Pathogenesis of Thyroid-Associated Ophthalmopathy: An Autoimmune Disorder of the Eye Muscle Associated with Graves' Hyperthyroidism and Hashimoto's Thyroiditis

Wall, Jack R.; Bernard, Nicole F.; Boucher, Andrée; Salvi, Mario; Zhang, Z.G.; Kennerdell, John S.; Tyutyunikov, Anna; Genovese, Christine

doi:10.1006/clin.1993.1087

Cited by 53 publications

(27 citation statements)

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“…Purified recombinant 1D3 stimulated one TAO and one control PBMC preparation; this is compatible with the presence of autoantibodies to this protein in normal subjects and patients with autoimmune thyroid disease [27]. Our findings are in contrast to preliminary results indicating that T cell responses to Dl are found in a third of TAO patients but are absent in normal subjects [12]. We also confirmed the low frequency of orbital antigen-sensitized T cells using the IFN-7 ELISPOT assay, which quantifies the number of T cells responding to an antigen [19].…”

Section: Discussionsupporting

confidence: 84%

T cell responses to orbital antigens in thyroid-associated ophthalmopathy

Arnold

Tandon

McIntosh

et al. 1994

Clinical and Experimental Immunology

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SUMMARYThyroid-associated ophthalmopathy (TAO) is most likely to be a T cell-mediated disease, in which cytokines released in the extraocular muscles activate fibroblasts, increasing glycosaminoglycan production. The nature of the orbital antigen recognized by the infiltrating T cells is unclear, although it is possible that there is cross-reactivity between this and a thyroid autoantigen to explain the close association with thyroid autoimmunity. We have tested the ability of human and porcine eye muscle antigen preparations to stimulate proliferation of circulating T cells from healthy subjects and patients with TAO or Graves' disease without clinical TAO. Occasional responses were seen, particularly after depletion of CD8"^ T cells, and two out of 10 TAO patients responded to eye muscle proteins of 25-50 kD after fractionation of antigens on gels and subsequent elution. There was no disease-specific response ofT cells to Rl, R14, Dl and 1D3, recombinant proteins identified from screening an eye muscle cDNA library with sera from patients with autoimmune thyroid disease. We have also found that interferon-gamma (IFN-7) production by T cells from TAO patients was not stimulated by eye muscle membrane antigens or by 1D3. These results suggest that the frequency of circulating T cells responding to eye muscle antigens in TAO is low, and that several candidate orbital antigens, including the 64-kD protein 1D3, are unlikely to be important T cell autoantigens in this condition.

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Section: Discussionsupporting

confidence: 84%

T cell responses to orbital antigens in thyroid-associated ophthalmopathy

Arnold

Tandon

McIntosh

et al. 1994

Clinical and Experimental Immunology

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“…[4,5] In an earlier study, T lymphocytes obtained from orbital tissue and peripheral blood of TAO patients were activated by protein fractions from the eye muscles and OCT. [6] We have postulated that a shared auto-antigen in the orbit and thyroid gland, such as G2s or the TSH receptor (TSHR), is the target(s) of the cellular and humoral immune reactions in TAO. [3,7,8] Of the several eye muscle antigens that have been identified as targets for autoantibodies in TAO (reviewed in Ref. [3]), the novel protein G2s, which is strongly expressed in eye muscles, thyroid and other skeletal muscles, [9] the "55 kDa eye muscle membrane protein" identified in our earlier studies (reviewed in Ref.…”

Section: Introductionmentioning

confidence: 99%

Peripheral Blood Lymphocyte Transformation to G2s in Patients with Autoimmune Thyroid Disease with and without Ophthalmopathy

et al. 2002

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Thyroid associated ophthalmopathy (TAO) is an autoimmune disease involving the extra ocular muscles and surrounding orbital connective and adipose tissues. The mechanism for the link between ophthalmopathy and thyroid autoimmunity is unknown but current evidence favors an immune reaction against a thyroid and orbital tissue shared antigen such as the novel protein G2s, which is highly expressed in both eye muscles and thyroid, or the TSH receptor (TSHR). Earlier, we showed that serum antibodies against G2s were closely linked to ophthalmopathy. Although lymphocytic infiltration of the eye muscles is a pathologic feature of TAO, it is unclear whether the reaction is in the eye muscle fiber or the surrounding connective tissue. We tested for peripheral blood mononuclear cell sensitization to G2s fusion protein in patients with TAO, Graves' hyperthyroidism or Hashimoto's thyroiditis without evident ophthalmopathy and normal subjects. Results were expressed as counts per min (cpm) and as stimulation indices (SI). Although proliferation tests were positive in 23% of patients with TAO, overall, there were no significant differences between the four groups. Tests were also positive in four out of seven patients with Hashimoto's thyroiditis, suggesting that immune reactivity against G2s could be a marker of this progressive thyroid disorder. There was no significant correlation between T cell reactivity to G2s and serum antibodies against the same protein, measured in enzyme linked immunosorbent assay. Failure to demonstrate significant T lymphocyte sensitization to G2s in the majority of patients with TAO may reflect the small number of sensitized T cells expected to be circulating in the peripheral blood which could be overcome by testing cloned orbital T cells, as available. Another possibility is that the T cell epitope(s) is not present on the 141 amino acid fragment of G2s that we have so far cloned. The finding of positive T cell tests in a small proportion of patients with ophthalmopathy suggests that future studies using cloned orbital T cells and full length G2s, or its dominant epitope, are indicated.

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“…2, mild gastritis in case No. 4 however, often controversial and not satisfactory, especially in the case of diplopia or proptosis [31][32][33]. Although the most effective of the drugs used for immune suppression seem to be steroids, high oral dosage is necessary for a long time, and causes serious adverse effects [16].…”

Section: Resultsmentioning

confidence: 99%

“…Although it also occurs, occasionally, in patients without hyperthyroidism, they often show some abnormalities in thyroid function and immunology [1]. TAO seems to be caused by an autoimmune mechanism related to the thyroid [2][3][4]. Various immunosuppressive therapies have been reported, including systemic steroids [5], retrobulbar steroids [6], azathioprine [7], cyclophosphamide [8], cyclosporine [9,10], plasmapheresis [11,12], high-dose immunoglobulin [13] and combinations thereof [14,15].…”

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confidence: 99%

High-Dose Intravenous Steroid Pulse Therapy in Thyroid-Associated Ophthalmopathy.

et al. 1996

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Abstract. To evaluate the efficacy of high-dose intravenous steroid pulse followed by oral steroids in the treatment of thyroid-associated ophthalmopathy, we performed clinical assessment and measurement of retroorbital muscle enlargement in 27 patients before and after the therapy, and followed them up longitudinally.The mean duration of follow up is (mean ± SD) 29.8 ± 23.8 months (range 4-92). Diplopia disappeared in 10 patients and ameliorated in 11 patients. The degree of proptosis decreased in 15 patients and the fall in visual acuity improved in a third of the patients. The total ophthalmopathy index (01) decreased from 7.0 ± 1.9 to 3.0 ± 1.5. The extraocular muscle enlargement (EME), expressed as the maximal ratio of extraocular muscle thickness to the diameter of the optic nerve, decreased from 2.33 ± 0.56 to 1.27 ± 0.26. No major side effects were found in any patient. The improvement in the eye disease was found immediately after the pulse therapy, prior to the start of the following therapy by oral steroids and/or orbital irradiation. Both of OI and EME decreased with time after the therapy and did not get worse after withdrawing oral steroids. The efficacy of the therapy evaluated by degrees of improvement in 01 and in EME was significantly greater in females than in males. Although there was a significant positive correlation between initial OI and EME values and initial TBII and TSAb activities, a significant correlation was seen only between the degrees of improvement in EME and changes in TBII activity due to the therapy. The duration of eye disease, thyroid status, treatment with anti-thyroid drug, smoking and experience of previous treatment did not affect the efficacy of the present therapy. We conclude that high-dose intravenous steroid pulse therapy is effective and safe for thyroid-associated ophthalmopathy.

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Pathogenesis of Thyroid-Associated Ophthalmopathy: An Autoimmune Disorder of the Eye Muscle Associated with Graves' Hyperthyroidism and Hashimoto's Thyroiditis

Cited by 53 publications

References 0 publications

T cell responses to orbital antigens in thyroid-associated ophthalmopathy

T cell responses to orbital antigens in thyroid-associated ophthalmopathy

Peripheral Blood Lymphocyte Transformation to G2s in Patients with Autoimmune Thyroid Disease with and without Ophthalmopathy

High-Dose Intravenous Steroid Pulse Therapy in Thyroid-Associated Ophthalmopathy.

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