �� 76�91% �� Hashimoto, �� 63�82% �� 40�60% �� Graves. �� -TG �� 28�65% �� , �� 28�50% �� , �� (�� 10%) �� . � �� -TG �� , �� , �� 21 �� 70 �� -TG �� ,�� . �� , �� -TG �� 10,6% �� 18�24 �� 33,3% �� 55�64 ��.⁴

�� , �� RIA �� ELISA �� , �� -TG �� ,�� . �� , �� -TG �� 86�100% �� , �� 87�89% �� Graves �� 69�94% �� .⁵

�� -TG �� IgG (IgA, �� 20% �� IgM, �� 1%). �� IgG ��-TG ��, �� . �� Hashimoto �� IgG₁(30%) �� IgG₂ (45%), �� Graves �� IgG₄ (60%).⁶

�� , �� ⁷ (��. 3). �� -TG �� , �� . � �� (��) (��-TG �� -��) �� , �� 80% �� .⁸

�� -TG �� (autoimmune thyroid diseases, AITD), �� TG. �� TG �� (� �� ) �� (� ��) �� , �� , �� TG.^9,10��, �� Hashimoto � �� Graves �� . � �� TG �� , �� . ��, �� . � �� Hashimoto (�� VI), �� Graves �� (�� ), �� .¹¹ �� Graves �� TG, �� (AchE, �� , �� ).¹² �� TG �� , �� AchE.¹³ ��, �� AchE �� 28% �� TG, �� 80�195 �� AchE �� 60% �� TG. ��, �� , �� AchE, �� TG, �� . �� AchE, �� , �� TG.

�� , �� -TG �� (�� ) �� TG, �� . �� : �� , �� Hashimoto, �� TG.¹⁴

2.1.2. �-�� TG. �� TG �� (��). �� -�� (CBA/C�, �-2^�), �� TG �� TG �� .¹⁵ �� (�� TG), �� (�� ) �� , �� 2553.¹⁶ �� 2553 �� . �� (� �� ) �� . � �� , �� (MHC), �� -��. �� in vivo ��. �-��, �� (�� in vitro ��), �� , �� .¹⁷

�� -2^q �� H-2^s �� TG �� , �� . �� Texier et al,¹⁸ �� 40 �� (�� , �� TG), �� -�� , �� TG. �� , �� .

�� (obese) �� , � �� .¹⁹ �� , � �� in ovo, �� . ��, � �� , �� MHC-�� , �� . �� .

�� .²⁰ �� TG �� , �� , �� , �� Chernobyl.²¹ �� , �� , �� TG �� -�� .

�� (� �� ) �� , �� TG �� .^15,16 �� in vitro �� . � �� TG �� (�� ) �� , �� 10% �� TG (�� ) �� .²²

��, ��, �� (2496�2504) �� TG �� (experimental autoimmune thyroiditis, EAT) �� -�� -2^� �� -2^s �� TG (�� IgG �� TG �� ).²³

�� (2695�2713) �� TG ��, �� -2^s �� -2^�, �� TG.²

2.2. ��

� �� (��) �� , �� , �� , �� TG �� ₃ �� ₄.²⁴ �� 107.000 (933 �� ) �� (��. 1, ��. 1). �� 1985 �� PO �� .^25,26

2.2.1. �� . �� , �� . � �� 1959.²⁷ �� . �� , �� 85�95% �� Hashimoto �� 66�86% �� Graves � �� (��. 2). �� , �� 18�24 �� 15% �� 55�64 �� 24%.⁴ �� , �� , �� RIA �� ELISA �� -�� . �� , �� (�� ).^28,29 �� -�PO �� Hashimoto �� . � �� -�� AITD, �� 20%.⁸ ��, �� Graves �� , �� Hashimoto � �� . �� , �� , �� (�� , �� .��.).

� �� (��-TG �� -��) �� , �� . �� , �� , �� , �� 20��, �� 8 �� 25 �� . �� , �� TSH �� ₃ �� ₄, � �� 38 �� 178 �� .⁴ ��, � �� -�� .³⁰

�� -�� IgG, �� IgG₁ �� IgG₄.³¹ �� -�� IgG₁ �� IgG₄.³² ��, �� IgE.³³

�� -TG, �� -�� , �� Hashimoto (�) �� in vitro �� ,²⁷ (�) �� ³⁴ �� (�) �� , in vitro, �� , �� -��.³⁵

�� , �� .³⁶ �� -��, �� 2�6 �� .^37�40 �� cDNA �� , �� -�� ,³⁹ �� Hashimoto,⁴⁰ �� 590�622 �� 713�721.

�� -�� , �� AITD. ��, �� Kohno et al⁴¹ �� -�� (�� -��, �� ). ��, �� .³⁷ ��, �� TG �� , �� .^42�44 �� .

�. �� TG. � �� TG �� . �� -TG/TPO �� . �� , �� .⁴⁴�� -TG/�� -TG �� TG. � �� AITD �� . �� . ��, �� Hashimoto �� , �� -TG �� -�� . ��, �� -TG/�� .⁴⁴

2.2.2. �-�� . �� C57BL/6 (H-2^b) �� Freund � �� -��. �� -�� (�� 774�788) ��, ��, �� cDNA �� .⁴⁵

�� -�� . �� , �� 16 �� (�� ), �� Tandon et al⁴⁶ �� (415�432, 439�457 �� 463�481), �� -�� Graves � �� (�� 23�37% �� ). �� -�� . ��, �� Dayan et al,⁴⁷ �� -�� (�� Graves), �� . �� . ��, �� -�� (535�551 �� 632�645) �� HLA �� . �� -�� Ewin et al⁴⁸ �� R1c (�� 145�250) �� 8 �� , �� -�� . � �� Kawakami et al⁴⁹ ��, ��, �� 60 �� , �� 110�129, 211�230, 842�861 �� 882�901, �� -�� . ��, � �� -�� , �� Hashimoto, �� Graves, �� 100�119 �� 625�644 �� Hashimoto (75% �� ).⁵⁰ �� , �� (��) �� (�� -��) �� .

2.3. ��

� �� TSH (TSH-R) �� TSH, �� , �� (cAMP) �� , �� (��. 1, ��. 1). � �� (�� 1989) �� TSH-R �� , �� .^51�55��, �� , �� (� �� ), �� .⁵⁴ �� cDNA �� TSH-R �� 764 ��, �� 7 �� (�� G-��) �� ܻ, �� . � �� , � �� , �� 418 �� (�� -�� 20 ��) �� 6 �� . �� TSH-R �� , �� , �� (�� ), �� Graves (�� ).^54,55 �� TSH-R, �� , �� -�� , �� . � TSH-R �� (70%) �� (LH) �� (hCG), �� G-��.^53,56

2.3.1. �� TSH-R. �� , �� . �� TSH (��-TSH-R) �� , �� (��. 4). �� TSH (TRAb: TSH receptor antibodies � TBII: TSH binding inhibitory immunoglobulins) �� , �� TSH (TSAb: thyroid stimulating antibodies) � �� (TBAb: thyroid binding antibodies). �� . �� cAMP � �� . �� Graves. �� cAMP � �� , �� .

�� Graves �� , �� 1956, �� Adams �� Purves,⁵⁷ �� (LATS: long acting thyroid stimulator) �� Graves, �� TSH. �� , �� LATS �� IgG. �� TSH, �� .^58�61

�� -TSH-R, �� , �� (�) �� ⁶¹ � (�) �� cAMP, �� FRTL-5 ��.⁶² �� , � �� -TSH-R �� TSH (¹²⁵I-TSH) �� , �� RIA �� .⁶³ �� FRTL-5 �� ¹²⁵�-TSH �� , �� .⁶⁴ � �� , �� 93�97% �� Graves �� .⁶⁵

�� , �� Graves �� -TSH-R ��. �� (��, ��, � �� ¹²⁵�-TSH �� cAMP), �� .⁶⁶ ��, �� ⁶⁷ � �� Hashimoto⁶⁸ �� , �� TSH �� , �� . �� -TSH-R, �� IgG, �� , �� IgG₁ (�� ) �� (�� -TG �� -��).^69,70

�� (�� ) �� TSH, �� -TSH-R, �� .^71�75 �� -TSH-R �� ,⁴⁰ �� , �� 8�165,⁷² 333�343⁷³ �� 352�366.⁷⁴ �� -TSH-R ��, �� , �� . �� , �� Tyr 385 �� 295�306 �� .⁷¹ � �� TSH-R ��, �� Cos-7, �� Thr 40 �� , �� TSH.⁷¹

�� , �� cAMP, �� -TSH-R �� mRNA �� TG �� ,⁷⁶ �� c-myc �� c-fos.^77,78 �� ₂,⁷⁹ ��, �� TSH, �� C.⁸⁰

�� 161 �� TSH-R �� Nef �� HIV.⁸¹ �� , �� TSH-R, �� Nef (�� Graves �� Nef). �� Graves.

�� TRAb, �� 70�90% �� Graves.^82,83 �� 10�25% �� Graves �� TRAb, �� .⁸² �� (�� Graves �� TRAb) �� , ��, �� . ��, �� Graves �� TRAb �� .⁸²

�� TRAb �� Graves �� . �� , �� , �� TRAb �� Graves.⁸²

�� Graves �� TRAb �� . �� , �� , �� .⁸⁴

�� TRAb �� , �� , �� ,�� . ��, �� TRAb �� .⁸⁵ �� , �� ,�� TRAb. �� -�� 18 �� , �� , �� , �� 75% �� . ��, �� TRAb �� 25% �� .^85,86

�� , �� , �� 53�72% �� TRAb �� Graves �� . ��, � �� , �� .^85�87 � �� . �� , �� ₂�� 1� �� 6. �� , �� -�� TSH-R.^88,89

�� , �� , �� , �� TRAb. �� , � �� TRAb, �� . �� , �� .⁹⁰ � �� , �� Graves.⁹¹ �� , �� .^85,92 � �� (�� ) �� .⁹²

��, ��, �� . �� , �� , �� .⁹³

2.3.2. �-�� TSH-R. � �� -�� TSH-R �� Graves �� (�� 1995), �� . �� -��, �� , �� 52�71,⁹⁴ 142�161⁹⁴/ 158�176,^50,95 202�221⁹⁴/207�222,⁵⁰237�252⁹⁵/248� 263⁹⁵/247�266⁹⁴ �� 343�362^50,95/357�376.⁵⁰ ��, � �� 158�176 �� , �� 158�176 �� 248�263, �� .⁹⁶ � �� -�� , ��, �� -�� , �� , �� (��, �� ).⁹⁷ �� , �� , �-�� (��) �� DBA/1J �� , �� -�� (�� 132�155, 145�163, 158�176, 172�186) � �� -�� . �� , �� , ��-TSH-R ��.⁹⁸ ��, �� (�� scid) �� -�� 158�176. � �� , �� TSH-R, �� Graves.⁹⁹ �� TSH-R, �� -�� (�� ThO⁵⁰), �� .

3. ��

�� -�� , �� (TG), �� (��) �� TSH (TSH-R), �� .

�� TG �� . �� . � �� , ��, �� , �� , �� , �� . �� , � �� , �� -��, �� . �� , �� -TG ��, �� TG, �� , ��, ��, �� -TG ��, �� , �� . �� . �� /�� , �� -TG/TPO ��, �� .

�� , �� TG � �� , �� Freund, � �� -��. �� TG, �� TG (�� 12�18 ��) �� -�� , �� . �� , �� TG �� -�� .

� TSH-R �� Graves. � �� , �� , �� . �� . �� -TSH-R �� Graves �� . � TSH �� -TSH-R �� . �-�� , �� . � �� -�� . �� -�� TSH-R �� (�� TSH-R, �� -��).

�� , �� , �� , �� -�� .

� �� - �� -�� , �� , �� (NIS, Na⁺/I-symporter) �� 64 kD �� , ��

�� Graves. �� , �� -��, �� .

��

VAN HERLE AJ, VASSART G, DUMONT JE. Control of thyroglobulin synthesis and secretion. N Engl J Med 1979, 301:239�249
CARAYANNIOTIS G, RAO V. Searching for pathogenic epitopes in thyroglobulin: parameters and caveats. Immunol Today 1997, 18:83�88
BIGAZZI PE, ROSE NR. Autoimmune thyroid disease. In: Rose NR, Mackay IR (eds) The Autoimmune diseases. Academic Press Inc, London, 1985:161�199
VANDERPUMP M, TUNBRIDGE W, FRENCH J, APPLETON D, BATES D, CLARK F. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endo crinol 1995, 43:55�68
McCOY JP, MICHAELSON JH, BIGAZZI PE. Anti-idiotypic immunity and autoimmunity: III. Investigations in human autoimmune thyroiditis. Life Sci 1983, 32:109�118
CATUREGLI P, KUPPERS RC, MARIOTTI S, LYNNE BUREK C, PINCHERA A, LADENSON PW ET AL. IgG subclass distribution of thyroglobulin antibodies in patients with thyroid disease. Clin Exp Immunol 1994, 98:464�469
TOMER Y. Anti-thyroglobulin autoantibodies in autoimmune thyroid diseases: cross-reactive or pathogenetic? Clin Immunol Immunopathol 1997, 82:3�11
HAYASHI Y, TAMAI H, FUGATA S, HIROTA Y, KATAYAMA S, KUMA K ET AL. A long-term clinical, immunological and histological follow-up study of patients with goitrous chronic lymphocytic thyroiditis. J Clin Endocrinol Metab 1985, 61:1172�1177
SCHULZ E, BENKER G, BETHAUSER H, STEMPKA L, HUFNER M. An autoimmuno-dominant thyroglobulin epitope characterized by a monoclonal antibody. J Endocrinol Invest 1992, 15:25�30
HENRY M, ZANELLI E, PIECHACZYK M, PAU B, MALTHIERY Y. A major human thyroglobulin epitope defined with monoclonal antibodies is mainly recognized by human autoantibodies. Eur J Immunol 1992, 22:315�319
CATUREGLI P, MARIOTTI S, KUPPERS RC, LYNNE BUREK C, PINCHERA A, LADENSON PW ET AL. Epitopes on thyroglobulin: a study of patients with thyroid disease. Autoimmunity 1994, 18:41� 49
MAPPOURAS DG, PHILIPPOU G, HARALAMBOUS S, TZARTOS S, BALAFAS A, SOUVATZOGLOU A ET AL. Antibodies to acetylcholinesterase and thyroglobulin in myasthenia gravis and Graves� disease. Clin Exp Immunol 1995, 100:336�343
SCHUMACHER M, CAMP S, MAULET Y, NEWTON M, MACPHEE-QUIGLEY K, FRIEDMANN ET AL. Primary structure of Torpedo californica acetylcholinesterase deduced from its cDNA sequence. Nature 1986, 319:407�409
FUKUMA N, PETERSEN VB, McLACHLAN SM, PEGG CA, REES SMITH B. Human monoclonal thyroglobulin autoantibodies of high affinity. I. Production, characterization and interaction with murine monoclonal thyroglobulin antibodies. Autoimmunity 1991, 10:291�295
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
CHAMPION BR, PAGE KR, PARISH N, RAYNER DC, DAWE K, BISWAS-HUGHES G ET AL. Identification of a thyroxine-containing self-epitope of thyroglobulin which triggers thyroid autoreactive T cells. J Exp Med 1991, 174:363�370
HUTCHINGS PR, COOKE A, DAWE K, CHAMPTION BR, GEYSEN M, VALERIO R ET AL. A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis. J Exp Med 1992, 175:869�872
TEXIER B, BEDIN C, TANG H, COMOIN 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
BROWN TR, SUNDICK RS, DHAR A, SHETH D, BAGGHI NI. Uptake and metabolism of iodine is crucial for the development of thyroiditis in obese strain chickens. J Clin Invest 1991, 88: 106�111
RAYNER DC, CHAMPION BR, COOKE A. Thyroglobulin as autoantigen and tolerogen. In: Bach J-F (ed) Monoclonal antibodies and peptide therapy in autoimmune disease. New York, Marcel Dekker, 1995:112�143
KINALSKA I, ZARZYCKI W, KRAWEZUK I, GOSIEWSKA A, GORSKA M, ZONENBERG A. Antithyroid autoantibodies in the examined population with iodine prophylaxis after the Chernobyl catastrophe. Horm Metab Res 1991, 23:236�238
GRUFFAT D, GONZALVEZ S, CHAMBARD M, MAUCHAMP J, CHABAUD O. Long-term iodination of thyroglobulin by porcine thyroid cells cultured in porous-bottomed culture chambers: regulation by thyrotrophin. J Endocrinol 1991, 128:51�61
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
DEGROOT LJ, NIEPOMNISZCZE H. Biosynthesis of thyroid hormone: basic and clinical aspects. Metabolism 1977, 26: 665�718
ZARNOCKA B, RUF J, FERRAND M, CARAYON P, LISSITZKY S. Purification of the human thyroid peroxidase and its identification as the microsomal antigen involved in thyroid diseases. FEBS Lett 1985, 190:147�152
LIBERT F, RUEL J, LUDGATE M, SWILLENS S, ALEXANDER N, VASSART G ET AL. Thyroperoxidase, an auto-antigen with a mosaic structure made of nuclear and mitochondrial gene modules. EMBO J 1987, 6:4193�4196
BELYAVIN G, TROTTER WR. Investigations of thyroid antigens reacting with Hashimoto sera. Lancet 1959, i:648�652
RUF J, CZARNOCKA B, FERRAND M, DOULLAIS F, CARAYON P. Novel routine assay of thyroperoxidase autoantibodies. Clin Chem 1988, 34:2231�2234
KAUFMAN KD, FILETTI S, SETO P, RAPOPORT B. Recombinant human thyroid peroxidase generated in eukaryotic cells: a source of specific antigen for the immunologic assay of anti-microsomal antibodies in the sera of patients with autoimmune thyroid disease. J Clin Endocrinol Metab 1990, 70:724�728
LAZARUS J, HALL R, OTHMAN A, PARKES C, RICHARDS C, McCULLOCH B ET AL. The clinical spectrum of postpartum thyroid disease. Q J Med 1996, 89:429�435
PARKES AB, McLACHLAN SM, BIRD P, REES SMITH B. The distribution of microsomal and thyroglobulin antibody activity among the IgG subclasses. Clin Exp Immunol 1984, 57:239�243
GUO J, JAUME J, RAPOPORT B, McLACHLAN S. 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 1997, 82: 925�931
GUO J, RAPOPORT B, McLACHLAN S. Thyroid peroxidase autoantibodies of IgE class in thyroid autoimmunity. Clin Immunol Immunopathol 1997, 82:157�162
JANSSON R, THOMPSON PM, CLARK F, McLACHLAN SM. Association between thyroid microsomal antibodies of IgG-1 and hypothyroidism in autoimmune postpartum thyroiditis. Clin Exp Immunol 1986, 63:80�86
BOGNER U, SCHLEUSENER H, WALL JR. Antibody-dependent cell-mediated cytotoxicity against human thyroid cells in Hashi moto's thyroiditis but not in Graves' disease. J Clin Endocrinol Metab 1984, 59:734�738
GIRAUD A, FRANC JL, LONG Y, RUF J. Effects of deglycosylation of human thyroid peroxidase on its catalytic activity and immu noreactivity. J Endocrinol 1992, 132:317�323
SALLER B, HORMANN R, MANN K. Heterogeneity of autoantibodies against thyroid peroxidase in autoimmune thyroid disease: evidence against antibodies directly inhibiting peroxidase activi ty as regulatory factors in thyroid hormone metabolism. J Clin Endocrinol Metab 1991, 72:188�195
ZANELLI E, HENRY M, MALTHIERY Y. Use of recombinant epitopes to study the heterogeneous nature of the autoantibodies against thyroid peroxidase in autoimmune thyroid disease. Clin Exp Immunol 1992, 87:80�86
FINKE R, SETO P, RUF J, CARAYON P, RAPOPORT B. Determination at the molecular level of a B cell epitope on thyroid peroxidase likely to be associated with autoimmune thyroid disease. J Clin Endocrinol Metab 1991, 73:919�921
LIBERT F, LUDGATE M, DINSART C, VASSART G. Thyroperoxidase but not the thyrotropin receptor, contains sequential epitopes recognized by autoantibodies in recombinant peptides expressed in the pUEX vector. J Clin Endocrinol Metab 1991, 73:857�860
KOHNO Y, YAMAGUCHI F, SAITO K, NIIMI H, NISHIKAWA T, HOSOYA T. Anti-thyroid peroxidase antibodies in sera from healthy subjects with chronic thyroiditis: differences in the ability to inhibit thyroid peroxidase activities. Clin Exp Immunol 1991, 85: 459�463
RUF J, FERRAND M, DURANDE-GORDE JM, CARAYON P. Immunopurification and characterization of thyroid autoantibodies with dual specificity for thyroglobulin and thyroperoxidase. Autoimmunity 1992, 11:179�188
HENRY M, ZANELLI E, MALTHIERY Y. Anti-human thyroid peroxidase and anti-human thyroglobulin antibodies present to cross-reactivity on recombinant peptides. Clin Exp Immu nol 1991, 86:478�482
RUF J, FELDT-RUSMUSSEN U, HEGEDUS L, FERRAND M, CARAYON P. Bispecific thyroglobulin and thyroperoxidase autoantibodies in patients with various thyroid and autoimmune disease. J Clin Endocrinol Metab 1994, 79:1404�1408
KOTANI T, UMEKI K, YAGIHASHI S, HIRAI K, OTHAKI S. Identification of thyroiditogenic epitope on porcine thyroid peroxidase for C57BL/6 mice. J Immunol 1992, 148:2084�2089
TANDON N, FREEMAN M, WEETMAN AP. T cell responses to synthetic thyroid peroxidase peptides in autoimmune thyroid disease. Clin Exp Immunol 1991, 86:56�60
DAYAN CM, LONDEI M, CORCORAN AE, GRUBECK-LOEBENSTEIN B, JA MES RF, RAPOPORT B ET AL. Autoantigen recognition by thyroid-infiltrating T cells in Graves' disease. Proc Natl Acad Sci USA 1991, 88:7415�7419
EWINS DL, BARNETT PS, RATANACHAIYAVONG S, SHARROCK C, LANCHBURY J, McGREGOR AM ET AL. Antigen-specific T cell recognition of affinity-purified and recombinant thyroid peroxidase in autoimmune thyroid disease. Clin Exp Immunol 1992, 90:93� 98
KAWAKAMI Y, FISFALEN ME, DEGROOT LJ. Proliferative responses of peripheral blood mononuclear cells from patients with autoimmune thyroid diseases to synthetic peptide epitopes of human thyroid peroxidase. Autoimmunity 1992, 13:17� 26
FISFALEN ME, PALMER EM, VAN SEVENTER GA, SOLTANI K, SAWAI Y, KAPLAN E ET AL. Thyrotropin receptor and thyroid peroxidase-specific T cell clones and their cytokine profile in autoimmune thyroid disease. J Clin Endocrinol Metab 1997, 82:3655�3663
NAGAYAMA Y, KAUFMAN KD, SETO P, RAPOPORT B. Molecular clo ning, sequence and functional expression of the cDNA for the human thyrotropin receptor. Biochem Biophys Res Commun 1989, 165:1184�1190
LIBERT F, LEFORT A, GERARD C, PARMENTIER M, PERRET J, LUDGATE M ET AL. Cloning, sequencing and expression of the human thyrotropin (TSH) receptor: evidence for binding of autoantibodies. Biochem Biophys Res Commun 1989, 165:1250� 1255
FRAZIER AL, ROBBINS LS, STORK PJ, SPRENGEL R, SEGALOFF DL, CONE RD. Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing. Mol Endocrinol 1990, 4:1264�1276
NAGAYAMA Y, RAPOPORT B. The thyrotropin receptor 25 years after its discovery: new insight after its molecular cloning. Mol Endocrinol 1992, 6:145�156
PRABHAKAR BS, FAN J-L, SEETHARAMAIAH GS. Thyrotropin-receptor-mediated diseases: a paradigm for receptor autoimmunity. Immunol Today 1997, 18:437�442
McFERLAND KC, SPRENGEL R, PHILLIPS HS, KOHLER M, ROSEMBLIT N, NIKOLICS K ET AL. Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 1989, 245:494�499
ADAMS DD, PURVES HD. Abnormal responses in the assays of thyrotrophin. Proc Univ Otago Med Sch 1956, 34:11�15
KRISS JP, PLESHAKOV V, CHIEN JR. Isolation and identification of the long-acting thyroid stimulation and its relation to hyperthy roidism and circumscribed pretibial myxedema. J Clin Endocri nol Metab 1964, 24:1005�1028
McKENZIE JM. Humoral factors in the pathogenesis of Graves' disease. Physiol Rev 1968, 43:252�310
SMITH BR, HALL R. Thyroid-stimulating immunoglobulins in Gra ves' disease. Lancet 1974, ii:427�431
DORRINGTON KJ, MUNRO DS. The long acting thyroid stimulator. Clin Pharmacol Ther 1966, 7:788�806
VITTI P, VALENTE WA, AMBESI-IMPIOMBATO FS, FENZI G, PINCHERA A, KOHN LD. Graves' IgG stimulation of continuously cultured rat thyroid cells: a sensitive and potentially useful clinical assay. J Endocrinol Invest 1982, 5:179�182
SOUTHGATE K, CREAGH FM, TEECE M, KINGSWOOD C, REES SMITH B. A receptor assay for the measurement of TSH receptor antibodies in unextracted serum. Clin Endocrinol (Oxf) 1984, 20:539�543
CREAGH F, TEECE M, WILLIAMS S, DIDCOTE S, PERKINS W, HASHIM F ET AL. An analysis of thyrotropin receptor binding and thyroid stimulating activities in a series of Graves' sera. Clin Endocrinol (Oxf) 1985, 23:395�404
FOLEY TP, WHITE C, NEW BA. Juvenile Graves' disease: usefulness and limitations of thyrotropin receptor antibody determinations. J Pediatr 1987, 110:378�389
HASHIM FA, CREAGH FM, EI HAWRANI A, PARKES AB, BUCKLAND PR, REES SMITH B. Characterization of TSH antagonist activity in the serum of patients with thyroid disease. Clin Endocrinol (Oxf) 1986, 25:275�281
KONISHI J, IIDA Y, ENDO K, MISAKI T, NOHARA Y, MATSUURA N ET AL. Inhibition of thyrotropin-induced adenosine 3.5-monophosphate increase by immunoglobulins from patients with primary myxedema. J Clin Endocrinol Metab 1983, 57:544�549
ENDO K, KASAGI K, KONISHI J, IKEKUBO K, OKUNO T, TAKEDA Y ET AL. Detection and properties of TSH-binding inhibitor immu noglobulins in patients with Graves' disease and Hashi moto's thyroiditis. J Clin Endocrinol Metab 1978, 46:770�777
WEETMAN AP, YATEMAN ME, EALEY PA, BLACK CM, REIMER LM, WILLIAMS RC ET AL. An investigation of thyroid stimulating activity between different IgG subclasses. J Clin Invest 1990, 86:723� 727
KRAIEM Z, CHO BY, SADEH O, SHONG MH, PICKERILL P, WEETMAN A. The IgG subclass distribution of TSH receptor blocking antibodies in primary hypothyroidism. Clin Endocrinol 1992, 37:135�140
KOSUGI S, BAN T, AKAMIZU T, KOHN LD. Identification of separate determinants on the thyrotropin receptor reactive with Graves' thyroid-stimulating antibodies and with thyroid-stimulating blocking antibodies in idiopathic myxedema: these determinants have no homologous sequence on gonadotropin receptors. Mol Endocrinol 1992, 6:168�180
TAHARA K, BAN T, MINEGISHI T, KOHN LD. Immunoglobulins from Graves' disease patients interact with different sites on TSH receptor/LH-CG receptor chimeras than either TSH or immu noglobulins form idiopathic myxedema patients. Biochem Biophys Res Commun 1991, 179:70�77
MORI T, SUGAWA H, PIRAPHATDIST T, INOUE D, ENOMOTO T, IMURA H. A synthetic oligopeptide derived from human thyrotropin receptor binds to Graves' immunoglobulin and inhibits thyroid stimulating antibody activity but lacks interactions with TSH. Biochem Biophys Res Commun 1991, 178:165�172
TAKAI O, DESAI RK, SEETHARAMAIAH GS, JONES CA, ALLAWAY GP, AKAMIZU T ET AL. Procaryotic expression of the thyrotropin receptor and identification of an immunogenic region of the protein using synthetic peptides. Biochem Biophys Res Commun 1991, 179:319�326
NAGAYAMA Y, WADSWORTH HL, RUSSO D, CHAZENALK GD, RAPOPORT B. Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors. J Clin Invest 1991, 88:336�340
COLLISON KS, BANGA JP, BARNETT PS, HUANG GC, McGREGOR AM. Autoantibody stimulation of the human thyrotropin receptor: regulation of adenylate cyclase activity, thyroglobulin and thyroid peroxidase mRNA levels in primary cultures of Graves' thyroid tissue. Clin Exp Immunol 1991, 86:61�65
HATABU H, KASAGI K, LIDA Y, NOSAKA T, MISAKI T, HIDAKA A ET AL. Induction of c-fos and c-myc mRNA expression by immu noglobulin G from patients with Graves' disease in thyrotropin-dependent rat thyroid cell line (FRTL5). Clin Endocrinol 1991, 34:349�356
HUBER GK, SAFIRSTEIN R, NEUFELT D, DAVIES TF. Thyrotropin receptor autoantibodies induce human thyroid cell growth and c-fos activation. J Clin Endocrinol Metab 1991, 72:1142�1147
DI CERBO A, DI GIROLAMO M, GUARDABASSO V, DE FILIPPIS V, CORDA D. Immunoglobulins from Graves' patients stimulate phospholipase-A₂ in FRTL5 thyroid cells. J Clin Endocrinol Metab 1992, 74:585�592
LAURENT E, VAN SANDE J, LUDGATE M, CORVILAIN B, ROCMANS P, DUMONT JE ET AL. Unlike thyrotropin, thyroid-stimulating antibodies do not activate phospholipase C in human thyroid slices. J Clin Invest 1991, 87:1634�1642
BURCH HB, NAGY EV, LUKES YG, CAI WY, WARTOFSKY L, BURMAN KD. Nucleotide and amino acid homology between the human thyrotropin receptor and the HIV-1 nef protein: identification and functional analysis. Biochem Biophys Res Commun 1991, 181:498�505
BENKER P, KOTULLA P, KENDALL-TAYLOR P, EMRICH D, REINWEIN D. TSH binding-inhibiting antibodies in hyperthyroidism: relationship to clinical signs and hormone levels. Clin Endocrinol 1989, 30:19�28
McKENZIE J, ZAKARIJA M. The clinical use of thyrotropin receptor antibody measurements. J Clin Endocrinol Metab 1989, 69: 1093�1096
REINWEIN D, BENKER G, LAZARUS JH, ALEXANDER D. A prospective randomized trial of antithyroid drug dose in Graves' disease therapy. European Multicenter Study Group on Antithyroid Drug Treatment. J Clin Endocrinol Metab 1993, 76:1516� 1521
FELDT-RASMUSSEN U, SCHLEUSENER H, CARAYON P. Meta-analysis evaluation of the impact of thyrotropin receptor antibodies on long-term remission after medical therapy of Graves' disease. J Clin Endocrinol Metab 1994, 78:98�102
BENKER G, VITTI P, KAHALY G, RAUE F, TEGLER L, HIRCHE H ET AL. Response to methimazole in Graves' disease. The European Multicenter Group. Clin Endocrinol 1995, 43:257�263
TORRING O, TALLSTEDT L, WALLIN G, LUNDELL G, LJURGGREN J, TAUBE A. Graves' hyperthyroidism: Treatment with antithyroid drugs, surgery, or radioiodine�a prospective, randomized study. J Clin Endocrinol Metab 1996, 81:2986�2993
WEETMAN A, FREEMAN M, MORGAN B. Thyroid follicular cell function after non-lethal complement membrane attack. Clin Exp Immunol 1990, 82:69�74
WEETMAN A. The immunomodulatory effect of antithyroid drugs. Thyroid 1994, 4:145�146
HASHIZUME K, ICHIKAWA K, SAKURAI A. Administration of thyroxine in treated Graves' disease: effects on the levels of antibodies to thyroid-stimulating hormone receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med 1991, 324: 947�953
HASHIZUME K, ICHIKAWA K, NISKI Y, KOBYASHI M, SAKURAI A, MIYA MOTO T ET AL. Effect of administration of thyroxine on the risk of post-partum recurrence of hyperthyroid Graves' disease. J Clin Endocrinol Metab 1992, 75:6�10
McLEVER B, RAE P, BECKETT G, WILKINSON E, GOLD A, TOFT A. Lack of effect of thyroxine in patients with Graves' hyperthyroi dism who are treated with an antithyroid drug. N Engl J Med 1996, 334: 220�224
MORGENTHALER NG, KIM MR, TREMBLE J, HUANG GC, RICHTER W, GUPTA M ET AL. Human immunoglobulin G autoantibodies to the thyrotropin receptor from Epstein-Barr virus transformed B lymphocytes: characterization by immunoprecipitation with recombinant antigen and biological activity. J Clin Endocrinol Metab 1996, 81:3155�3161
MARTIN A, NAKASHIMA M, ZHOU A, ARONSON D, WERNER AJ, DAVIES TF. Detection of major T cell epitopes on human thyroid stimulating hormone receptor by overriding immune heterogeneity in patients with Graves' disease. J Clin Endoc rinol Metab 1997, 82:3361�3366
SOLIMAN M, KAPLAN E, YANAGAWA T, HIDAKA Y, FISFALEN M, DEGROOT L. T-cells recognize multiple epitopes in the human thyro tropin receptor extracellular domain. J Clin Endocrinol Metab 1995, 80:905�914
SOLIMAN M, KAPLAN E, GUIMARAES V, YANAGAWA T, DEGROOT LJ. T-cell recognition of residue 158�176 in thyrotropin receptor confers risk for development of thyroid autoimmunity in siblings in a family with Graves' disease. Thyroid 1996, 6:545� 551
SOLIMAN M, KAPLAN E, ABDE-LATIF A, SCHERBERG N, DEGROOT L. Does thyroidectomy, radioactive iodide therapy, or antithyroid drug treatment alter reactivity of patients' T cells to epitopes of thyrotropin receptor in autoimmune thyroid diseases? J Clin Endocrinol Metab 1995, 80:2312� 2321
HIDAKA Y, GUIMARAES V, SOLIMAN M, YANAGAWA T, OKAMOTO Y, QUINTANS J ET AL. Production of thyroid-stimulating antibodies in mice by immunization with T-cell epitopes of human thyrotropin receptor. J Endocrinol 1995, 136:1642�1647
SOLIMAN M, KAPLAN E, STRAUS F, FISFALEN M, HIDAKA Y, GUIMARAES V ET AL. Graves� disease in severe combined immunodeficient mice. J Clin Endocrinol Metab 1995, 80:2848�2855

� 2000, ��