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Horm Metab Res 2008; 40(6): 361-368
DOI: 10.1055/s-2008-1073153
Review

© Georg Thieme Verlag KG Stuttgart · New York

Chemokines and Autoimmune Thyroid Diseases

C. Liu 1 , C. Papewalis 2 , J. Domberg 2 , W. A. Scherbaum 2 , M. Schott 2
  • 1Department of Endocrinology, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
  • 2Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Düsseldorf, Germany
Further Information

Publication History

received 19.12.2007

accepted 23.01.2008

Publication Date:
16 April 2008 (online)

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Abstract

Chemokines are a family of small, structurally related molecules that regulate cell trafficking of various types of leukocytes through interactions with their seven-transmembrane, G protein-coupled receptors. Their major function is the recruitment of leukocytes to inflammation sites, but they also play roles in tumor growth, angiogenesis, organ sclerosis, and autoimmunity. A variety of evidence has accumulated to support the concept that thyroid follicular cells as well as intrathyroidal lymphocytes are able to produce CC and CXC chemokines, which, in turn, promote the initiation and maintenance of an inflammatory process resulting in autoimmune thyroid diseases (AITD). Overexpression of several chemokines in AITD has been demonstrated. Moreover, alterations of CCL2, CCL5, CXCL9, and CXCL10 have been shown in circulation of many patients with AITD. In subjects with Graves’ disease, antithyroid drug treatment, radioactive iodine ablation, and thyroidectomy can significantly reduce CXCL10 levels. The measurement of chemokines in serum of AITD patients might provide a useful parameter for the evaluation and prediction of disease activity and progression. Further experimental and clinical studies will expand our understanding of the clinical implications of chemokine detection and the effects of chemokines on the pathogenesis of AITD.

Key words

chemokine - autoimmune thyroid disease - Graves’ disease - Hashimoto's thyroiditis - thyroid cell

References

  • 1 Zlotnik A, Yoshle O. Chemokines: a new classification system and their role in immunity.  Immunity. 2000;  12 121-127
    CrossrefPubMedGoogle Scholar
  • 2 Bacon K, Baggiolini M, Broxmeyer H, Horuk R, Lindley I, Mantovani A, Maysushima K, Murphy P, Nomiyama H, Oppenheim J, Rot A, Schall T, Tsang M, Thorpe R, Damme J Van, Wadhwa M, Yoshie O, Zlotnik A, Zoon K. IUIS/WHO Subcommittee on Chemokine Nomenclature. Chemokine/chemokine receptor nomenclature.  J Interferon Cytokine Res. 2002;  22 1067-1068
    CrossrefPubMedGoogle Scholar
  • 3 Walz DA, Wu VY, Lamo R de, Dene H, MacCoy LE. Primary structure of human platelet factor 4.  Thromb Res. 1977;  11 893-898
    CrossrefPubMedGoogle Scholar
  • 4 Lindley IJD, Westwick J, Kunkel SL. Nomenclature announcement: the chemokines.  Immunol Today. 1998;  14 24
    PubMedGoogle Scholar
  • 5 Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation.  N Engl J Med. 2006;  354 610-621
    CrossrefPubMedGoogle Scholar
  • 6 Rot A, Andrian UH von. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells.  Annu Rev Immunol. 2004;  22 891-928
    CrossrefPubMedGoogle Scholar
  • 7 Zlotnik A, Yoshie O, Nomiyama H. The chemokine and chemokine receptor superfamilies and their molecular evolution.  Genome Biol. 2006;  7 243
    CrossrefPubMedGoogle Scholar
  • 8 Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control.  Trends Immunol. 2004;  25 75-84
    CrossrefPubMedGoogle Scholar
  • 9 Kimura1 H, Caturegli P. Chemokine orchestration of autoimmune thyroiditis.  Thyroid. 2007;  17 1005-1010
    CrossrefPubMedGoogle Scholar
  • 10 Rotondi M, Chiovato L, Romagnani S, Serio M, Romagnani P. Role of chemokines in endocrine autoimmune diseases.  Endocr Rev. 2007;  28 492-520
    CrossrefPubMedGoogle Scholar
  • 11 Butera D, Marukian S, Iwamaye AE, Hembrador E, Chambers TJ, Bisceglie AM Di, Charles ED, Talal AH, Jacobson IM, Rice CM, Dustin LB. Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C.  Blood. 2005;  106 1175-1182
    CrossrefPubMedGoogle Scholar
  • 12 Carella C, Mazziotti G, Amato G, Braverman LE, Roti E. Clinical review 169: interferon-α-related thyroid disease: pathophysiological, epidemiological, and clinical aspects.  J Clin Endocrinol Metab. 2004;  89 3656-3661
    CrossrefPubMedGoogle Scholar
  • 13 Rotondi M, Minelli1 R, Magri F, Leporati P, Romagnani P, Baroni MC, Delsignore R, Serio M, Chiovato L. Serum CXCL10 levels and occurrence of thyroid dysfunction in patients treated with interferon-a therapy for hepatitis C virus-related hepatitis.  Eur J Endocrinol. 2007;  156 409-414
    CrossrefPubMedGoogle Scholar
  • 14 Braunersreuther V, Mach F, Steffens S. The specific role of chemokines in atherosclerosis.  Thromb Haemost. 2007;  97 714-721
    PubMedGoogle Scholar
  • 15 Ruffini PA, Morandi P, Cabioglu N, Altundag K, Cristofanilli M. Manipulating the chemokine-chemokine receptor network to treat cancer.  Cancer. 2007;  109 2392-2404
    CrossrefPubMedGoogle Scholar
  • 16 Pease JE. Asthma, allergy and chemokines.  Curr Drug Targets. 2006;  7 3-12
    CrossrefPubMedGoogle Scholar
  • 17 Matz M, Beyer J, Wunsch D, Mashreghi MF, Seiler M, Pratschke J, Babel N, Volk HD, Reinke P, Kotsch K. Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function.  Kidney Int. 2006;  69 1683-1690
    CrossrefPubMedGoogle Scholar
  • 18 Sorensen T, Trebst C, Kivisakk P, Klaege K, Majmudar A, Ravid R, Lassmann H, Olsen D, Strieter R, Ransohoff R, Sellebjerg F. Multiple sclerosis: a study of CXCL10 and CXCR3 co-localization in the inflamed central nervous system.  J Neuroimmunol. 2002;  127 59-68
    CrossrefPubMedGoogle Scholar
  • 19 Muller A, Rotondi M, Lazzeri E, Romagnani P, Serio M. Role for interferon-α inducible chemokines in endocrine autoimmunity: an expanding field.  J Endocrinol Invest. 2003;  26 177-180
    PubMedGoogle Scholar
  • 20 Shigihara T, Oikawa Y, Kanazawa Y, Okubo Y, Narumi S, Saruta T, Shimada A. Significance of serum CXCL10/IP-10 level in type 1 diabetes.  J Autoimmun. 2006;  26 66-71
    CrossrefPubMedGoogle Scholar
  • 21 Rotondi M, Falorni A, Bellis A De, Laureti S, Ferruzzi P, Romagnani P, Buonamano A, Lazzeri E, Crescioli C, Mannelli M, Santeusanio F, Bellastella A, Serio M. Elevated serum interferon-γ-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.  J Clin Endocrinol Metab. 2006;  90 2357-2363
    PubMedGoogle Scholar
  • 22 Schott M, Eckstein A, Willernberg HS, Nguyen TBT, Morgenthaler NG, Scherbaum WA. Improved prediction of relapse of Graves’ thyroitoxicosis by combined determination of TSH receptor and thyroperoxidase antibodies.  Horm Metab Res. 2007;  39 56-61
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Weetman AP. Cellular immune responses in autoimmune thyroid disease.  Clin Endocrinol. 2004;  61 405-413
    Google Scholar
  • 24 Weetman AP, Bennett GL, Wong WL. Thyroid follicular cells produce interleukin-8.  J Clin Endocrinol Metab. 2002;  75 328-330
    PubMedGoogle Scholar
  • 25 Kasai K, Banba N, Motohashi S, Hattor Y, Manaka K, Shimoda SI. Expression of monocyte chemoattractant protein-1 mRNA and protein in cultured human thyrocytes.  FEBS Letters. 1996;  394 137-140
    CrossrefPubMedGoogle Scholar
  • 26 Ashhab Y, Dominguez O, Sospedra M, Roura-Mir C, Lucas-Martin A, Pujol-Borrell R. A one-tube polymerase chain reaction protocol demonstrates CC chemokine overexpression in Graves’ disease glands.  J Clin Endocrinol Metab. 1999;  84 2873-2882
    CrossrefPubMedGoogle Scholar
  • 27 Simchen C, Lehmann I, Sittig D, Steinert M, Aust G. Expression and regulation of regulated on activation, normal T cells expressed and secreted in thyroid tissue of patients with Graves’ disease and thyroid autonomy and in thyroid-derived cell populations.  J Clin Endocrinol Metab. 2000;  85 4758-4764
    CrossrefPubMedGoogle Scholar
  • 28 Aust G, Steinert M, Kieseling S, Kamprad M, Simchen C. Reduced expression of stromal-derived factor 1 in autonomous thyroid adenomas and its regulation in thyroid-derived cells.  J Clin Endocrinol Metab. 2001;  86 3368-3376
    CrossrefPubMedGoogle Scholar
  • 29 Aust G, Steinert M, Boltze C, Kieseling A, Simchen C. GRO-a in normal and pathological thyroid tissues and its regulation in thyroid-derived cells.  J Endocrinol. 2001;  170 513-520
    CrossrefPubMedGoogle Scholar
  • 30 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
    CrossrefPubMedGoogle Scholar
  • 31 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
    CrossrefPubMedGoogle Scholar
  • 32 Kokkotou E, Marafelia P, Mantzos EI, Tritos NA. Serum monocyte chemoattractant protein-1 is increased in chronic autoimmune thyroiditis.  Metabolism. 2002;  51 1489-1493
    CrossrefPubMedGoogle Scholar
  • 33 Goulvestre C, Batteux F, Charreire J. Chemokines modulate experimental autoimmune thyroiditis through attraction of autoreactive or regulatory T cells.  Eur J Immunol. 2002;  32 3435-3442
    PubMedGoogle Scholar
  • 34 Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease.  Clin Endocrinol (Oxf). 2003;  59 207-213
    CrossrefPubMedGoogle Scholar
  • 35 Aust G, Sittig D, Becherer L, Anderegg U, Schutz A, Lamesch P, Schmucking E. The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases.  Eur J Endocrinol. 2004;  150 225-234
    CrossrefPubMedGoogle Scholar
  • 36 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Buonamano A, Ferrannini E, Serio M. High levels of circulating CXC chemokine ligand 10 are associated with chronic autoimmune thyroiditis and hypothyroidism.  J Clin Endocrinol Metab. 2004;  89 5496-5499
    CrossrefPubMedGoogle Scholar
  • 37 Martin AP, Coronel EC, Sano G, Chen SC, Vassileva G, Canasto-Chibuque C, Sedgwick JD, Frenette PS, Lipp M, Furtado GC, Lira SA. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21.  J Immunol. 2004;  173 4791-4798
    PubMedGoogle Scholar
  • 38 Antonelli A, Rotondi M, Fallahi1 P, Romagnani P, Ferrari1 SM, Paolicchi A, Ferrannini1 E, Serio M. Increase of interferon-g inducible αchemokine CXCL10 but not βchemokine CCL2 serum levels in chronic autoimmune thyroiditis.  Eur J Endocrinol. 2005;  152 171-177
    CrossrefPubMedGoogle Scholar
  • 39 Chen K, Wei Y, Alter A, Sharp GC, Braley-Mullen H. Chemokine expression during development of fibrosis versus resolution in a murine model of granulomatous experimental autoimmune thyroiditis.  J Leukoc Biol. 2005;  78 716-724
    CrossrefPubMedGoogle 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
    CrossrefPubMedGoogle Scholar
  • 41 Ferrer-Francesch X, Caro P, Alcalde L, Armengol MP, Ashhab Y, Lucas-Martin A, Martinez-Caceres EM, Juan M, Pujol-Borrell R. One-tube-PCR technique for CCL2, CCL3, CCL4 and CCL5 applied to fine needle aspiration biopsies shows different profiles in autoimmune and non-autoimmune thyroid disorders.  J Endocrinol Invest. 2006;  29 342-349
    PubMedGoogle Scholar
  • 42 Antonelli A, Rotondi M, Fallahi P, Romagnani P, Ferrari SM, Barani L, Ferrannini E, Serio M. Increase of interferongamma-inducible CXC chemokine CXCL10 serum levels in patients with active Graves’ disease, and modulation by methimazole therapy.  Clin Endocrinol (Oxf). 2006;  64 189-195
    CrossrefPubMedGoogle Scholar
  • 43 Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Romagnani P, Grosso M, Ferrannini E, Serio M. Increased serum CXCL10 in Graves’ disease or autoimmune thyroiditis is not associated with hyper- or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process.  Eur J Endocrinol. 2006;  154 651-658
    CrossrefPubMedGoogle Scholar
  • 44 Antonelli A, Fallahi P, Rotondi M, Ferrari SM, Serio M, Miccoli P. Serum levels of the interferon-gammainducible alpha chemokine CXCL10 in patients with active Graves’ disease, and modulation by methimazole therapy and thyroidectomy.  Br J Surg. 2006;  93 1226-1231
    CrossrefPubMedGoogle Scholar
  • 45 Antonelli A, Rotondi M, Ferrari SM, Fallahi P, Romagnani P, Franceschini SS, Serio M, Ferrannini E. Interferon-gamma-inducible alpha-chemokine CXCL10 involvement in Graves’ ophthalmopathy: modulation by peroxisome proliferator-activated receptor-gamma agonists.  J Clin Endocrinol Metab. 2006;  91 614-620
    CrossrefPubMedGoogle Scholar
  • 46 Aso Y, Matsuura H, Momobayashi A, Inukai Y, Sugawara N, Nakano T, Yamamoto R, Wakabayashi S, Takebayashi K, Inukai T. Profound reduction in T-helper (Th) 1 lymphocytes in peripheral blood from patients with concurrent type 1 diabetes and Graves’ disease.  Endocr J. 2006;  53 377-385
    CrossrefPubMedGoogle Scholar
  • 47 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
    CrossrefPubMedGoogle Scholar
  • 48 Crescioli1 C, Cosmi L, Borgogni1 E, Santarlasci V, Gelmini1 S, Sottili1 M, Sarchielli E, Mazzinghi1 B, Francalanci1 M, Pezzatini1 A, Perigli G, Vannelli GB, Annunziato F, Serio M. Methimazole inhibits CXC chemokine ligand 10 secretion in human thyrocytes.  J Endocrinol. 2007;  195 145-155
    CrossrefPubMedGoogle Scholar
  • 49 Antonelli A, Rotondi M, Fallahi P, Grosso M, Boni G, Ferrari SM, Romagnani P, Serio M, Mariani G, Ferrannini E. Iodine-131 given for therapeutic purposes modulates differently interferon-gamma-inducible alpha-chemokine CXCL10 serum levels in patients with active Graves’ disease or toxic nodular goiter.  J Clin Endocrinol Metab. 2007;  92 1485-1490
    CrossrefPubMedGoogle Scholar
  • 50 Inukai Y, Momobayashi A, Sugawara N, Aso Y. 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
    CrossrefPubMedGoogle Scholar
  • 51 Gianoukakis AG, Martino LJ, Horst N, Cruikshank WW, Smith TJ. Cytokine-induced lymphocyte chemoattraction from cultured human thyrocytes: evidence for interleukin-16 and regulated upon activation, normal T cell expressed, and secreted expression.  Endocrinology. 2003;  144 2856-2864
    CrossrefPubMedGoogle Scholar
  • 52 Hirooka Y, Mitsuma T, Nogimori T, Ishizuki Y. Deregulated production of interleukin-8 (IL-8) in autoimmune thyroid disease studied by newly developed IL-8 radioimmunoassay.  Endocr Regul. 1993;  27 11-15
    PubMedGoogle Scholar
  • 53 Armengol MP, Juan M, Lucas-Martin A, Fernandez-Figueras MT, Jaraquemada D, Gallart T, Pujol-Borrell R. Thyroid autoimmune disease: demonstration of thyroid antigenspecific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers.  Am J Pathol. 2001;  159 861-873
    PubMedGoogle Scholar
  • 54 Ledur A, Fitting C, David B, Hamberger C, Cavaillon JM. Variable estimates of cytokine levels produced by commercial ELISA kits: results using international cytokine standards.  J Immunol Methods. 1999;  186 171-179
    PubMedGoogle Scholar
  • 55 Khan SS, Smith MS, Reda D, Suffredini AF, MacCoy JP. Multiplex bead array assays for detection of soluble cytokines: comparisons of sensitivity and quantitative values among kits from multiple manufacturers.  Clin Cytometry. 2004;  61B 35-39
    PubMedGoogle Scholar
  • 56 Liu MY, Xydakis AM, Hoogeveen RC, Jones PH, O’Brian Smith E, Nelson KW, Ballantyne CM. Multiplexed analysis of bomarkers related to obesity and the metabolic syndrome in human plasma, using the Luminex-100 System.  Clin Chem. 2005;  51 1102-1109
    CrossrefPubMedGoogle Scholar
  • 57 Aziz N, Nishanian P, Mitsuyasu R, Detels R, Fahey JL. Variables that affect assays for plasma cytokines and soluble activation markers.  Clin Diag Lab Immunol. 1999;  6 89-95
    PubMedGoogle Scholar
  • 58 Antonelli A, Rotondi M, Fallahi P, Ferrari SM, Paolicchi A, Romagnani P, Serio M, Ferrannini E. Increase of CXCL chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing.  Cytokine. 2006;  34 32-38
    CrossrefPubMedGoogle Scholar
  • 59 Siddiqi A, Monson JP, Wood DF, Besser GM, Burrin JM. Serum cytokines in thyrotoxicosis.  J Clin Endocrinol Metab. 1999;  84 435-439
    CrossrefPubMedGoogle Scholar
  • 60 Nicoletti F, Conget I, Mauro M Di, Marco R Di, Mazzarino MC, Bendtzen K, Messina A, Gomis R. Serum concentrations of the interferon-γ-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed type I diabetes mellitus patients and subjects at risk of developing the disease.  Diabetologia. 2002;  45 1107-1110
    CrossrefPubMedGoogle Scholar
  • 61 Schott M, Morgenthaler NG, Fritzen R, Feldkamp J, Willenberg HS, Scherbaum WA, Seissler S. Levels of autoantibodies against human TSH receptor predict relapse of hyperthyroidism in Graves’ disease.  Horm Metab Res. 2004;  36 92-96
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Paunkovic J, Paunkovic N. Does autoantibody-negative Graves’ disease exist? A second evaluation of the clinical diagnosis.  Horm Metab Res. 2006;  38 53-56
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Quadbeck B, Hoermann R, Hahn S, Roggenbuck U, Mann K, Janssen OE. Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor antibodies as predictors of relapse of Graves’ disease after withdrawal of antithyroid treatment.  Horm Metab Res. 2005;  37 745-750
    Article in Thieme ConnectPubMedGoogle Scholar

Correspondence

M. SchottMD 

Department of Endocrinology

Diabetes and Rheumatology

University Hospital Düsseldorf

Moorenstr. 5

40225 Düsseldorf

Germany

Phone: +49/211/811 78 10

Fax: +49/211/811 78 60

Email: matthias.schott@med.uni-duesseldorf.de

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