Download PDF
Horm Metab Res 2009; 41(6): 456-464
DOI: 10.1055/s-0029-1220935
Review

© Georg Thieme Verlag KG Stuttgart · New York

Current Insights into the Pathogenesis of Graves’ Orbitopathy

A. K. Eckstein 1 , K. T. M. Johnson 1 , M. Thanos 1 , J. Esser 1 , M. Ludgate 2
  • 1Endocrine Orbitopathy Research and Therapy in Essen (EORT E), Centre for Ophthalmology, University Hospital Essen, Essen, Germany
  • 2Centre for Endocrine and Diabetes Science, School of Medicine, Cardiff University, Cardiff, UK
Further Information

Publication History

received 06.02.2009

accepted 29.04.2009

Publication Date:
20 May 2009 (online)

Also available at
    Permissions and Reprints

Abstract

Graves’ orbitopathy (GO) is part of an autoimmune disease constellation comprising hyperthyroidism, orbitopathy, pretibial myxedema, and acropachy. Signs and symptoms of GO occur due to inflammation of the orbital connective tissue, inflammation and fibrosis of the extraocular muscles, and adipogenesis. Stimulatory TSH receptor (TSHR) antibodies (TRAb) cause hyperthyroidism, but pathogenetic mechanisms in the orbit are less clear. The TSHR is one of the favoured candidate antigens; others such as the IGF1R might also play a role. Compared with other anatomical locations, orbital fibroblasts are extremely reactive to inflammatory stimuli, especially via CD40 activation. Orbital fibroblasts also differentiate into adipocytes, in response to the prevailing inflammatory cytokine milieu. Consequently TSHR gene expression increases together with expression of adipogenesis related genes. The same genes that confer susceptibility to Graves’ disease (GD), both thyroid specific and immunoregulatory, also influence GO, although an increasing number of candidate genes with higher impact on orbitopathy are being identified. Smoking is the only environmental factor known to increase the likelihood and severity of GO developing in GD patients. A robust animal model of GO would facilitate the evaluation of new treatments. To date most models have centered on provoking autoimmune responses to the TSHR, but other antigens, alone or in combination with this receptor, hopefully will succeed in inducing the full spectrum of GD.

Key words

Graves’ orbitopathy - environmental factors - genetic susceptibility - orbital autoantigens - orbital fibroblast - adipogenesis

References

  • 1 Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy.  Thyroid. 2002;  12 855-860
    Google Scholar
  • 2 Villadolid MC, Yokoyama N, Izumi M, Nishikawa T, Kimura H, Ashizawa K, Kiriyama T, Uetani M, Nagataki S. Untreated Graves’ disease patients without clinical ophthalmopathy demonstrate a high frequency of extraocular muscle (EOM) enlargement by magnetic resonance.  J Clin Endocrinol Metab. 1995;  80 2830-2833
    Google Scholar
  • 3 Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. Chronology of Graves’ ophthalmopathy in an incidence cohort.  Am J Ophthalmol. 1996;  121 426-434
    Google Scholar
  • 4 Eckstein AK, Loesch C, Okundia H, Mann K, Esser J, Morgenthaler NG. Patients with euthyroid and primarily hypothyroid status have low TRAb levels and develop a tendentious milder and significantly more asymmetric Graves’ Ophthalmopathy.  Br J Ophthalmol. 2009;  , (in press)
    Google Scholar
  • 5 Khoo DH, Eng PH, Ho SC, Tai ES, Morgenthaler NG, Seah LL, Fong KS, Chee SP, Choo CT, Aw SE. Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels.  Thyroid. 2000;  10 1093-1100
    Google Scholar
  • 6 Bartley GB, Fatourechi V, Kadrmas EF, Jacobsen SJ, Ilstrup DM, Garrity JA, Gorman CA. Clinical features of Graves’ ophthalmopathy in an incidence cohort.  Am J Ophthalmol. 1996;  121 284-290
    Google Scholar
  • 7 Wiersinga W, Kahaly G. Graves's ophthalmopathy. A multidisciplinary approach. Basel: Karger 2007
  • 8 Brix TH, Kyvik KO, Christensen K, Hegedus L. Evidence for a major role of heredity in Graves’ disease: a population-based study of two Danish twin cohorts.  J Clin Endocrinol Metab. 2001;  86 930-934
    Google Scholar
  • 9 Manji N, Carr-Smith JD, Boelaert K, Allahabadia A, Armitage M, Chatterjee VK, Lazarus JH, Pearce SH, Vaidya B, Gough SC, Franklyn JA. Influences of age, gender, smoking, and family history on autoimmune thyroid disease phenotype.  J Clin Endocrinol Metab. 2006;  91 4873-4880
    Google Scholar
  • 10 Ban Y, Tomer Y. Genetic susceptibility in thyroid autoimmunity.  Pediatr Endocrinol Rev. 2005;  3 20-32
    Google Scholar
  • 11 Jacobson EM, Tomer Y. The genetic basis of thyroid autoimmunity.  Thyroid. 2007;  17 949-961
    Google Scholar
  • 12 Tomer Y, Huber A. The etiology of autoimmune thyroid disease: A story of genes and environment.  J Autoimmun. 2009;  32 ((3-4)) 231-219
    Google Scholar
  • 13 Aust G, Krohn K, Morgenthaler NG, Schroder S, Schutz A, Edelmann J, Brylla E. Graves’ disease and Hashimoto's thyroiditis in monozygotic twins: case study as well as transcriptomic and immunohistological analysis of thyroid tissues.  Eur J Endocrinol. 2006;  154 13-20
    Google Scholar
  • 14 Yin X, Latif R, Bahn R, Tomer Y, Davies TF. Influence of the TSH receptor gene on susceptibility to Graves’ disease and Graves’ ophthalmopathy.  Thyroid. 2008;  18 1201-1206
    Google Scholar
  • 15 Huber AK, Jacobson EM, Jazdzewski K, Concepcion ES, Tomer Y. Interleukin (IL)-23 receptor is a major susceptibility gene for Graves’ ophthalmopathy: the IL-23/T-helper 17 axis extends to thyroid autoimmunity.  J Clin Endocrinol Metab. 2008;  93 1077-1081
    Google Scholar
  • 16 Afzali B, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease.  Clin Exp Immunol. 2007;  148 32-46
    Google Scholar
  • 17 Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.  Nat Med. 2002;  8 500-508
    Google Scholar
  • 18 Ludgate M, Baker G. Inducing Graves’ ophthalmopathy.  J Endocrinol Invest. 2004;  27 211-215
    Google Scholar
  • 19 Konishi J, Herman MM, Kriss JP. Binding of thyroglobulin and thyroglobulin-antithyroglobulin immune complex to extraocular muscle membrane.  Endocrinology. 1974;  95 434-446
    Google Scholar
  • 20 Marino M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A. Role of thyroglobulin in the pathogenesis of Graves’ ophthalmopathy: the hypothesis of Kriss revisited.  J Endocrinol Invest. 2004;  27 230-206
    Google Scholar
  • 21 Kodama K, Sikorska H, Bandy-Dafoe P, Bayly R, Wall JR. Demonstration of a circulating autoantibody against a soluble eye-muscle antigen in Graves’ ophthalmopathy.  Lancet. 1982;  2 ((8312)) 1353-1356
    Google Scholar
  • 22 Dong Q, Ludgate M, Vassart G. Cloning and sequencing of a novel 64-kDa autoantigen recognized by patients with autoimmune thyroid disease.  J Clin Endocrinol Metab. 1991;  72 1375-1381
    Google Scholar
  • 23 Mizokami T, Salvi M, Wall JR. Eye muscle antibodies in Graves’ ophthalmopathy: pathogenic or secondary epiphenomenon?.  J Endocrinol Invest. 2004;  27 221-229
    Google Scholar
  • 24 Gerding MN, van der Meer JW, Broenink M, Bakker O, Wiersinga WM, Prummel MF. Association of thyrotrophin receptor antibodies with the clinical features of Graves’ ophthalmopathy.  Clin Endocrinol (Oxf). 2000;  52 267-271
    Google Scholar
  • 25 Khoo DH, Ho SC, Seah LL, Fong KS, Tai ES, Chee SP, Eng PH, Aw SE, Fok AC. The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves’ disease identifies a group at markedly increased risk of ophthalmopathy.  Thyroid. 1999;  9 1175-1180
    Google Scholar
  • 26 Eckstein AK, Plicht M, Lax H, Neuhauser M, Mann K, Lederbogen S, Heckmann C, Esser J, Morgenthaler NG. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease.  J Clin Endocrinol Metab. 2006;  91 3464-3670
    Google Scholar
  • 27 Schott M, Morgenthaler NG, Fritzen R, Feldkamp J, Willenberg HS, Scherbaum WA, Seissler J. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease.  Horm Metab Res. 2004;  36 92-96
    Google Scholar
  • 28 Quadbeck B, Hoermann R, Hahn S, Roggenbuck U, Mann K, Janssen OE. Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor as predictors of relapse of Graves’ disease after withdrawal of antithyroid treatment.  Horm Metab Res. 2005;  37 745-750
    Google Scholar
  • 29 Carella C, Mazziotti G, Sorvillo F, Piscopo M, Cioffi M, Pilla P, Nersita R, Iorio S, Amato G, Braverman LE, Roti E. Serum thyrotropin receptor antibodies concentrations in patients with Graves’ disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.  Thyroid. 2006;  16 295-302
    Google Scholar
  • 30 Eckstein AK, Lax H, Losch C, Glowacka D, Plicht M, Mann K, Esser J, Morgenthaler NG. Patients with severe Graves’ ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.  Clin Endocrinol (Oxf). 2007;  67 607-612
    Google Scholar
  • 31 Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 1998;  83 998-1002
    Google Scholar
  • 32 Bell A, Gagnon A, Grunder L, Parikh SJ, Smith TJ, Sorisky A. Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts.  Am J Physiol Cell Physiol. 2000;  279 C335-C340
    Google Scholar
  • 33 Crisp M, Starkey KJ, Lane C, Ham J, Ludgate M. Adipogenesis in thyroid eye disease.  Invest Ophthalmol Vis Sci. 2000;  41 3249-3255
    Google Scholar
  • 34 Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients.  Clin Endocrinol (Oxf). 2003;  58 280-287
    Google Scholar
  • 35 Crisp MS, Lane C, Halliwell M, Wynford-Thomas D, Ludgate M. Thyrotropin receptor transcripts in human adipose tissue.  J Clin Endocrinol Metab. 1997;  82 2003-2005
    Google Scholar
  • 36 Polak M. Hyperthyroidism in early infancy: pathogenesis, clinical features and diagnosis with a focus on neonatal hyperthyroidism.  Thyroid. 1998;  8 1171-1177
    Google Scholar
  • 37 Gruters A. Ocular manifestations in children and adolescents with thyrotoxicosis.  Exp Clin Endocrinol Diabetes. 1999;  107 ((Suppl 5)) S172-S174
    Google Scholar
  • 38 Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy.  Autoimmunity. 1993;  16 251-257
    Google Scholar
  • 39 Kohn LD, Alvarez F, Marcocci C, Kohn AD, Corda D, Hoffman WE, Tombaccini D, Valente WA, de Luca M, Santisteban P, Grollmann EF. Monoclonal antibody studies defining the origin and properties of autoantibodies in Graves’ disease.  Ann N Y Acad Sci. 1986;  475 157-173
    Google Scholar
  • 40 Gianoukakis AG, Douglas RS, King CS, Cruikshank WW, Smith TJ. Immunoglobulin G from patients with Graves’ disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmune disease.  Endocrinology. 2006;  147 1941-1949
    Google Scholar
  • 41 Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease.  J Immunol. 2008;  181 4397-4405
    Google Scholar
  • 42 Smith TJ, Tsai CC, Shih MJ, Tsui S, Chen B, Han R, Naik V, King CS, Press C, Kamat S, Goldberg RA, Phipps RP, Douglas RS, Gianoukakis AG. Unique attributes of orbital fibroblasts and global alterations in IGF-1 receptor signaling could explain thyroid-associated ophthalmopathy.  Thyroid. 2008;  18 983-988
    Google Scholar
  • 43 Weetman AP, Cohen S, Gatter KC, Fells P, Shine B. Immunohistochemical analysis of the retrobulbar tissues in Graves’ ophthalmopathy.  Clin Exp Immunol. 1989;  75 222-227
    Google Scholar
  • 44 Pappa A, Lawson JM, Calder V, Fells P, Lightman S. T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy.  Br J Ophthalmol. 2000;  84 517-522
    Google Scholar
  • 45 Pappa A, Calder V, Ajjan R, Fells P, Ludgate M, Weetman AP, Lightman S. Analysis of extraocular muscle-infiltrating T cells in thyroid-associated ophthalmopathy (TAO).  Clin Exp Immunol. 1997;  109 362-369
    Google Scholar
  • 46 Heufelder AE, Herterich S, Ernst G, Bahn RS, Scriba PC. Analysis of retroorbital T cell antigen receptor variable region gene usage in patients with Graves’ ophthalmopathy.  Eur J Endocrinol. 1995;  132 266-277
    Google Scholar
  • 47 Aniszewski JP, Valyasevi RW, Bahn RS. Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 2000;  85 776-780
    Google Scholar
  • 48 Eckstein AK, Quadbeck B, Tews S, Mann K, Kruger C, Mohr CH, Steuhl KP, Esser J, Gieseler RK. Thyroid associated ophthalmopathy: evidence for CD4(+) gammadelta T cells; de novo differentiation of RFD7(+) macrophages, but not of RFD1(+) dendritic cells; and loss of gammadelta and alphabeta T cell receptor expression.  Br J Ophthalmol. 2004;  88 803-808
    Google Scholar
  • 49 Smith RS, Smith TJ, Blieden TM, Phipps RP. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation.  Am J Pathol. 1997;  151 317-322
    Google Scholar
  • 50 Sempowski GD, Rozenblit J, Smith TJ, Phipps RP. Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production.  Am J Physiol. 1998;  274 ((3 Pt 1)) C707-C714
    Google Scholar
  • 51 Heufelder AE, Smith TJ, Gorman CA, Bahn RS. Increased induction of HLA-DR by interferon-gamma in cultured fibroblasts derived from patients with Graves’ ophthalmopathy and pretibial dermopathy.  J Clin Endocrinol Metab. 1991;  73 307-313
    Google Scholar
  • 52 Feldon SE, Park DJ, O’Loughlin CW, Nguyen VT, Landskroner-Eiger S, Chang D, Thatcher TH, Phipps RP. Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves’ ophthalmopathy.  Invest Ophthalmol Vis Sci. 2005;  46 3913-3921
    Google Scholar
  • 53 Smith TJ. Insights into the role of fibroblasts in human autoimmune diseases.  Clin Exp Immunol. 2005;  141 388-397
    Google Scholar
  • 54 Koumas L, Smith TJ, Phipps RP. Fibroblast subsets in the human orbit: Thy-1+ and Thy-1− subpopulations exhibit distinct phenotypes.  Eur J Immunol. 2002;  32 477-485
    Google Scholar
  • 55 Khoo TK, Coenen MJ, Schiefer AR, Kumar S, Bahn RS. Evidence for enhanced Thy-1 (CD90) expression in orbital fibroblasts of patients with Graves’ ophthalmopathy.  Thyroid. 2008;  18 1291-1296
    Google Scholar
  • 56 Gianoukakis AG, Khadavi N, Smith TJ. Cytokines, Graves’ disease, and thyroid-associated ophthalmopathy.  Thyroid. 2008;  18 953-958
    Google Scholar
  • 57 Kumar S, Bahn RS. Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 2003;  88 4246-4250
    Google Scholar
  • 58 Han R, Smith TJ. T helper type 1 and type 2 cytokines exert divergent influence on the induction of prostaglandin E2 and hyaluronan synthesis by interleukin-1beta in orbital fibroblasts: implications for the pathogenesis of thyroid-associated ophthalmopathy.  Endocrinology. 2006;  147 13-19
    Google Scholar
  • 59 Cawood TJ, Moriarty P, O’Farrelly C, O’Shea D. The effects of tumour necrosis factor-alpha and interleukin1 on an in vitro model of thyroid-associated ophthalmopathy; contrasting effects on adipogenesis.  Eur J Endocrinol. 2006;  155 395-403
    Google Scholar
  • 60 Smith TJ, Hoa N. Immunoglobulins from patients with Graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor.  J Clin Endocrinol Metab. 2004;  89 5076-5080
    Google Scholar
  • 61 Pritchard J, Horst N, Cruikshank W, Smith TJ. Igs from patients with Graves’ disease induce the expression of T cell chemoattractants in their fibroblasts.  J Immunol. 2002;  168 942-950
    Google Scholar
  • 62 Vaidya B, Shenton BK, Stamp S, Miller M, Baister E, Andrews CD, Dickinson AJ, Perros P, Kendall-Taylor P. Analysis of peripheral blood T-cell subsets in active thyroid-associated ophthalmopathy: absence of effect of octreotide-LAR on T-cell subsets in patients with thyroid-associated ophthalmopathy.  Thyroid. 2005;  15 1073-1078
    Google Scholar
  • 63 Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Serio M, Miccoli P. Serum levels of the interferon-gamma-inducible alpha chemokine CXCL10 in patients with active Graves’ disease, and modulation by methimazole therapy and thyroidectomy.  Br J Surg. 2006;  93 1226-1231
    Google Scholar
  • 64 Liu C, Papewalis C, Domberg J, Scherbaum WA, Schott M. Chemo-kines and autoimmune thyroid diseases.  Horm Metab Res. 2008;  40 361-368
    Google Scholar
  • 65 Romagnani P, Rotondi M, Lazzeri E, Lasagni L, Francalanci M, Buonamano A, Milani S, Vitti P, Chiovato L, Tonacchera M, Bellastella A, Serio M. Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves’ disease.  Am J Pathol. 2002;  161 195-206
    Google Scholar
  • 66 Garcia-Lopez MA, Sancho D, Sanchez-Madrid F, Marazuela M. Thyrocytes from autoimmune thyroid disorders produce the chemokines IP-10 and Mig and attract CXCR3+ lymphocytes.  J Clin Endocrinol Metab. 2001;  86 5008-5016
    Google Scholar
  • 67 Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy.  Endocr Rev. 2003;  24 802-835
    Google Scholar
  • 68 Toussirot E, Wendling D. The use of TNF-alpha blocking agents in rheumatoid arthritis: an update.  Expert Opin Pharmacother. 2007;  8 2089-2107
    Google Scholar
  • 69 Nishida Y, Tian S, Isberg B, Hayashi O, Tallstedt L, Lennerstrand G. Significance of orbital fatty tissue for exophthalmos in thyroid-associated ophthalmopathy.  Graefes Arch Clin Exp Ophthalmol. 2002;  240 515-520
    Google Scholar
  • 70 Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM, Heufelder AE, Jyonouchi SC, Bahn RS. Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor.  J Clin Endocrinol Metab. 1999;  84 2557-2562
    Google Scholar
  • 71 Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Stimulation of adipogenesis, peroxisome proliferator-activated receptor-gamma (PPARgamma), and thyrotropin receptor by PPARgamma agonist in human orbital preadipocyte fibroblasts.  J Clin Endocrinol Metab. 2002;  87 2352-2358
    Google Scholar
  • 72 Starkey KJ, Janezic A, Jones G, Jordan N, Baker G, Ludgate M. Adipose thyrotrophin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo.  J Mol Endocrinol. 2003;  30 ((3)) 369-380
    Google Scholar
  • 73 Kumar S, Coenen MJ, Scherer PE, Bahn RS. Evidence for enhanced adipogenesis in the orbits of patients with Graves’ ophthalmopathy.  J Clin Endocrinol Metab. 2004;  89 930-935
    Google Scholar
  • 74 Zhang L, Baker G, Janus D, Paddon CA, Fuhrer D, Ludgate M. Biological effects of thyrotropin receptor activation on human orbital preadipocytes.  Invest Ophthalmol Vis Sci. 2006;  47 ((12)) 5197-5203
    Google Scholar
  • 75 Feldon SE, WO’Loughlin C, Ray DM, Landskroner-Eiger S, Sewerynaik KE, Phipps RP. Activated human T lymphocytes express cyclooxygenase-2 and produce proadipogenic prostaglandins that drive human orbital fibroblast differentiation to adipocytes.  Am J Pathol. 2006;  169 ((4)) 1183-1193
    Google Scholar
  • 76 Starkey K, Heufelder A, Baker G, Joba W, Evans M, Davies S, Ludgate M. Peroxisome proliferator-activated receptor-gamma in thyroid eye disease: contraindication for thiazolidinedione use?.  J Clin Endocrinol Metab. 2003;  88 55-59
    Google Scholar
  • 77 Levin F, Kazim M, Smith TJ, Marcovici E. Rosiglitazone-induced proptosis.  Arch Ophthalmol. 2005;  123 119-121
    Google Scholar
  • 78 Dorkhan M, Lantz M, Frid A, Groop L, Hallengren B. Treatment with a thiazolidinedione increases eye protrusion in a subgroup of patients with type 2 diabetes.  Clin Endocrinol (Oxf). 2006;  65 35-39
    Google Scholar
  • 79 Costagliola S, Rodien P, Many MC, Ludgate M, Vassart G. Genetic immunization against the human thyrotropin receptor causes thyroiditis and allows production of monoclonal antibodies recognizing the native receptor.  J Immunol. 1998;  160 1458-1465
    Google Scholar
  • 80 Many MC, Costagliola S, Detrait M, Denef F, Vassart G, Ludgate MC. Development of an animal model of autoimmune thyroid eye disease.  J Immunol. 1999;  162 4966-4974
    Google Scholar
  • 81 Ludgate M, Baker G. Inducing Graves’ ophthalmopathy.  J Endocrinol Invest. 2004;  27 ((3)) 211-215
    Google Scholar
  • 82 Hurst J, von Landenberg P. Toll-like receptors and autoimmunity.  Autoimmun Rev. 2008;  7 204-208
    Google Scholar
  • 83 Pfeilschifter J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs. lifetime cigarette consumption.  Clin Endocrinol (Oxf). 1996;  45 477-481
    Google Scholar
  • 84 Bartalena L, Marcocci C, Tanda ML, Manetti L, Dell’Unto E, Bartolomei MP, Nardi M, Martino E, Pinchera A. Cigarette smoking and treatment outcomes in Graves ophthalmopathy.  Ann Intern Med. 1998;  129 632-635
    Google Scholar
  • 85 Eckstein A, Quadbeck B, Mueller G, Rettenmeier AW, Hoermann R, Mann K, Steuhl P, Esser J. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy.  Br J Ophthalmol. 2003;  87 773-776
    Google Scholar
  • 86 Glinoer D, de Nayer P, Bex M. Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves’ hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study.  Eur J Endocrinol. 2001;  144 475-483
    Google Scholar
  • 87 Quadbeck B, Roggenbuck U, Janssen OE, Hahn S, Mann K, Hoermann R. for the Basedow Study Group . Impact of smoking on the course of Graves’ disease after withdrawal of antithyroid drugs.  Exp Clin Endocrinol Diabetes. 2006;  114 406-411
    Google Scholar
  • 88 Hegedius L, Brix TH, Vestergaard P. Relationship between cigarette smoking and Graves’ ophthalmopathy.  J Endocrinol Invest. 2004;  27 265-271
    Google Scholar
  • 89 Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice.  Nat Med. 2005;  11 491-498
    Google Scholar
  • 90 Giordano RJ, Lahdenranta J, Zhen L, Chukwueke U, Petrache I, Langley RR, Fidler IJ, Pasqualini R, Tuder RM, Arap W. Targeted induction of lung endothelial cell apoptosis causes emphysema-like changes in the mouse.  J Biol Chem. 2008;  283 29447-29460
    Google Scholar
  • 91 Baker GR, Morton M, Rajapaska RS, Bullock M, Gullu S, Mazzi B, Ludgate M. Altered tear composition in smokers and patients with graves ophthalmopathy.  Arch Ophthalmol. 2006;  124 1451-1456
    Google Scholar
  • 92 Cawood TJ, Moriarty P, O’Farrelly C, O’Shea D. Smoking and thyroid-associated ophthalmopathy: A novel explanation of the biological link.  J Clin Endocrinol Metab. 2007;  92 59-64
    Google Scholar
  • 93 Kuriyan AE, Phipps RP, O’Loughlin CW, Feldon SE. Improvement of thyroid eye disease following treatment with the cyclooxygenase-2 selective inhibitor celecoxib.  Thyroid. 2008;  18 911-914
    Google Scholar
  • 94 Bagriacik EU, Klein JR. The thyrotropin (thyroid-stimulating hormone) receptor is expressed on murine dendritic cells and on a subset of CD45RBhigh lymph node T cells: functional role for thyroid-stimulating hormone during immune activation.  J Immunol. 2000;  164 6158-6165
    Google Scholar
  • 95 Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves’ ophthalmopathy: a pilot study.  Eye. 2005;  19 1286-1289
    Google Scholar
  • 96 van Steensel L, Paridaens D, Schrijver B, Dingjan GM, van Daele PL, van Hagen PM, van den Bosch WA, Drexhage HA, Hooijkaas H, Dik WA. Imatinib Mesylate and Amn107 Are Potential Drugs for Graves Ophthalmopathy by Inhibition of Pdgf-Signaling in Orbital Fibroblasts.  Invest Ophthalmol Vis Sci. 2009;  Feb 21 , [Epub ahead of print]
    Google Scholar
  • 97 El Fassi D, Banga JP, Gilbert JA, Padoa C, Hegedus L, Nielsen CH. Treatment of Graves’ disease with rituximab specifically reduces the production of thyroid stimulating autoantibodies.  Clin Immunol. 2009;  130 252-258
    Google Scholar
  • 98 Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study.  Eur J Endocrinol. 2007;  156 33-40
    Google Scholar
  • 99 Shimojo N, Kohno Y, Yamaguchi K, Kikuoka S, Hoshioka A, Niimi H, Hirai A, Tamura Y, Saito Y, Kohn LD, Tahara K. 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. 1996;  93 11074-11079
    Google Scholar
  • 100 Kaithamana S, Fan J, Osuga Y, Liang SG, Prabhakar BS. Induction of experimental autoimmune Graves’ disease in BALB/c mice.  J Immunol. 1999;  163 5157-5164
    Google Scholar
  • 101 Kita-Furuyama M, Nagayama Y, Pichurin P, McLachlan SM, Rapoport B, Eguchi K. Dendritic cells infected with adenovirus expressing the thyrotrophin receptor induce Graves’ hyperthyroidism in BALB/c mice.  Clin Exp Immunol. 2003;  131 234-240
    Google Scholar
  • 102 Costagliola S, Many MC, Denef JF, Pohlenz J, Refetoff S, Vassart G. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves’ disease.  J Clin Invest. 2000;  105 803-811
    Google Scholar
  • 103 Nagayama Y, Kita-Furuyama M, Ando T, Nakao K, Mizuguchi H, Hayakawa T, Eguchi K, Niwa M. A novel murine model of Graves’ hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor.  J Immunol. 2002;  168 2789-2794
    Google Scholar
  • 104 Ho SC, Goh SS, Kee IH, Chow PK, Yeo CP, Khoo DH. Effects of genetic immunization of Swiss outbred mice with human thyroid stimulating hormone receptor cDNA plasmids harboring gain-of-function mutations.  J Mol Endocrinol. 2007;  38 277-288
    Google Scholar
  • 105 Saitoh O, Nagayama Y. Regulation of Graves’ hyperthyroidism with naturally occurring CD4+CD25+regulatory T cells in a mouse model.  Endocrinology. 2006;  147 2417-2422
    Google Scholar

Correspondence

A. K. EcksteinMD 

University Eye Hospital

Hufelandstr. 55

45122 Essen

Germany

Phone: +49/201/723 29 62

Fax: +49/201/723 56 41

Email: anja.eckstein@uk-essen.de

      >