Pappa, Anastasia; (1998) Pathogenic mechanisms in thyroid-associated ophthalmopathy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Thyroid-associated ophthalmopathy (TAO) is a disfiguring and potentially sight-threatening manifestation of autoimmune thyroid disease. Current therapy is limited to addressing the complications of the disease which include exposure keratitis, impairment of eye movements due to extraocular muscle (EOM) inflammatory involvement, and optic nerve compression with possible loss of vision. TAO is characterised by mononuclear cell infiltration, many of which are T cells, of the EOMs and/or the orbital fat/connective tissue with associated deposition of glycosaminoglycans (GAGs) in the interstitial spaces. In this thesis, the presence and distribution of the vascular adhesion molecules ICAM-1, ELAM-1, VCAM-1 and the leukocyte integrins CD11a/CD 18, CD11b/CD18, CD11c/CD18 were investigated, by immunohistochemistry, on EOM biopsies harvested from early, active and late, inactive TAO patients as well as non-TAO strabismus control subjects. Because of small biopsy size, on different EOM biopsies collected from the same groups of patients the mononuclear cell infiltrate as well as the expression and localisation of HLA-DR were also characterised immunohistochemically. Further EOM biopsies were taken from TAO patients and the infiltrating T cells were isolated and expanded in vitro with mitogen. Their phenotype was determined by FACS analysis and compared to peripheral blood-derived T cell lines, grown in vitro in the same way, from the same patient. Cytokines present in the supernatant after mitogen stimulation of the T cell lines, were assayed by ELISA techniques. Moreover, the pattern of cytokine gene expression in EOMs was studied ex vivo in biopsies taken from different TAO patients, and results were compared with the data derived from the T cell lines. With the T cell lines from two patients, proliferation assays were carried out using antigens derived from thyroid gland, EOM and a TSH-receptor preparation. In addition, the presence and localisation of GAGs on TAO and control EOM biopsies was examined by transmission electron microscopy and immunogold staining. Serum hyaluronan was measured using a radioimmunoassay in patients with TAO as well as control subjects, and urinary GAG levels assessed by photometric quantitation of hexuronic acid after reaction with carbazole. Finally, the excretion pattern of the urinary GAGs was determined by means of discontinuous electrophoresis.

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