Etiopathogenesis of Basedow's disease

Summary

Basedow's disease (BD) owes its name to the German physician Karl Adolph von Basedow, who described in 1840 the clinical picture of exophthalmic toxic goitre. More than one century after the seminal paper of Karl von Basedow, the ultimate cause of BD remains to be fully elucidated. In the last years, evidence was accumulated indicating that BD is a polygenic and multifactorial disease that develops as a result of a complex interplay between genetic susceptibility and environmental and endogenous factors, which leads to the loss of immune tolerance to thyroid antigens and in particular to the TSH receptor.

Our aim is to review the current knowledge on the pathogenesis of BD. To this purpose, we will firstly focus our attention on the role of genetic factors (the HLA complex, the genes encoding for thyroglobulin, the TSH receptor, CD40, CTLA-4 and PTPN22), and of environmental factors (iodine, infections, psychological stress, gender, smoking, thyroid damage, vitamin D, selenium, immune modulating agents) as possible causes of BD. Taking advantage of the experimental animal models of BD, we will then focus on the immunological mechanisms leading to the loss of tolerance in BD. The pathogenic role played by the chemokine system will be also reviewed.

Zusammenfassung

Morbus Basedow (MB) ist nach dem deutschen Arzt Karl Adolph von Basedow benannt, der 1840 das klinische Bild eines Exophthalmus mit toxischer Struma beschrieb. Über ein Jahrhundert nach dem bahnbrechenden Artikel von Karl von Basedow ist die Ursache des MB letztendlich nicht völlig geklärt. In den vergangenen Jahren haben sich Hinweise darauf ergeben, dass MB eine polygene, multifaktorielle Erkrankung ist, die als Folge eines komplexen Zusammenspiels zwischen genetisch bedingter Anfälligkeit sowie Umweltfaktoren und endogenen Faktoren entsteht, die zu einem Verlust der Immuntoleranz für Schilddrüsenantigene und insbesondere des TSH-Rezeptors führen.

Wir möchten hier den aktuellen Kenntnisstand zur Pathogenese des MB darlegen. Hierzu richten wir zunächst unser Augenmerk auf die Rolle der genetischen Faktoren (HLAKomplex, Gene, die Thyreoglobulin kodieren, TSH-Rezeptor, CD40, CTLA-4 und PTPN22) sowie die Umweltfaktoren (Iod, Infektionen, psychischer Stress, Geschlecht, Rauchen, Schilddrüsenschädigung, Vitamin D, Selen, Immunmodulatoren) als mögliche Ursachen des MB. Anhand von Tierversuchen zum MB werden wir dann vorrangig den Immun - mechanismus erläutern, der zum Toleranzverlust bei MB führt. Die pathogene Rolle des Chemokin-Systems wird ebenfalls dargestellt.

Keywords

Basedow - Graves - chemokines - thyroid - autoimmunity

Schlüsselwörter

Basedow - Graves - Chemokine - Schilddrüse - Autoimmunität

• References

• 1 Antonelli A, Fallahi P, Rotondi M. et al. Increase of interferon-gamma inducible alpha chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy and thyroidectomy. Br J Surg 2006; 93: 1226-1231.
• 2 Antonelli A, Rotondi M, Fallahi P. et al. Increase of interferon-gamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy. Clin Endocrinol (Oxf) 2006; 64: 189-195.
• 3 Armitage RJ, Macduff BM, Spriggs MK. et al. Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines. J Immunol 1993; 150: 3671-3680.
• 4 Ban Y, Davies TF, Greenberg DA. et al. Arginine at position 74 of the HLA-DRb1 chain is associated with Graves' disease. Genes Immun 2004; 5: 203-208.
• 5 Bartalena L, Fatourechi V. Extrathyroidal manifestations of Graves' disease: a 2014 update. J Endocrinol Invest 2014; 37: 691-700.
• 6 Bartalena L, Macchia PE, Marcocci C. et al. Effects of treatment modalities for Graves' hyperthyroidism on Graves' orbitopathy: a 2015 Italian Society of Endocrinology Consensus Statement. J Endocrinol Invest 2015; 38: 481-487.
• 7 Bernecker C, Halim F, Lenz L. et al. microRNA expressions in CD4+ and CD8+ T-cell subsets in autoimmune thyroid diseases. Exp Clin Endocrinol Diabetes 2014; 122: 107-112.
• 8 Bottazzo GF, Pujol-Borrell R, Hanafusa T. et al. Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity. Lancet 1983; 2: 1115-1118.
• 9 Brix TH, Hansen PS, Kyvik KO. et al. Aggregation of thyroid autoantibodies in twins from opposite-sex pairs suggests that microchimerism may play a role in the early stages of thyroid autoimmunity. J Clin Endocrinol Metab 2009; 94: 4439-4443.
• 10 Brix TH, Kyvik KO, Christensen K. et al. 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.
• 11 Chailurkit LO, Aekplakorn W, Ongphiphadhanakul B. The relationship between circulating estradiol and thyroid autoimmunity in males. Eur J Endocrinol 2013; 170: 63-67.
• 12 Chen W, Lin H, Wang M. Immune intervention effects on the induction of experimental autoimmune thyroiditis. J Huazhong Univ Sci Technol Med Sci 2002; 22: 343-345.
• 13 Chu X, Pan CM, Zhao SX. et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet 2011; 43: 897-901.
• 14 Cloutier JF, Veillette A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J Exp Med 1999; 189: 111-121.
• 15 Colobran R, Armengol Mdel P, Faner R. et al. Association of an SNP with intrathymic transcription of TSHR and Graves' disease: a role for defective thymic tolerance. Hum Mol Genet 2011; 20: 3415-3423.
• 16 Corona G, Biagini C, Rotondi M. et al. Correlation between, clinical, biochemical, color doppler ultrasound thyroid parameters, and CXCL-10 in autoimmune thyroid diseases. Endocr J 2008; 55: 345-350.
• 17 Costagliola S, Many MC, Denef JF. et al. Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease. J Clin Invest 2000; 105: 803-811.
• 18 Davies TF. Infection and autoimmune thyroid disease. J Clin Endocrinol Metab 2008; 93: 674-676.
• 19 Davies TF. Really significant genes for autoimmune thyroid disease do not exist--so how can we predict disease?. Thyroid 2007; 17: 1027-1029.
• 20 De Groot L, Abalovich M, Alexander EK. et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2543-2565.
• 21 Duntas LH. A tribute to Carl Adolph von Basedow: to commemorate 150 years since his death. Hormones (Athens) 2004; 3: 208-209.
• 22 Duntas LH. Selenium and the thyroid: a close-knit association. J Clin Endocrinol Metab 2010; 95: 5180-5188.
• 23 Inukai Y, Momobayashi A, Sugawara N. et al. Changes in expression of T-helper (Th) 1- and Th2-associated chemokine receptors on peripheral blood lymphocytes and plasma concentrations of their ligands, interferon-inducible protein-10 and thymus and activation-regulated chemokine, after antithyroid drug administration in hyperthyroid patients with Graves' disease. Eur J Endocrinol 2007; 156: 623-630.
• 24 Kaithamana S, Fan J, Osuga Y. et al. Induction of experimental autoimmune Graves' disease in BALB/c mice. J Immunol 1999; 163: 5157-5164.
• 25 Laurberg P, Cerqueira C, Ovesen L. et al. Iodine intake as a determinant of thyroid disorders in populations. Best Pract Res Clin Endocrinol Metab 2010; 24: 13-27.
• 26 Marcocci C, Bartalena L. Role of oxidative stress and selenium in Graves' hyperthyroidism and orbitopathy. J Endocrinol Invest 2013; 36: 15-20.
• 27 Marinò M, Latrofa F, Menconi F. et al. An update on the medical treatment of Graves' hyperthyroidism. J Endocrinol Invest 2014; 37: 1041-1048.
• 28 Marinò M, Latrofa F, Menconi F. et al. Role of genetic and non-genetic factors in the etiology of Graves' disease. J Endocrinol Invest 2015; 38: 283-294.
• 29 McLachlan SM, Nagayama Y, Rapoport B. Insight into Graves' hyperthyroidism from animal models. Endocr Rev 2005; 26: 800-832.
• 30 McLachlan SM, Rapoport B. Breaking tolerance to thyroid antigens: changing concepts in thyroid autoimmunity. Endocr Rev 2014; 35: 59-105.
• 31 Nagayama Y, Kita-Furuyama M, Ando T. et al. A novel murine model of Graves' hyperthyroidism with intramuscular injection of adenovirus expressing the thyrotropin receptor. J Immunol 2002; 168: 2789-2794.
• 32 Paunkovic N, Paunkovic J, Pavlovic O. et al. The significant increase in incidence of Graves' disease in eastern Serbia during the civil war in the former Yugoslavia (1992 to 1995). Thyroid 1998; 8: 37-41.
• 33 Piantanida E, Tanda ML, Lai A. et al. Prevalence and natural history of Graves' orbitopathy in the XXI century. J Endocrinol Invest 2013; 36: 444-449.
• 34 Purves HD, Adams DD. Thyroid-stimulating hormone. Br Med Bull 1960; 16: 128-132.
• 35 Romagnani P, Rotondi M, Lazzeri E. et al. 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.
• 36 Rotondi M, Chiovato L. The chemokine system as a therapeutic target in autoimmune thyroid diseases: A focus on the interferon-γ inducible chemokines and their receptors. Curr Pharm Des 2011; 17: 3202-3216.
• 37 Rotondi M, Chiovato L. Vitamin D deficiency in patients with Graves' disease: probably something more than a casual association. Endocrine 2013; 43: 3-5.
• 38 Rotondi M, Cappelli C, Pirali B. et al. The effect of pregnancy on subsequent relapse from Graves' disease after a successful course of antithyroid drug therapy. J Clin Endocrinol Metab 2008; 93: 3985-3988.
• 39 Rotondi M, Chiovato L, Romagnani S. et al. Role of chemokines in endocrine autoimmune diseases. Endocr Rev 2007; 28: 492-520.
• 40 Rotondi M, Pirali B, Lodigiani S. et al. The post partum period and the onset of Graves' disease: an overestimated risk factor. Eur J Endocrinol 2008; 159: 161-165.
• 41 Shimojo N, Kohno Y, Yamaguchi K-I. et al. Induction of Graves-like disease in mice by immunization with fibroblasts transfected with the thyrotropin repector and a class II molecule. Proc Natl Acad Sci USA 1996; 93: 11074-11079.
• 42 Simmonds MJ, Kavvoura FK, Brand OJ. et al. Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis. J Clin Endocrinol Metab 2014; 99: E127-E131.
• 43 Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol 2006; 24: 65-97.
• 44 Teng X, Shan Z, Teng W. et al. Experimental study on the effects of chronic iodine excess on thyroid function, structure, and autoimmunity in autoimmune-prone NOD.H-2h4 mice. ClinExp Med 2009; 9: 51-59.
• 45 Tomer Y. Genetic susceptibility to autoimmune thyroid disease: past, present, and future. Thyroid 2010; 20: 715-725.
• 46 Weetman AP. Immune reconstitution syndrome and the thyroid. Best Practice and Research in Clinical Endocrinology and Metabolism 2009; 23: 693-702.
• 47 Wiersinga WM. Smoking and thyroid. Clin Endocrinol 2013; 79: 145-151.
• 48 Yin X, Sachidanandam R, Morshed S. et al. mRNASeq reveals novel molecular mechanisms and a robust fingerprint in Graves' disease. J Clin Endocrinol Metab 2014; 99: E2076-2083.