Skip to main content

Role of Cytokines in the Pathogenesis of Graves’ Ophthalmopathy

  • Chapter
Thyroid Eye Disease

Part of the book series: Endocrine Updates ((ENDO,volume 14))

  • 151 Accesses

Abstract

Graves’ ophthalmopathy (GO) is generally accepted to be an autoimmune inflammatory disorder of the extraocular muscles (EM) and the orbital fatty/connective tissue (OCT) that is closely associated with Graves’ disease (13).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Wall JR, Salvi M, Bernard NF, Boucher A, Haegert D 1991 Thyroid-associated ophthalmopathy: a model for the association of organ-specific autoimmune disorders. Immunol Today 12:150–153.

    PubMed  CAS  Google Scholar 

  2. Burch HB, Wartofsky L 1993 Graves’ ophthalmopathy, current concepts regarding pathogenesis and management. Endocrine Reviews 14: 747–793.

    PubMed  CAS  Google Scholar 

  3. Bednarczuk T, Kennerdell JS, Wall JR 1997 Thyroid-Associated OphthalmopathyPathophysiology and Etiology. In: Falk SA (ed) Thyroid Disease - Endocrinology, Surgery, Nuclear Medicine and Radiotherapy. Raven Press, New York, p 341–358.

    Google Scholar 

  4. Weetman AP, Cohen K, Gatter P, Fells, Shine B 1989 Immunohistochemical analysis of retrobulbar tissues in Graves’ ophthalmopathy. Clin Exp Immunol 75:222–227.

    PubMed  CAS  Google Scholar 

  5. Kahaly G, Hansen C, Felke B, Dienes HP 1994 Immunohistochemical staining of retrobulbar adipose tissue in Graves’ ophthalmopathy. Clin Immunol Immunopathol 73:53–62.

    Article  PubMed  CAS  Google Scholar 

  6. Hiromatsu Y, Tanaka K, Ishisaka N, et al. 1995 Human histocompatibility leukocyte antigen-DR and heat shock protein-70 expression in eye muscle tissue in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 80:685–691.

    Article  PubMed  CAS  Google Scholar 

  7. Hiromatsu Y 1996 In situ studies of orbital tissue from patients with thyroid-associated ophthalmopathy. Orbit 15: 147–158.

    Article  Google Scholar 

  8. Pappa A, Lawson JMM, Calder V, Fells P, Lightman S 2000 T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 84: 517–522.

    Article  PubMed  CAS  Google Scholar 

  9. Kiljanski JI, Nebes V, Wall JR 1995 The ocular muscle cell is a target of the immune system in endocrine ophthalmopathy. Int Arch Allergy Immunol 106:204–212.

    Article  PubMed  CAS  Google Scholar 

  10. Hiromatsu Y, Kojima K, Ishisaka N, Tanaka K, Sato M, Nonaka K, Nishimura H, Nishida H. 1993 Role of magnetic resonance imaging in thyroid-associated ophthalmopathy: its predictive value for therapeutic outcome of immunosuppressive therapy. Thyroid 2:299–305.

    Article  Google Scholar 

  11. Gunji K, De Bellis A, Li AW, Yamada M, Kubota S, Ackrell B, Wengrowicz S, Bellastella A, Bizzarro A, Sinisi A, Wall JR 2000 Cloning and characterization of the novel thyroid and eye muscle shared protein G2s: autoantibodies against G2s are closely associated with ophthalmopathy in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab 85:1641–1647.

    Article  PubMed  CAS  Google Scholar 

  12. Hiromatsu Y, Yang D, Bednarczuk T, Miyake I, Nonaka K, Inoue Y 2000 Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 85:1194–1199.

    Article  PubMed  CAS  Google Scholar 

  13. Heufelder AE, Herterich S, Ernst G, Bahn RS, Scriba PC 1995 Analysis of retroorbital T cell antigen receptor variable region gene usage in patients with Graves’ ophthalmopathy. Eur J Endocrinol 132: 266–277.

    Article  PubMed  CAS  Google Scholar 

  14. Heufelder AE, Wenzel BE, Scriba PC 1996 Antigen Receptor Variable Region Repertoires Expressed by T Cells Infiltrating Thyroid, Retroorbital, and Pretibial Tissue in Graves Disease. J Clin Endocrinol Metab 81: 3733–3739.

    Article  PubMed  CAS  Google Scholar 

  15. Kubota S, Gunji K, Ackrell BA, Cochran B, Stolarski C, Wengrowicz S, Kennerdell JS, Hiromatsu Y, Wall J 1998 The 64-kilodalton eye muscle protein is the flavoprotein subunit of mitochondrial succinate dehydrogenase: the corresponding serum antibodies are good markers of an immune-mediated damage to the eye muscle in patients with Graves’ hyperthyroidism. J Clin Endocrinol Metab 83:443–447.

    Article  PubMed  CAS  Google Scholar 

  16. Bednarczuk T, Stolarski C, Pawlik E, Slon M, Rowinski M, Kubota S, Hiromatsu Y, Bartoszewicz Z, Wall JR, Nauman J 1999 Autoantibodies reactive with extracellular matrix (ECM) proteins in patients with thyroid-associated ophthalmopathy. Thyroid 9: 289–295.

    Article  PubMed  CAS  Google Scholar 

  17. Salgame P, Abrams JS, Clayberger C, et al. 1991 Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 254:279–282.

    Article  PubMed  CAS  Google Scholar 

  18. Liblau RS, Singer SM, McDevitt HO 1995 Thl and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 16:34–38.

    Article  PubMed  CAS  Google Scholar 

  19. Romagnani S 1997 The Thl/Th2 paradigm. Immunol Today 18:263–266.

    Article  PubMed  CAS  Google Scholar 

  20. McLachlan SM, Prummel MF, Rapoport B 1994 Cell-mediated or humoral immunity in Graves’ ophthalmopathy? Profiles of T-cells cytokines amplified by polymerase chain reaction from orbital tissue. J Clin Endocrinol Metab 78:1070–1074.

    Article  PubMed  CAS  Google Scholar 

  21. Pappa A, Calder V, Ajjan R, et al. 1997 Analysis of extraocular muscle infiltrating T cells in thyroid-associated ophthalmopathy (TAO). Clin Exp Immunol 109:362–369.

    Article  PubMed  CAS  Google Scholar 

  22. Grubeck-Loebenstein B, Trieb K, Sztankay A, Holter W, Anderi H, Wick G 1994 Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts. J Clin Invest 93:2738–2743.

    Article  PubMed  CAS  Google Scholar 

  23. De Carli M, D’Elios MM, Mariotti S, et al. 1993 Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves’ ophthalmopathy. J Clin Endocrinol Metab 77:1120–1124.

    Article  PubMed  Google Scholar 

  24. Forster G, Otto E, Hansen C, Ochs K, Kahaly G 1998 Analysis of orbital T cells in thyroid-associated ophthalmopathy. Clin Exp Immunol 112:427–434.

    Article  PubMed  CAS  Google Scholar 

  25. Yang D, Hiromatsu Y, Hoshino T, Inoue Y, Itoh K, Nonaka K 1999 Dominant infiltration of T(H) 1-type CD4+ T cells at the retrobulbar space of patients with thyroid-associated ophthalmopathy. Thyroid. 9:305–310.

    Article  PubMed  CAS  Google Scholar 

  26. Aniszewski JP, Valyasevi RW, Bahn RS 2000 Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy. J Clin Endocrinol Metab 85:776–780.

    Article  PubMed  CAS  Google Scholar 

  27. Natt N, Bahn RS 1997 Cytokines in the evolution of Graves’ ophthalmopathy. Autoimmunity 26:129–136.

    Article  PubMed  CAS  Google Scholar 

  28. Heufelder AE, Bahn RS 1993 Detection and localization of cytokine immunoreactivity in retroocular connective tissue in Graves’ ophthalmopathy. Eur J Clin Invest 23:10–17.

    Article  PubMed  CAS  Google Scholar 

  29. Hoshino T, Itoh K, Gouhara R, et al. 1995 Spontaneous production of various cytokines except IL-4 from CD4+ T cells in the affected organs of sarcoidosis patients. Clin Exp Immunol 102:399–405.

    Article  PubMed  CAS  Google Scholar 

  30. Gup J, Rapoport B, McLachlan SM 1997 Cytokine profiles of in vivo activated thyroid-infiltrating T cells cloned in the presence or absence of interleukin 4. Autoimmunity 26:103–110.

    Article  Google Scholar 

  31. Van der Gaag R, Schmidt ED, Zonnerveld FW, Koornneef L 1995 Orbital pathology in thyroid-associated ophthalmopathy. Orbit 15: 109–118.

    Article  Google Scholar 

  32. Kamizono S, Hiromatsu Y, Seki N, Bednarczuk T, Matsumoto H, Kimura A, Itoh K. 2000 A polymorphism of the 5’ flanking region of tumor necrosis factor alpha gene is associated with thyroid-associated ophthalmopathy in Japanese. Clin Endocrinol (Oxf) 52:759–764.

    Article  CAS  Google Scholar 

  33. Salvi M, Pedrazzoni M, Girasole G, Giuliani N, Minelli R, Wall JR, Roti E 2000 Serum concentrations of proinflammatory cytokines in Graves’ disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking. Eur J Endocrinol 143: 197–202.

    Article  PubMed  CAS  Google Scholar 

  34. Komorowski J, Jankiewicz J, Robak T, Blasinska-Morawiec M, Stepien H 1998 Cytokine levels as the marker of thyroid activation in Graves’ disease. Immunol Lett 60: 143–148.

    Article  PubMed  CAS  Google Scholar 

  35. Tan GH, Dutton CM, Bahn RS 1996 Interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptor inhibit IL-1-induced glycosaminoglycan production in cultured human orbital fibroblasts from patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab. 81: 449–452.

    Article  PubMed  CAS  Google Scholar 

  36. Hofbauer LC, Muhlberg T, Konig A, Heufelder G, Schworm HD, Heufelder AE 1997 Soluble interleukin-1 receptor antagonist serum levels in smokers and nonsmokers with Graves’ ophthalmopathy undergoing orbital radiotherapy. J Clin Endocrinol Metab 82: 2244–2247.

    Article  PubMed  CAS  Google Scholar 

  37. Mysliwiec J, Kretowski A, Szelachowska M, Mikita A, Kinalska I 1999 Serum pro-and anti-inflammatory cytokines in patients with Graves’ disease with ophthalmopathy during treatment with glucocorticoids. Rocz Akad Med Bialymst 44: 160–169.

    PubMed  CAS  Google Scholar 

  38. Wakelkamp IM, Gerding MN, Van der Meer JW, Prummel MF, Wiersinga WM 2000 Both Thl-and Th2- derived cytokines in serum are elevated in Graves’ ophthalmopathy. Clin Exp Immunol 121: 453–457.

    Article  PubMed  CAS  Google Scholar 

  39. Yamada T, Sato A, Komiya I, Nishimori T, Ito Y, Terao A, Eto S, Tanaka Y 2000 An elevation of serum immunoglobulin E provides a new aspect of hyperthyroid Graves’ disease. J Clin Endocrinol Metab 85:2775–2778.

    CAS  Google Scholar 

  40. Raikow RB, Dalbow MH, Kennerdell JS, Compher K, Machen L, Hiller W, Blendermann D 1990 Immunohistochemical evidence for IgE involvement in Graves’ orbitopathy. Ophthalmology 97:629–35.

    PubMed  CAS  Google Scholar 

  41. Smith TJ, Parikh SJ 1999 HMC-1 mast cells activate human orbital fibroblasts in coculture: evidence for upregulation of prostaglandin E2 and hyaluronan synthesis. Endocrinology 140: 3518–3525.

    Article  PubMed  CAS  Google Scholar 

  42. Heufelder AE, Bahn RS 1993 Elevated expression in situ of selectin and immunoglobulin superfamily type adhesion molecules in retroocular connective tissues from patients with Graves’ ophthalmopathy. Clin Exp Immunol 91: 381–389.

    Article  PubMed  CAS  Google Scholar 

  43. Pappa A, Calder V, Fells P, Lightman S 1997 Adhesion molecule expression in vivo on extraocular muscles (EOM) in thyroid-associated ophthalmopathy (GO). Clin Exp Immunol 108: 309–313.

    Article  PubMed  CAS  Google Scholar 

  44. Burnstine MA, Elner SG, Strieter RM, Kunkel SL, Elner VM 1999 Orbital fibroblast interleukin —6 gene expression and immunomodulation. Ophthal Plast Reconstr Surg 15: 306–311.

    Article  PubMed  CAS  Google Scholar 

  45. Molnar I, Balzacs C 1997 High circulating IL-6 level in Graves’ ophthalmopathy. Autoimmunity 25: 91–96.

    Article  PubMed  CAS  Google Scholar 

  46. Melchers F, Rolink AG, Schmid C 1999 The role of chemokines in regulating cell migration during humoral immune responses. Cell. 99: 351–354.

    Article  PubMed  CAS  Google Scholar 

  47. Elner VM, Burnstine MA, Kunkel SL, Stricter RM, Einer SG 1998 Interleukin-8 and monocyte chemotactic protein-1 gene expression and protein production by human orbital fibroblasts. Ophthal Plast Reconstr Surg. 14: 119–125.

    Article  PubMed  CAS  Google Scholar 

  48. Smith TJ, Bahn RS, Gorman CA, Cheavens M 1991 Stimulation of glycosaminoglycans by interferon gamma in cultured human retroocular fibroblasts. J Clin Endocrinol Metab 72: 1169–1171.

    Article  PubMed  CAS  Google Scholar 

  49. Smith TJ, Wang H-S, Evans CH 1995 Leukoregulin is a potent inducer of hyaluronan synthesis in cultured human orbital fibroblasts. Am J Physiol 268: C382–C388

    Google Scholar 

  50. Smith TJ, Bahn RS, Gorman CA 1989 Hormonal regulation of hyaluronate synthesis in cultured human fibroblasts: evidence for differences between retroocular and dermal fibroblasts. J Clin Endocrinol Metab 69: 1019–1023.

    Article  PubMed  CAS  Google Scholar 

  51. Heufelder AE, Bahn RS 1994 Modulation of Graves’ orbital fibroblasts proliferation by cytokines and glucocorticoid receptor agonists. Invest Ophthalmol Vis Sci 35: 120–127.

    PubMed  CAS  Google Scholar 

  52. Cao Hi, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith Ti 1998 Activation of human orbital fibroblasts through CD40 engagement results in dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanism of thyroid associated ophthalmopathy. J Biol Chem 273: 29615–29625.

    Article  Google Scholar 

  53. Sempowski GD, Rozenblit J, Smith TJ, Phipps RP 1998 Human orbital fibroblasts are activated by through CD40 to induce proinflammatory cytokine production. Am J Physiol 274: C707–C714.

    PubMed  CAS  Google Scholar 

  54. Hynes RO 1992 Integrins: Versatility, Modulation and Signaling in Cell Adhesion. Cell 69: 11–25.

    Article  PubMed  CAS  Google Scholar 

  55. Springer TA 1994 Traffic Signals for Lymphocyte Recirculation and Leukocyte Emigration: The Multistep Paradigm. Cell 76: 301–314.

    Article  PubMed  CAS  Google Scholar 

  56. Baggiolini M 1998 Chemokines and leukocyte traffic. Nature 392: 565–568.

    Article  PubMed  CAS  Google Scholar 

  57. Heufelder AE, Scriba PC 1996 Characterization of receptors on cultured microvascular endothelial cells derived from the retroorbital connective tissue of patients with Graves’ ophthalmopathy. Eur J Endocrinol 134: 51–60.

    Article  PubMed  CAS  Google Scholar 

  58. Heufelder AE, Bahn RS 1992 Graves’ immunoglobuline and cytokines stimulate the expression of intercellular adhesion molecule-1 (ICAM-1) in cultured orbital fibroblasts. European Journal of Clinical Investigation 22: 529–537.

    Article  PubMed  CAS  Google Scholar 

  59. Sciaky D, Brazer W, Center DM, Cruikshank WW, Smith TJ 2000 Cultured fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol 164: 3806–3814.

    PubMed  CAS  Google Scholar 

  60. Wang H-S, Cao Hi, Winn VD, Rezanka LJ, Frobert Y, Evans CH, Sciaky D, Young DA, Smith TJ 1996 Leukoregulin induction of prostaglandin-endoperoxide H synthase-2 in human orbital fibroblasts. Anin vitromodel for connective tissue inflammation. J Biol Chem 271: 22718–22728.

    Article  PubMed  CAS  Google Scholar 

  61. Cao HJ, Smith TJ 1999 Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts. Am J Physiol 277: C1075-C 1085.

    PubMed  CAS  Google Scholar 

  62. Mühlberg T, Heberling H-J, Joba W, Schworm H-D, Heufelder AE 1997 Detection and modulation of interleukin-1 receptor antagonist messenger ribonucleic acid and immunoreactivity in Graves’ orbital fibroblasts. Invest Ophthalmol Vis Sci 38: 1018–1028.

    PubMed  Google Scholar 

  63. Mack WP, Stasior GO, Cao HJ, Stasior OG, Smith TJ 1999 The effects of cigarette smoke constituents on the expression of HLA-DR in orbital fibroblasts derived from patients with Graves ophthalmopathy. Ophthal Plast Reconstr Surg 15: 260–271.

    Article  PubMed  CAS  Google Scholar 

  64. Hiromatsu Y, Fukazawa H, How J, Wall JR 1987 Antibody-dependent cell-mediated cytotoxicity against human eye muscle cells and orbital fibroblasts in Graves’ ophthalmopathy - roles of Class II MHC antigen expression and 0-interferon action on effector and target cells. Clin Exp Immunol 70: 593–603.

    PubMed  CAS  Google Scholar 

  65. Heufelder AE, Wenzel BE, Bahn RS 1992 Cell surface localization of a 72 kilodalton heat shock protein in retroocular fibroblasts from patients with Graves’ Ophthalmopathy. J Clin Endocrinol Metab 74: 732–736.

    Article  PubMed  CAS  Google Scholar 

  66. Eden W, van der Zee R, Paul A, Prakken BJ, Wendling U, Anderton SM, Wauben MHM 1998 Do heat shock proteins control the balance of T-cell regulation in inflammatory diseases. Immunol Today 19: 303–307.

    Article  PubMed  Google Scholar 

  67. Balzacs C, Kiss H, Farid NR 1998 Inhibitory effects of pentoxifylline on HLA-DR expression and glycosaminoglycan synthesis by retrobulbar fibroblasts. Horm Metab Res 30: 496–499.

    Article  Google Scholar 

  68. Hiromatsu Y, Yang D, Miyake I, Koga M, Kameo J, Sato M, Inoue Y, Nonaka K 1998 Nicotinamide decreases cytokine-induced activation of orbital fibroblasts from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 83: 121–124.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer Science+Business Media New York

About this chapter

Cite this chapter

Hiromatsu, Y., Bednarczukt, T. (2001). Role of Cytokines in the Pathogenesis of Graves’ Ophthalmopathy. In: Bahn, R.S. (eds) Thyroid Eye Disease. Endocrine Updates, vol 14. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-1447-3_4

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-1447-3_4

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-5558-8

  • Online ISBN: 978-1-4615-1447-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics