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PubMed1992

The regulation of thyroid hormone receptor beta genes by thyroid hormone in Xenopus laevis.

The mRNA level of the two Xenopus laevis thyroid hormone receptor beta (TR beta) genes is up-regulated in tadpoles and cultured cells by the addition of thyroid hormone (TH). Up-regulation of transcripts of the 5' most exon is detectable 2-3 h before that of full-length TR beta mRNA, strongly suggesting that up-regulation is under transcriptional control. The TH-induced up-regulation in cultured cells is inhibited by cycloheximide when measured either by a transcription initiation assay that measures transcripts of the 5' most exon or by synthesis of full-length TR beta mRNA. From this we conclude that in cultured cells protein synthesis is required for up-regulation of TR beta mRNA. The up-regulation of TR beta mRNA by TH in tadpoles is only partially inhibited by protein synthesis inhibitors. A survey of "thyroid response" genes in the literature reveals that the reported change in gene expression is, in most cases, sensitive to protein synthesis inhibition. This is true of genes with demonstrable thyroid hormone response elements. If an unknown protein must be synthesized to effect up-regulation of a thyroid hormone response gene, it calls into question assays that only take into account the binary reaction between thyroid hormone receptor and a putative thyroid hormone response element.

Animals↗
PubMed1990

Coated vesicles from thyroid cells carry iodinated thyroglobulin molecules. First indication for an internalization of the thyroid prohormone via a mechanism of receptor-mediated endocytosis.

We have tried to identify iodinated thyroglobulin molecules in purified thyroid-coated vesicles to determined whether the internalization of the thyroid prohormone could proceed via a mechanism of receptor-mediated endocytosis. Coated vesicles isolated from pig thyroids by differential centrifugation and centrifugation on 2H2O-sucrose cushion were characterized by transmission electron microscopy and analyses of the polypeptide composition by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and Western blot using anti-clathrin heavy chain and anti-thyroglobulin antibodies. Clathrin and thyroglobulin (Tg) appeared as the two major components of the purified thyroid coated vesicles (TCV). Purified TCV fraction was homogeneous when analyzed by isopycnic centrifugation on 30% Percoll gradient. TCV had an apparent buoyant density of 1.035 g/ml. The presence of Tg molecules inside TCV was ascertained by (a) immunogold labeling on cryosections of TCV pellet and (b) identification by gel electrophoresis and radio-immunoassay of a definite fraction of Tg (3-5% of total protein) in TCV treated by Triton X-100. The detergent-treated TCV also contained protein-bound iodine: 0.5-0.7 micrograms of iodine/mg protein. Pulse-chase experiments on in vitro reconstituted thyroid follicles have been used to further document the presence of iodinated Tg molecules in coated vesicles. TCV were isolated from reconstituted thyroid follicles previously labeled with [125I]iodide to radioiodinate Tg of the follicular lumen (the pre-endocytotic compartment) and incubated with or without thyrotropin or dibutyryl cyclic AMP to activate intraluminal 125I-Tg endocytosis. Autoradiographic analyses revealed the presence of 125I-Tg in purified TCV and Triton X-100-treated TCV. 125I-Tg present in TCV represented 1-2% of the total intracellular protein-bound radioactivity. Thyrotropin and dibutyryl cyclic AMP increased 2-3-fold the 125I-Tg content of TCV. Our results clearly show that iodinated Tg, the molecular form of the thyroid prohormone known to be internalized, is present into TCV. The data suggest that coated vesicles are involved in the uptake and transport of Tg from the follicular lumen to the lysosomal compartment and therefore, that the internalization of Tg could proceed, at least for a part, via a mechanism of receptor-mediated endocytosis.

Animals↗
PubMed1990

The relationship between Hashimoto's thyroiditis, thyroid neoplasia, and primary hyperparathyroidism.

The relationship between Hashimoto's thyroiditis and follicular cell carcinoma of the thyroid remains controversial. Hashimoto's thyroiditis is regarded by some as a premalignant lesion for which thyroidectomy is definitely indicated. In contrast, other investigators have found no increased evidence of thyroid carcinoma in patients with this disease. As a result, the management of thyroid nodules in patients with Hashimoto's thyroiditis remains highly individualized. A program for the management of patients with chronic Hashimoto's thyroiditis with co-existing neoplasia or primary hyperparathyroidism is outlined.

Adenocarcinoma↗
PubMed1990

Thyrotropin (TSH) action on thyroid hormone deiodination and secretion: one aspect of thyrotropin regulation of thyroid cell biology.

TSH, the major signalling factor for the thyroid follicles, controls thyrocyte function in concert with other modulators of cell growth, differentiation and structural organization of the follicular-endothelial network. Most of the TSH effects are mediated by TSH binding to the TSH receptor which stimulates adenylate cyclase catalyzed cAMP production. TSH is involved in the regulation of thyroidal uptake of small molecules and nutrients, intracellular transport of thyrocyte specific proteins, and in most of the steps of thyroid hormone synthesis, storage and release. These cellular events require the fine tuned regulation of metabolic reactions, morphological differentiation and cell proliferation. Thyrocytes also express a highly active Type I iodothyronine 5' deiodinase which is controlled by TSH stimulated cAMP production. The thyrocyte specific 5' deiodinase isozyme has marked influence on the amount of T3 secreted by the thyroid. This 5' deiodinase isozyme shows most of the characteristics of the type I 5' deiodinase found in liver and kidney and is also blocked by PTU, other 5' deiodinase inhibitors, and iodinated X-ray contrast agents such as iopanoic acid, which are occasionally used in thyrotoxicosis to inhibit thyroidal T3-production by this enzyme. In contrast to the liver and kidney type I 5' deiodinase T4 and T3 are not able to induce this enzyme in thyrocytes. However, TSH stimulated cAMP production increases the thyroidal isozyme activity in contrast to the liver and kidney enzyme. This review summarizes the data on the various experimental models used up to date to characterize the thyroidal type I 5' deiodinase in various species including man.

Animals↗
PubMed1990

Thyrotropin receptors, thyroid hormones and thyroglobulin in patients with Hashimoto's thyroiditis.

TSH receptors in plasma membranes of thyroid nodular and perinodular tissue and the concentration of thyroid hormones and thyroglobulin in serum were estimated in patients with Hashimoto's thyroiditis (HT) and in six persons with scintigraphically cold thyroid nodules (AFN). In perinodular tissue of HT patients specific binding of 125I-bTSH was found to be significantly decreased (1.50 +/- 0.13%; mean +/- S.E.) as compared with AFN patients (2.79 +/- 0.53%), whereas any significant difference in hormone binding to nodular tissues between both examined groups was not detected. Scatchard analysis of TSH binding revealed two kinds of binding sites for both thyroid tissues of all examined patients. The capacity of high affinity binding sites in both thyroid tissues of HT patients was found to be decreased (3.92 +/- 0.86 fmol/mg protein in nodular tissue and 5.93 +/- 1.16 fmol/mg protein in perinodular tissue) in comparison with these tissues of AFN patients (18.80 +/- 18.36 and 32.24 +/- 33.38, respectively). Any differences in dissociation constant and capacity of low affinity binding sites between analysed groups were not observed. Serum TSH levels of HT patients were higher than these in AFN patients and were not significantly changed after surgical treatment. Any difference in triiodothyronine (T3) levels between analysed groups was not detected, while the concentration of thyroxine (T4) was lower in HT than in AFN and significantly decreased after the excision of thyroid gland. Thyroglobulin levels were significantly changed after surgical treatment in both analysed groups.

Adult↗
PubMed1985

[Antigenic relation between thyroid peroxidase and the microsomal antigen implicated in auto-immune diseases of the thyroid].

Pools of sera from patients with Graves' disease or Hashimoto's thyroiditis highly inhibit the binding to human thyroid membranes of one of 19 monoclonal antibodies raised against preparations of human thyroid membranes. This monoclonal antibody reacts with human and bovine thyroid peroxidase and bovine lactoperoxidase but not with human hemoglobin, cytochrome c and other related molecules. These results indicate that the thyroid peroxidase and the microsomal antigen are antigenically related. These data taken together with those from other groups, highly suggest that thyroid peroxidase is the microsomal antigen involved in autoimmune thyroid diseases.

Adult↗
PubMed1989

'Natural' desiccated thyroid. A 'health-food' thyroid preparation.

"Natural" thyroid preparations, a type of bovine desiccated thyroid, are sold without prescription in "health-food" stores or by mail; they may or may not contain thyroid hormone. One such preparation was the cause of erratic thyroid test results in a patient who took it instead of thyroxine. Further study showed that the preparation contained biologically active thyroid hormone and was capable of causing hyperthyroidism. Natural thyroid preparations are biologically active yet unstandardized; because the hormonal content of a natural thyroid product is unknown, its use as a substitute for thyroxine can lead either to relapse of hypothyroidism or to hyperthyroidism.

Adult↗
PubMed1987

Cells infiltrating the thyroid in juvenile autoimmune thyroiditis.

Cell samples derived from the thyroid glands of twelve children with juvenile autoimmune thyroiditis (JAIT) were analysed. The cytological findings were those of chronic lymphocytic thyroiditis in eight and suggestive of that disease in four patients. About 86% of the cells infiltrating the thyroid were lymphocytes, 4% were lymphoid blasts, 6% neutrophils and 3% monocytes. Analysis using monoclonal antibodies showed that about 60% of the lymphocytes were T cells and half of the lymphocytes expressed HLA Class II-antigens. T helper cells dominated with a T helper/suppressor ratio of 2.2 in thyroid while the ratio was 1.2 in peripheral blood. Of the thyroid epithelial cells, 80% also expressed HLA class II. The immune activation and immunoglobulin synthesis within the thyroid are discussed.

Antibodies, Monoclonal↗
PubMed1986

In vivo activated cytotoxic T cells in the thyroid infiltrate of patients with Hashimoto's thyroiditis.

High proportions of T8+ cells with inverted T4/T8 ratio were found in freshly isolated thyroid lymphocytes from patients with Hashimoto's thyroiditis. In addition, about one third of thyroid infiltrating cells expressed the TAC antigen, whereas in patient peripheral blood (PB) or normal lymphocytes from PB or lymphoid organs the percentage of TAC-positive cells was consistently lower than 10%. Following negative selection with OKT4 or OKT8 monoclonal antibodies and complement, TAC+ T cells were enriched in the T8+ cell population. Thyroid infiltrating T cells from two patients underwent two different cloning procedures. In the first, single T cells were initially activated with phytohaemagglutinin (PHA) and interleukin 2 (IL-2), in the other with recombinant IL-2 (rIL-2) alone. The majority of T cell clones obtained by initial PHA-stimulation (55-65%) had the T8+ phenotype, but the frequency of T8+ clones obtained by stimulating T cells with rIL-2 alone was even higher (78 & 71%, respectively). The majority of T8+ clones elicited by PHA (35/37 & 36/38) and all the T8+ clones (36/36 & 22/22) obtained from thyroid infiltrates with initial stimulation by rIL-2 displayed cytolytic activity. Most of cytolytic T8+ clones obtained from thyroid infiltrates with both cloning procedures, displayed NK activity against human K562 and MOLT-4 target cells, but not against a NK-resistant target, such as Raji cells. These data suggest that in Hashimoto's disease a considerable proportion of thyroid infiltrating T cells are in vivo activated T8+ cytolytic T cells with NK activity, which may be of importance in determining or maintaining the tissue damage of the target gland.

Adult↗
PubMed1987

Thyroid cell MHC class II antigens: a perspective on the aetiology of autoimmune thyroid disease.

An association exists between certain MHC polymorphisms and autoimmune thyroid disease in animals and humans. The observation of MHC class II antigen expression by the thyroid suggests that such associations may have mechanistic explanations at the level of the thyroid cell. Such class II antigen expression, rather than being a constitutive property of thyroid epithelium, appears to be primarily mediated by lymphokine secretion from intrathyroidal T lymphocytes and a variety of agents, for example TSh and TSH receptor antibodies, may amplify such lymphokine action. Thyroid cell class II antigens participate in activation and amplification of T cells and are involved in presentation of thyroid antigen to the immune system. The relationship between these local immune interactions and the initial events leading to the development of autoimmune thyroid disease requires a more fundamental understanding of the workings of the immune system at the site of antigenic stimulation.

HLA-D Antigens↗
PubMed1986

Subpopulations of thyroid autoantibody secreting lymphocytes in Graves' and Hashimoto thyroid glands.

Lymphocytes isolated from Graves' and Hashimoto thyroid tissue by enzymatic (dispase) digestion or mechanical disaggregation were markedly different in terms of their ability to synthesize thyroid autoantibodies in culture. Dispase digestion, followed by removal of thyroid follicular cells, gave a lymphocyte population with a high T:B cell ratio (6:1). However, the ability of these cell suspensions to synthesize microsomal (Mic) and thyroglobulin (Tg) antibodies spontaneously was significantly increased compared with lymphoid suspensions isolated by mechanical means. Spontaneous synthesis of thyroid autoantibodies was not markedly enhanced in cell suspensions prepared from patients' lymph node tissue by digestion compared with mechanical disaggregation. Further, Mic and Tg antibody production by thyroid lymphocytes prepared using dispase was inhibited by pokeweed mitogen (PWM) whereas in most cases suspensions prepared from the same tissues by mechanical dispersion synthesized low or undetectable levels of autoantibodies whether PWM was present or absent. Digestion of tissue debris remaining after mechanical removal of lymphocytes gave suspensions which had an increased proportion of suppressor/cytotoxic T cells compared with suspensions produced mechanically or by digestion alone; however, in terms of spontaneous autoantibody synthesis and PWM induced inhibition, these suspensions were similar to these obtained by digestion alone. It would therefore seem that enzymatic digestion of thyroid tissue resulted in the isolation of a lymphoid population which was different from that extracted by mechanical disaggregation. The digestion process appears to permit the recovery of lymphocytes closely associated with thyroid follicular cells and our studies suggest that it is this population which makes the major contribution to autoantibody synthesis.

Adult↗
PubMed1986

[Detection of thyroid cancer : utopia or reality? Or the value of thallium 201 in thyroid pathology].

Faced with a diagnosis of cold thyroid nodule as evidenced by routine scintigraphy, the clinician has to determine whether this nodule is malignant or not. This is a serious problem since, according to literature, 7-20% of cold thyroid nodules are malignant. In 1982 some Japanese authors demonstrated the possibility of using 201 T1 in diagnosing thyroid tumors. This study refers to 120 patients who underwent an operation for thyroid disorders characterized by the presence of one or several cold nodules (as evaluated with conventional scintigraphy) and enables a comparison between a thorough evaluation of the thyroidal status and the 201 T1 scintigrams. These were obtained with a gamma-camera using a pinhole collimator. If a cold nodule is positive with 201 T1, surgery is incontestably indicated, as such a finding correlates with the existence of a thyroid tumor (benign follicular adenoma or carcinoma) in 89.5% of the observed cases. In the cancer group the sensibility of the Thallium test is of 85% and its specificity 80%. We may assert that there is a very low risk of Thallium negative (old) nodules being malignant. The pre-operative 201 T1 scintigraphy is easy to perform in any Nuclear Medicine department. Nowadays, the combination of aspiration cytology and 201 T1 scintigraphy should make it possible to make and accurate diagnosis in the vast majority of differentiated and undifferentiated thyroid cancers.

Adenoma↗
PubMed1985

Thyroid autoantigen-induced lymphocyte proliferation in Graves' disease and Hashimoto's thyroiditis.

Further progress in understanding T-cell interactions in autoimmune thyroid disease would be possible if T-cell lines and clones could be established. We have therefore examined peripheral blood lymphocyte proliferation in response to a variety of thyroid antigens in Graves' disease and Hashimoto's thyroiditis. A number of different culture conditions were used but in all cases the frequency and magnitude of positive responses were low, the maximum stimulation found for any individual culture with antigen being less than 4-fold above background proliferation. In addition we have examined the blastogenic response of Graves' lymphocytes from thyroid, cervical lymph node and thymus. Positive responses were again found but the stimulation produced by antigen was only 3-fold above background. These results are compatible with recent findings in experimental autoimmune thyroiditis and suggest either that very few antigen-specific T cells are involved in the autoimmune process or that antigen-specific cells exist which can suppress the proliferative response in vitro. It therefore seems unlikely that randomly collected peripheral blood T cells from patients with autoimmune thyroid disease can be sufficiently stimulated by thyroid autoantigens to establish lines or clones without additional manoeuvres such as fractionation into subsets.

Antigens↗
PubMed1983

Thyroid autoantibody synthesis by cultures of thyroid and peripheral blood lymphocytes. I. Lymphocyte markers and response to pokeweed mitogen.

Thyroid lymphocytes from Graves' and Hashimoto patients have been investigated and compared with lymphocytes from the peripheral blood. Considerably more lymphocytes (20-30 X 10(6)/g) could be isolated from Hashimoto thyroids than from Graves' tissue (1-5 X 10(6)/g) but the cell suspensions extracted from Hashimoto and Graves' glands were similar in terms of cell surface markers and the ability to synthesize immunoglobulin. Thyroid lymphocytes contained a lower proportion of T cells (OKT3+ cells) and in some cases more B cells than the peripheral blood but the ratio of helper to suppressor T cells (OKT4+:OKT8+ cells) was similar to the values obtained for blood lymphocytes. Further, thyroid lymphocytes (unlike blood lymphocytes) synthesized relatively large amounts of microsomal and/or thyroglobulin antibody when cultured in medium only and these levels were significantly decreased by the addition of pokeweed mitogen. The results of this study provide further evidence for the role of the thyroid as a major site of thyroid autoantibody synthesis and emphasize the importance of characterizing the cells infiltrating the gland in autoimmune thyroid disease.

Adult↗
PubMed1981

Induced lymphocytic thyroiditis in dogs: effect of intrathyroidal injection of thyroid autoantibodies.

Multifocal infiltrations of lymphocytes and macrophages were present in the thyroid glands of dogs 1 month after an intrathyroidal injection (0.5 ml) of canine serum containing thyroglobulin autoantibodies. The development of thyroiditis was associated with a gradual increase in the incorporation of tritiated thymidine by the peripheral blood mononuclear cells. There was no alteration in circulating thyroid hormone values or thyroglobulin autoantibody titer for 1 month. Control dogs given a similar volume of canine serum without thyroglobulin antibodies did not have an inflammatory reaction in the thyroid gland, and the phytomitogen responses of lymphocytes did not change, compared with base-line values. An intrathyroidal injection of canine thyroglobulin autoantibodies induced lesions similar to naturally occurring lymphocytic thyroiditis in dogs, indicating that thyroid autoantibodies have an important role in the pathogenesis of immune-mediated thyroiditis.

Animals↗
PubMed1994

A high iodine intake in Wistar rats results in the development of a thyroid-associated ectopic thymic tissue and is accompanied by a low thyroid autoimmune reactivity.

Evidence is accumulating that dietary iodine intake is an important modulator of autoimmune thyroid reactions. To study this role of iodine intake further, female Wistar rats were kept on an enriched iodine diet (EID, iodine intake 100 micrograms iodine/day) for a period of up to 18 weeks. Control rats were either on a normal iodine diet (NID, iodine intake 7 micrograms iodine/day) or a low iodine diet (LID, 2 days of 1% KClO4 followed by iodine-deficient drinking water/pellets). During the first 6 weeks of the EID rats developed a thyroid-associated ectopic thymic tissue (50-57% of the animals on EID versus 7-14% of NID rats and 0% of LID rats). This thyroid-associated ectopic thymic tissue showed a similar histology (cortex and medulla) and a similar marker pattern as normal rat thymus concerning TdT expression (positive cells in the cortex) and CD4/CD8 positivity (double-positive cells in the cortex, single-positive cells in the medulla). The excessive iodine diet also resulted in a lowered thyroid autoimmune reactivity as compared to the NID and LID, viz. (1) in a lower incidence of anti-colloid antibodies in serum (12.5% positivity in EID rats versus 36% in NID and 60% in LID rats at 18 weeks) and (2) lower numbers of intrathyroidal lymphoid cells, viz. lower numbers of dendritic cells and lower numbers of CD4 and CD8 positive lymphocytes. It is hypothesized that the development of the thyroid-associated ectopic thymic tissue in the EID rats is related to their low thyroid autoimmune responsiveness; the tissue might play a role in tolerance induction to thyroidal autoantigens.

Animals↗
PubMedDate not supplied

[Mathematical modeling of the dynamics of structural thyroid parameters in thyroid disease with immune disorders].

The material of the study was surgical thyroid biopsies from 126 patients, males and females, aged 14-69 years. 5 groups were studied depending upon the histological picture and the degree of lymphoid infiltration. Thyroids from 10 persons without thyroid pathology who died a violant life served as control. As a result of the factor analysis 5 main factors were distinguished. The first one is lymphoid infiltration, the 2nd and 3rd ones-factors of thyroid epithelium characterizing the structure and the size of thyrocytes, the 4th and the 5th factors characterize the structure of the thyroid as an organ. The analysis confirmed lymphoid infiltration and thyrocyte dimensional parameters are the most important morphological criteria in the diagnosis of thyroid pathology with immune disturbances. Six equations are derived allowing to classify new cases of thyroid pathology.

Adolescent↗
PubMed1996

Occult micropapillary carcinoma associated with benign follicular thyroid disease and unrelated thyroid neoplasms.

Surgically resected thyroids from 425 patients with thyroid disease other than carcinoma of follicular cell derivation were thoroughly examined for occult micropapillary carcinoma (MPC). There were 317 cases of nodular hyperplasia, 36 of thyroiditis, 44 follicular adenomas, and 28 others. Glands were sectioned at 2- to 3-mm intervals and fixed in formalin. Every section was examined histologically. There were 71 cases (16.7%) of MPC containing 118 tumors. Among 343 women, 51 (14.9%) had MPC; among 82 men, 20 (24.4%) had MPC. The average age of all of the patients was 46.9 years and of those with MPC, 50.5 years. The occurrence of MPC peaked between 40 and 70 years and declined in older patients. MPC was found in 8.9% of patients who underwent lobectomies, 10.8% who had hemithyroidectomies, and 24.1% of those who had total thyroidectomies. Logistic regression analysis revealed significant associations between the presence of MPC and the patient sex, age, and extent of surgery; in contrast, there was no association between the occurrence of MPC and the underlying thyroid disease. These data indicate that MPC is present in up to 24.1% of thyroids removed for unrelated thyroid disease. The predominance of this lesion in men is in striking contrast to the occurrence of clinically significant thyroid cancer. This suggests that the initiation of carcinogenesis is not sexually dimorphic, whereas promoters of tumor growth are. A rational management of this common disease awaits the results of careful controlled trials.

Adolescent↗