title: Immunopathogenesis of thyroid eye disease: emerging paradigms.
abstract: Graves disease represents a systemic autoimmune process targeting the thyroid, orbit, and pretibial skin. The thyroid dysfunction is treatable, but no consistently effective medical therapy has yet been described for the orbital manifestations of Graves disease, also known as thyroid-associated ophthalmopathy or thyroid eye disease. Several autoantigens are potentially relevant to the pathogenesis of thyroid eye disease. Activating antibodies generated against the thyrotropin receptor can be detected in a majority of patients, and these drive hyperthyroidism. However, stimulating antibodies against the insulin-like growth factor-1 receptor (IGF-1R) may also play a role in the extra-thyroid manifestations of Graves disease. IGF-1R is overexpressed by orbital fibroblasts derived from patients with thyroid eye disease, whereas IGF-1R(+) T and IGF-1R(+) B cells are considerably more frequent in Graves disease. Actions of several cytokines and the molecular interplay peculiar to the orbit appear to provoke the inflammation, fat expansion, and deposition of excessive extracellular matrix molecules in thyroid eye disease. Based upon these new insights, several therapeutic strategies can now be proposed that, for the first time, might specifically interrupt its pathogenesis.
authors.affiliation: Jules Stein Eye Institute, Los Angeles, CA, USA.
authors.forename: Vibhavari M
authors.initials: VM
authors.lastname: Naik
authors.forename: Milind N
authors.initials: MN
authors.lastname: Naik
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goldberg
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Smith
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Douglas
mesh_terms: D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D005347:Fibroblasts / Q000378:metabolism; D049970:Graves Ophthalmopathy / Q000209:etiology* / Q000276:immunology*; D006801:Humans; D009915:Orbit / Q000166:cytology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D017526:Receptor, IGF Type 1
references.citation: Eur J Endocrinol. 2002 Apr;146(4):457-61
references.pmid: 11916611
references.citation: Thyroid. 1993 Winter;3(4):297-300
references.pmid: 7509671
references.citation: Lancet. 1999 Nov 13;354(9191):1691-5
references.pmid: 10568572
references.citation: Am J Physiol. 1998 Mar;274(3):C707-14
references.pmid: 9530102
references.citation: J Immunol. 2003 Jun 15;170(12):6348-54
references.pmid: 12794168
references.citation: Blood. 1994 Oct 15;84(8):2457-66
references.pmid: 7522629
references.citation: Eur J Cancer. 2007 Sep;43(13):1895-904
references.pmid: 17624760
references.citation: Nat Rev Immunol. 2005 Apr;5(4):343-9
references.pmid: 15775994
references.citation: Clin Exp Immunol. 1998 Jun;112(3):427-34
references.pmid: 9649211
references.citation: J Clin Endocrinol Metab. 1999 Nov;84(11):4079-84
references.pmid: 10566653
references.citation: Hum Immunol. 2006 Aug;67(8):618-26
references.pmid: 16916658
references.citation: Am J Pathol. 1997 Aug;151(2):317-22
references.pmid: 9250144
references.citation: J Biol Chem. 1998 Sep 25;273(39):25117-24
references.pmid: 9737970
references.citation: J Immunol. 2005 Mar 1;174(5):3072-9
references.pmid: 15728522
references.citation: Comb Chem High Throughput Screen. 2008 Jan;11(1):62-9
references.pmid: 18220543
references.citation: J Clin Invest. 1990 Sep;86(3):723-7
references.pmid: 2168443
references.citation: J Nucl Med. 2008 Jun;49(6):923-30
references.pmid: 18483104
references.citation: J Clin Endocrinol Metab. 2004 Oct;89(10):5076-80
references.pmid: 15472208
references.citation: J Endocrinol Invest. 2004 Mar;27(3):221-9
references.pmid: 15164997
references.citation: Thyroid. 2007 Oct;17(10):911-22
references.pmid: 17822379
references.citation: Thyroid. 1998 May;8(5):429-32
references.pmid: 9623737
references.citation: Thyroid. 2008 Sep;18(9):953-8
references.pmid: 18713026
references.citation: J Immunol. 2007 Mar 1;178(5):3281-7
references.pmid: 17312178
references.citation: Eye (Lond). 2005 Dec;19(12):1286-9
references.pmid: 15550932
references.citation: Curr Opin Immunol. 2005 Dec;17(6):638-42
references.pmid: 16209918
references.citation: J Dermatol. 1995 Dec;22(12):948-52
references.pmid: 8648004
references.citation: J Neuroophthalmol. 1995 Sep;15(3):166-70
references.pmid: 8574362
references.citation: Br J Haematol. 2004 Apr;125(2):232-9
references.pmid: 15059147
references.citation: J Biol Chem. 1998 Nov 6;273(45):29615-25
references.pmid: 9792671
references.citation: Eur J Endocrinol. 2001 Apr;144(4):311-8
references.pmid: 11275939
references.citation: Endocrinology. 2006 Jan;147(1):13-9
references.pmid: 16210363
references.citation: N Engl J Med. 1993 Nov 11;329(20):1468-75
references.pmid: 8413459
references.citation: J Clin Endocrinol Metab. 2007 Jan;92(1):59-64
references.pmid: 17047020
references.citation: Thyroid. 2002 Mar;12(3):217-21
references.pmid: 11952042
references.citation: Eur J Clin Invest. 1993 Jan;23(1):10-7
references.pmid: 8444271
references.citation: Lancet. 1990 May 26;335(8700):1261-3
references.pmid: 1971331
references.citation: Nat Rev Immunol. 2002 Jun;2(6):389-400
references.pmid: 12093005
references.citation: Clin Exp Immunol. 1993 Mar;91(3):390-6
references.pmid: 8443961
references.citation: J Biol Chem. 2002 May 10;277(19):16355-64
references.pmid: 11847219
references.citation: J Clin Endocrinol Metab. 1996 Sep;81(9):3428-31
references.pmid: 8784110
references.citation: JAMA. 1993 Jan 27;269(4):479-82
references.pmid: 8419666
references.citation: Lancet. 1993 Aug 7;342(8867):337-8
references.pmid: 8101586
references.citation: Curr Opin Immunol. 1997 Oct;9(5):648-54
references.pmid: 9368773
references.citation: J Clin Invest. 1997 Dec 15;100(12):3149-53
references.pmid: 9399962
references.citation: Clin Endocrinol (Oxf). 2006 Jul;65(1):35-9
references.pmid: 16817816
references.citation: Am J Ophthalmol. 1996 Mar;121(3):284-90
references.pmid: 8597271
references.citation: Thyroid. 2008 Sep;18(9):967-71
references.pmid: 18713027
references.citation: Orbit. 2005 Jun;24(2):117-9
references.pmid: 16191800
references.citation: Clin Endocrinol (Oxf). 2000 Mar;52(3):267-71
references.pmid: 10718823
references.citation: J Immunol. 2008 Sep 15;181(6):4397-405
references.pmid: 18768899
references.citation: J Immunol. 1995 Feb 1;154(3):1470-80
references.pmid: 7529804
references.citation: Autoimmun Rev. 2005 Nov;4(8):491-6
references.pmid: 16214084
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8904-9
references.pmid: 9671777
references.citation: J Clin Endocrinol Metab. 2002 May;87(5):2352-8
references.pmid: 11994387
references.citation: J Biol Chem. 2006 Jul 7;281(27):18296-306
references.pmid: 16675443
references.citation: Thyroid. 2003 May;13(5):447-51
references.pmid: 12855011
references.citation: Nat Genet. 2001 Jan;27(1):68-73
references.pmid: 11138001
references.citation: J Immunol. 2002 Jul 1;169(1):424-33
references.pmid: 12077273
references.citation: Clin Exp Immunol. 2003 Dec;134(3):396-402
references.pmid: 14632743
references.citation: J Am Acad Dermatol. 2006 Jul;55(1):143-8
references.pmid: 16781310
references.citation: Thyroid. 2002 Mar;12(3):197-203
references.pmid: 11952039
references.citation: J Clin Endocrinol Metab. 1994 Aug;79(2):542-6
references.pmid: 7913934
references.citation: Horm Metab Res. 2008 Jun;40(6):361-8
references.pmid: 18418812
references.citation: Neurology. 2008 Sep 16;71(12):917-24
references.pmid: 18794494
references.citation: J Immunol. 2005 Oct 1;175(7):4283-91
references.pmid: 16177068
references.citation: J Immunol. 2001 Jul 15;167(2):1072-80
references.pmid: 11441118
references.citation: Ann Oncol. 2003 Apr;14(4):520-35
references.pmid: 12649096
references.citation: J Mammary Gland Biol Neoplasia. 2006 Jan;11(1):27-39
references.pmid: 16947084
references.citation: J Immunol. 2005 Apr 15;174(8):4525-34
references.pmid: 15814673
references.citation: J Clin Invest. 2004 Oct;114(7):979-87
references.pmid: 15467837
references.citation: Endocr Rev. 2003 Dec;24(6):802-35
references.pmid: 14671007
references.citation: J Immunol. 2008 Oct 15;181(8):5768-74
references.pmid: 18832736
references.citation: J Immunol. 2004 Sep 1;173(5):3564-9
references.pmid: 15322222
references.citation: J Clin Endocrinol Metab. 2000 Feb;85(2):776-80
references.pmid: 10690890
references.citation: Clin Immunol. 2005 Apr;115(1):3-9
references.pmid: 15870014
references.citation: Nat Rev Immunol. 2006 Mar;6(3):205-17
references.pmid: 16498451
references.citation: J Exp Med. 1991 Mar 1;173(3):759-62
references.pmid: 1847724
references.citation: Eur J Immunol. 2005 May;35(5):1347-59
references.pmid: 15832291
references.citation: Clin Endocrinol (Oxf). 1994 Jan;40(1):67-72
references.pmid: 8306483
references.citation: J Clin Endocrinol Metab. 2002 Jan;87(1):385-92
references.pmid: 11788681
references.citation: Eur J Endocrinol. 2006 May;154(5):623-32
references.pmid: 16645007
references.citation: Am J Ophthalmol. 1996 Apr;121(4):426-34
references.pmid: 8604736
references.citation: J Clin Endocrinol Metab. 1999 Jul;84(7):2557-62
references.pmid: 10404836
references.citation: J Clin Endocrinol Metab. 2003 Jan;88(1):132-5
references.pmid: 12519841
references.citation: J Immunol. 1998 May 15;160(10):4841-9
references.pmid: 9590231
references.citation: Clin Sci (Lond). 1994 Feb;86(2):141-8
references.pmid: 8143424
references.citation: J Immunol. 1994 Mar 1;152(5):2190-7
references.pmid: 7510740
references.citation: Res Immunol. 1994 Mar-Apr;145(3):200-5; discussion 244-9
references.pmid: 7527576
references.citation: Int Immunopharmacol. 2006 Jun;6(6):880-91
references.pmid: 16644473
references.citation: Arthritis Rheum. 2004 Aug;50(8):2580-9
references.pmid: 15334472
references.citation: Nat Clin Pract Rheumatol. 2008 Nov;4(11):605-14
references.pmid: 18813220
references.citation: Autoimmunity. 2003 Sep-Nov;36(6-7):409-15
references.pmid: 14669949
references.citation: N Engl J Med. 2004 Jun 17;350(25):2572-81
references.pmid: 15201414
references.citation: N Engl J Med. 2002 May 30;346(22):1692-8
references.pmid: 12037148
references.citation: N Engl J Med. 2005 Jun 23;352(25):2598-608
references.pmid: 15972866
references.citation: Thyroid. 2006 Jul;16(7):709-10
references.pmid: 16889501
references.citation: Clin Rev Allergy Immunol. 2008 Feb;34(1):118-23
references.pmid: 18270865
references.citation: J Immunol. 2002 Jan 15;168(2):942-50
references.pmid: 11777993
references.citation: J Clin Invest. 2003 Jul;112(2):286-97
references.pmid: 12865416
references.citation: J Mol Endocrinol. 2003 Jun;30(3):369-80
references.pmid: 12790806
references.citation: Lancet. 1986 Jul 26;2(8500):219-20
references.pmid: 2873461
references.citation: Am J Ophthalmol. 2006 Jul;142(1):147-153
references.pmid: 16815265
references.citation: Int Arch Occup Environ Health. 1997;69(3):157-64
references.pmid: 9049666
references.citation: J Exp Med. 1997 Apr 21;185(8):1413-22
references.pmid: 9126922
references.citation: Eur J Endocrinol. 2006 Apr;154(4):511-7
references.pmid: 16556712
references.citation: BMC Ophthalmol. 2007 Apr 26;7:8
references.pmid: 17462097
references.citation: Nat Immunol. 2006 Apr;7(4):344-53
references.pmid: 16550197
references.citation: Arthritis Rheum. 2005 Feb;52(2):501-13
references.pmid: 15693003
references.citation: Clin Exp Immunol. 1989 Feb;75(2):222-7
references.pmid: 2784734
references.citation: Eur J Endocrinol. 2005 May;152(5):777-84
references.pmid: 15879364
references.citation: Trans Am Ophthalmol Soc. 1994;92:477-588
references.pmid: 7886878
references.citation: Am J Physiol. 1999 Dec;277(6):C1075-85
references.pmid: 10600759
references.citation: Expert Opin Biol Ther. 2007 Jul;7(7):1061-78
references.pmid: 17665994
references.citation: Clin Endocrinol Metab. 1978 Mar;7(1):31-45
references.pmid: 580600
references.citation: Nat Immunol. 2002 Oct;3(10):944-50
references.pmid: 12244307
references.citation: Clin Endocrinol (Oxf). 2004 Jun;60(6):726-33
references.pmid: 15163337
references.citation: Clin Gastroenterol Hepatol. 2008 Jun;6(6):644-53
references.pmid: 18550004
references.citation: Nat Med. 2004 Aug;10(8):801-5
references.pmid: 15286781
references.citation: Clin Endocrinol (Oxf). 2004 Nov;61(5):612-8
references.pmid: 15521965
references.citation: Exp Eye Res. 1997 Aug;65(2):311-6
references.pmid: 9268599
references.citation: J Immunol. 2000 Dec 15;165(12):7262-9
references.pmid: 11120860
references.citation: Blood. 2004 Nov 15;104(10):3021-7
references.pmid: 15284119
references.citation: Exp Clin Endocrinol Diabetes. 1999;107 Suppl 3:S75-8
references.pmid: 10522810
references.citation: Klin Oczna. 2007;109(10-12):457-60
references.pmid: 18488396
references.citation: Eye (Lond). 1998;12 ( Pt 2):237-44
references.pmid: 9683947
references.citation: Autoimmun Rev. 2003 Mar;2(2):101-8
references.pmid: 12848966
references.citation: Ann Rheum Dis. 2008 Dec;67 Suppl 3:iii64-5
references.pmid: 19022817
references.citation: J Endocrinol Invest. 2004 Mar;27(3):216-20
references.pmid: 15164996
references.citation: Arch Ophthalmol. 2005 Jan;123(1):119-21
references.pmid: 15642828
references.citation: Ophthalmology. 1984 Nov;91(11):1411-9
references.pmid: 6240008
references.citation: Am J Pathol. 2003 Oct;163(4):1291-300
references.pmid: 14507638
references.citation: Am J Physiol. 1995 Feb;268(2 Pt 1):C382-8
references.pmid: 7864077
references.citation: Clin Exp Immunol. 2005 Mar;139(3):526-33
references.pmid: 15730399
references.citation: Invest Ophthalmol Vis Sci. 1988 Feb;29(2):175-84
references.pmid: 2448263