Time-dependent stabilisation of the TSH-TSH receptor complex.
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Biomedical subjects
Publications and source records attributed to B R Smith.
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Patients with Graves' disease (n = 105) had an increased frequency of HLA-B8 (40%) and a reduced frequency of HLA-B12 (24.8%) when compared with random controls (n = 117; 24.8% and 40.2% respectively). Comparison of patients with their first degree relatives (n = 118) shows the frequency deviations in these antigens to be characteristic of the families from which patients with Graves' disease are drawn, rather than of the disease itself. The haplotypes, identified in eight-six patients and 113 relatives, indicate that the excess of HLA-B8 in patients and their relatives is primarily due to the halpotype 1-8. The relative risk for an HLA-B8 individual of developing Graves' disease is 2.02, whilst the relative risk for an individual of haplotype 1-8 is 4.23. No significant associations were found between the incidence of any HLA antigen or combination thereof and the presence or absence of thyroglobulin and thyroid microsomal antibodies, or antibodies which interact with the TSH receptor.
Isolated porcine thyroid cells were surface-labelled with 125I using the lactoperoxidase technique. Samples of the cells were then cultured and harvested at various intervals for up to 7 days. The labelled proteins remaining on the cells or shed into the culture medium were analysed by electrophoresis on polyacrylamide gels run in sodium dodecyl sulphate. These studies indicated that the several different surface proteins of the thyroid cells were lost from the cell surface at similar rates (half-time of approximately 28 h) as the result, at least in part, of a process which depended on active cell metabolism. In addition, the gel profiles obtained from analysis of both medium and membrane-bound labelled proteins were similar and this suggested that peptide cleavage was not involved in the shedding of the majority of these proteins.
A current hypothesis suggests that autoimmune responses are prevented in normal individuals by a population of suppressor cells. We have investigated this using a system in which thyroid autoantibodies are synthesised in culture by peripheral blood mononuclear cells (PBM) from patients with Hashimoto's thyroiditis. A group of 8 Hashimoto patients and 17 normal subjects were used in the study. PBM from the group of patients did not differ significantly from those of the control group in terms of their ability to synthesise IgG in culture, to respond to allogeneic cells or to PHA. (Nor were any genetic differences observed between the two groups in terms of HLA-A, B or C antigens.) In 6 co-culture experiments involving equal numbers of PBM from patients and normal donors, inhibition of thyroid antibody production was not observed. Additionally, T-cell enriched populations from 2 normal donors were unable to specifically inhibit thyroid antibody synthesis by Hashimoto B-cell enriched fractions from 2 Hashimoto patients. Consequently, we were unable to show suppressor cell activity in normal PBM and it is suggested that these cells may need to be activated by antigen before their presence can be demonstrated.
Extrapolation of in vitro data to predict occurrences in vivo is an uncertain process at best. In this study, clearance concepts initially developed to describe elimination of drugs and other substances by kidney and liver have been extended to calculate pulmonary extraction of circulating benzo(a)pyrene 4,5-oxide. Apparent kinetic parameters (Km and Vmax) for pulmonary microsomal epoxide hydrolase and cytosolic glutathione S-transferase were estimated by using in vitro enzyme assays, and whole tissue Vmax values of the two epoxide-metabolizing pathways were determined. From these data, a whole organ extraction ratio for benzo(a)pyrene 4,5-oxide was derived. The calculated extraction ratio (nearly one) was greater than, but in reasonable agreement with, the measured extraction ratio determined by using isolated perfused rabbit lungs exposed to circulating benzo(a)pyrene 4,5-oxide. The actual extraction ratio was 0.64 +/- 0.04 (x +/- S.D.,N = 3), which indicated that the rabbit lung was capable of removing a large percentage of circulating benzo(a)pyrene 4,5-oxide in a single pass through the organ. Therefore, the lung may play an important role in removing and biotransforming circulating arene oxides, as the entire cardiac output passes through the pulmonary capillary bed.
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Irradiated lymphocytes have been found to stimulate thyroid-autoantibody synthesis by lymphocyte cultures. It is proposed that a similar effect is involved in the increased autoimmune response which follows radioiodine treatment for Graves' disease.
Microsomal and thyroglobulin autoantibody activity has been detected in synovial fluid from 34 of 50 patients with various arthritides (rheumatoid arthritis, ankylosing spondylitis, osteoarthrosis, and gout). Serum from only 4 of these patients showed thyroid-autoantibody activity, and the serum titres were considerably lower than the synovial-fluid titres. This suggests that thyroid autoantibody is produced locally in the joints of these patients.
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Prazosin hydrochloride, an oral antihypertensive, is reported to inhibit phosphodiesterase and block postsynaptic alpha-adrenergic receptors, intraocular pressure (IOP) in rabbits was reduced in a dose-related manner following topical ocular application of concentrations of 0.0001% to 0.1%. The ocular hypotensive response lasted six to eight hours with a maximum effect at approximately two hours. The IOP of unilaterally sympathectomized rabbits treated in both eyes with prazosin decreased more in the normal eyes than in the sympathectomized eyes. Treatment of only the unsympathectomized eyes of these rabbits elicited a similar response. Normal rabbits elicited a similar response. Normal rabbits treated in only one eye also showed a slight response in the contralateral eye. Preliminary experiments did not support the hypothesis that these effects were due to a decrease of systemic blood pressure. No substantial ocular toxicity or pupillary changes were observed.
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A patient with previously treated follicular carcinoma of the thyroid developed Graves' disease with a high titre of thyroid-stimulating antibodies (TSAb). He developed functioning pulmonary metastases leading to hyperthyroidism. Levels of TSAb paralleled the functional status of the metastases suggesting that hyperfunction of the neoplastic tissues was caused by TSAb.
We have studied the effects of 131I therapy on thyrotrophin binding inhibiting immunoglobulins (TBII) in fifty-five patients with Graves' disease and five patients with toxic multinodular goitre (MNG). A group of forty patients with Graves' disease and four patients with toxic MNG were treated with drugs and acted as controls. In 78% of patients treated with 131I there was a marked increase in the serum TBII activity during the 3 months following therapy, whereas drug-treated patient showed a decrease (77%) or no change in TBII activity over the same period. TBII activity was not detectable in patients with toxic MNG before or after drug or 131I therapy. Consideration of the mechanisms involved in the changes in serum TBII activity after 131I treatment or during drug treatment provide insight into the basic defects responsible for the development of hyperthyroid Graves' disease and suggest that both the thyroid and immune system are involved.