Association of HLA Antigen and Restriction Fragment Length Polymorphism of T Cell Receptor β- Chain Gene with Graves' Disease and Hashimoto's Thyroiditis*
Masafumi ItoMitsune TanimotoHiromi KamuraMasahiro YonedaYasuo MorishimaKAZUYUKI YAMAUCHITakeharu ItatsuKensuke TakatsukiHidehiko Saito
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Abstract:
HLA antigen phenotypes and BglII restriction fragment length polymorphism of T cell receptor β-chain (TCRβ) gene were analyzed in 61 patients with Graves' disease and 50 patients with Hashimoto's thyroiditis. The antigen frequency of HLA-Bw46 in both Graves' disease (23.0%) and Hashimoto's thyroiditis (24.0%) was significantly higher than that in normal population (8.0%), with relative risks (RR) of 3.45 [corrected P (Pc) < 0.009] and 3.66 (Pc < 0.02), respectively. Significantly increased frequency of HLA-B51 antigen was also found in Hashimoto's thyroiditis (40.0% vs. 16.3% in controls; RR, 3.42; Pc < 0.002). Hybridization of BglII-digested DNA with TCRβ probe revealed two alleles of 9.3 and 8.6 kilobases. The allele frequency of 8.6 kilobases in Graves' disease (79%) and Hashimoto's thyroiditis (76%) was significantly higher (P < 0.01 and P < 0.05, respectively) than that in controls (64%). The frequency of homozygous state 8.6/8.6 was significantly increased in both Graves' disease (62%) and Hashimoto's thyroiditis (60%) over that in controls (39%); the RR of 8.6/8.6 in Graves' disease and Hashimoto's thyroiditis were 2.55 (P < 0.01) and 2.31 (P < 0.05), respectively. These results indicate that in Japanese subjects at least two loci are involved in the susceptibility to Graves' disease and Hashimoto's thyroiditis, one related to HLA and another to TCRβ.Keywords:
Thyrotropin receptor
Antithyroid treatment for Graves' hyperthyroidism restores euthyroidism clinically within 1–2 months, but it is well known that TSH levels can remain suppressed for many months despite normal free T4 and T3 levels. This has been attributed to a delayed recovery of the pituitary-thyroid axis. However, we recently showed that the pituitary contains a TSH receptor through which TSH secretion may be down-regulated via a paracrine feedback loop. In Graves' disease, TSH receptor autoantibodies may also bind this pituitary receptor, thus causing continued TSH suppression. This hypothesis was tested in a rat model. Rat thyroids were blocked by methimazole, and the animals were supplemented with l-T4. They were then injected with purified human IgG from Graves' disease patients at two different titers or with IgG from a healthy control (thyroid hormone binding inhibitory Ig, 591, 127, and < 5 U/liter). Despite similar T4 and T3 levels, TSH levels were indeed lower in the animals treated with high TSH receptor autoantibodies containing IgGs; the 48-h mean TSH concentration (mean ± sem; n = 8) was 11.6 ± 1.3 ng/ml compared with 16.2 ± 0.9 ng/ml in the controls (P < 0.01). The intermediate strength TSH receptor autoantibody-treated animals had levels in between the other two groups (13.5 ± 2.0 ng/ml). We conclude that TSH receptor autoantibodies can directly suppress TSH levels independently of circulating thyroid hormone levels, suggesting a functioning pituitary TSH receptor.
Thyrotropin receptor
Anti-thyroid autoantibodies
Thyroid-stimulating hormone
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In patients, inactivating mutations in the gene encoding the thyroid hormone-transporting monocarboxylate transporter 8 (Mct8) are associated with severe mental and neurological deficits and disturbed thyroid hormone levels. The latter phenotype characterized by high T3 and low T4 serum concentrations is replicated in Mct8 knockout (ko) mice, indicating that MCT8 deficiency interferes with thyroid hormone production and/or metabolism. Our studies of Mct8 ko mice indeed revealed increased thyroidal T3 and T4 concentrations without overt signs of a hyperactive thyroid gland. However, upon TSH stimulation Mct8 ko mice showed decreased T4 and increased T3 secretion compared with wild-type littermates. Moreover, similar changes in the thyroid hormone secretion pattern were observed in Mct8/Trhr1 double-ko mice, which are characterized by normal serum T3 levels and normal hepatic and renal D1 expression in the presence of very low T4 serum concentrations. These data strongly indicate that absence of Mct8 in the thyroid gland affects thyroid hormone efflux by shifting the ratio of the secreted hormones toward T3. To test this hypothesis, we generated Mct8/Pax8 double-mutant mice, which in addition to Mct8 lack a functional thyroid gland and are therefore completely athyroid. Following the injection of these animals with either T4 or T3, serum analysis revealed T3 concentrations similar to those observed in Pax8 ko mice under thyroid hormone replacement, indicating that indeed increased thyroidal T3 secretion in Mct8 ko mice represents an important pathogenic mechanism leading to the high serum T3 levels.
Monocarboxylate transporter
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Observations on the effect of thyroid hormones on mouse submaxillary gland epidermal growth factor (EGF) and on the complementary effect of EGF on cultured thyroid cells led us to examine the interaction between EGF and thyroid hormones in the whole animal, during and after 24 h of infusion of 3.3 μg/kg-h mouse EGF into 6 merino ewes. There was a profound depression of both circulating T4 and T3 levels, to less than 20% of saline-infused control values, extending beyond the end of infusion. Plasma TSH concentrations were unchanged during the first 8 h of the infusion, excluding the likelihood of a suppressive effect of EGF on the hypothalamic-pituitary axis. Serum rT3 and 3,3′-diiodothyronine, however, experienced a more transitory 6-fold increase. These findings are consistent with a dual inhibitory effect of EGF on both thyroid hormone secretion and peripheral metabolism. (Endocrinology119: 214–217,1986)
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The thyrocalcitonin content of the thyroid glands of euthyroid, hyperthyroid and hypothyroid rats fed a calcium deficient diet was determined in 2 separate experiments by bioassay. Hyperthyroidism was produced by the injection of 50 μg l-thyroxine or 200 mU thyrotropin per day, and hypothyroidism by the dietary administration of 0.05% propylthiouracil or an iodine deficient diet. The log-dose response curve for the hypocalcemic activity of the thyroid homogenates from the euthyroid rats was linear between 0.24 and 0.96 mg thyroid tissue, equivalent to 0.018–0.072 of a single rat thyroid gland. No significant differences in the hypocalcemic response of assay rats was observed when a comparison was made of thyroid tissue homogenates that included parathyroid tissue and thyroid homogenates in which the parathyroid gland was removed prior to tissue homogenization. Thyroxine consistently caused a significant 27–35% reduction in the thyroidal content of thyrocalcitonin, whereas the administration of thyrotropin caused a significant 33% reduction in only 1 of the 2 experiments. Hypothyroidism induced by propylthiouracil or a low iodide diet resulted in a slight increase in thyroidal content of thyrocalcitonin, which was significant in one experiment but no different from the control levels in the second experiment. The results obtained in the rats made hyperthyroid with thyroxine are probably due to an increased recycling of skeletal calcium secondary to the ability of thyroid hormone to accelerate bone resorption rather than a direct effect of thyroid hormone on the secretion of thyrocalcitonin. (Endocrinology81: 256, 1967)
Propylthiouracil
Wolff–Chaikoff effect
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Glucocorticoids are known regulators of thyroid function in vertebrates. In birds they have clear tissue-specific and age-dependent effects on thyroid hormone metabolism. In mammals, however, few studies exist addressing these aspects using an in vivo model system. We therefore set out to examine the acute effects of a single dose of dexamethasone (DEX) on plasma 3,5,3′-tri-iodothyronine (T 3 ) and thyroxine (T 4 ) levels, as well as on the activity of the different deiodinases in liver, kidney and brain in the developing rat. In 20-day-old fetuses (E20), glucocorticoids had no effects on circulating thyroid hormone levels despite their clear effects on hepatic and renal deiodinases, thereby indicating that under these conditions circulating thyroid hormone levels are more dependent on thyroidal secretion than on peripheral deiodination. In contrast, in 5-day-old rat pups, DEX did not seem to have any effects on hepatic and renal T 3 production (via the type I deiodinase), whereas type III deiodinase (D3) activity in both these tissues increased significantly. These observations therefore suggested that the DEX-induced increase in circulating T 3 levels is a direct consequence of the increase in plasma T 4 levels. In 12-day-old pups (P12), however, the main effect of glucocorticoids on circulating levels was by increasing inner ring deiodination T 3 through induction of D3 in both liver and kidney. Finally, in the brain, glucocorticoids stimulated thyroid hormone activity only during a short period of time (between E20 and P12) that largely overlaps with the transient window in time during which brain development is thyroid hormone sensitive. This was in contrast to the E20 and P12 brain, where the glucocorticoid-induced changes in type II deiodinase and D3 seemed to favor a status quo in local T 3 availability.
Iodothyronine deiodinase
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Placing rats soon after weaning on a low idoine diet and KClO4 resulted in hypothyroidism which was intense enough to produce effects similar to those following thyroid-ectomy on the plasma PBI, body growth and pituitary content of a protein associated with GH. Plasma insulin levels were also very low. Once growth stasis had occurred, l-T4 in very low doses (0.13−0.28 μg/100 g/day) or KI (1−11.5 μg I/day) was administered, while KClO4 treatment was continued until the animals were killed. These treatments were accompanied by an increase in the weight of the body and organs, the pituitary protein associated with GH, the plasma insulin levels, the plasma PBI, and sometimes the thyroidal 127I content. The weight of the thyroid gland increased significantly. The last of these effects was induced by exogenous insulin in the rats on low iodine diet + KClO4, although plasma TSH activity did not increase further. The results are discussed in relation to the hypothesis that a) the “goitrogenic” effects of small doses of thyroid hormones might be a consequence of partial restitution of the function of the pituitary and/or glands dependent on it, and b) full response of the thyroid to intense stimulation by TSH might require adequate levels of other hormones. (Endocrinology83: 41, 1968)
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Crystalline dihydrotachysterol (DHT) stimulates the activity of the thyroid gland in puberal female rats. After i.p. injection of 350 or 500 µ g/kg/day DHT, the height of epithelial thyroid cells increased, resulting in an increase of thyroid cells from 19 to 26% of the total follicle area. The secretory activity of the gland increased, serum TSH rising from 1.1 to 2.1 mU/ml and serum thyroxine rising from 2.5 to 6 µ g%. The basal metabolic rate increased from 1,400 to 1,810 ml O2/kg/h oxygen consumption. Body weight, however, did not differ from that of the control group. At a dosage of 750 µ g/kg/day, the above reaction was accompanied by a body weight drop of 20%. Within 4 h after implantation of crystalline DHT into the anterior basal hypothalamus, the thyroid reacted histologically with the above pattern of an active gland. These changes could not be elicited in hypophysectomized rats. These results would indicate that the stimulatory effect of DHT on the thyroid gland acts via the hypothalamo-pituitary axis.
Basal (medicine)
Hypothalamic–pituitary–thyroid axis
Endocrine gland
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Severe iodine deficiency is characterized by goiter, preferential synthesis, and secretion of T3 in thyroids, hypothyroxinemia in plasma and tissues, normal or low plasma T3, and slightly increased plasma TSH. We studied changes in deiodinase activities and mRNA in several tissues of rats maintained on low-iodine diets (LIDs) or LIDs supplemented with iodine (LID+I). T4 and T3 concentrations decreased in plasma, tissues, and thyroids of LID rats, and T4 decreased more than T3 (50%). The highest type 1 iodothyronine deiodinase (D1) activities were found in the thyroid, kidney, and the liver; pituitary, lung, and ovary had lower D1 activities; but the lowest levels were found in the heart and skeletal muscle. D1 activity decreased in all tissues of LID rats (10–40% of LID+I rats), except for ovary and thyroids, which D1 activity increased 2.5-fold. Maximal type 2 iodothyronine deiodinase (D2) activities were found in thyroid, brown adipose tissue, and pituitary, increasing 6.5-fold in thyroids of LID rats and about 20-fold in the whole gland. D2 always increased in response to LID, and maximal increases were found in the cerebral cortex (19-fold), thyroid, brown adipose tissue, and pituitary (6-fold). Lower D2 activities were found in the ovary, heart, and adrenal gland, which increased in LID. Type 3 iodothyronine deiodinase activity was undetectable. Thyroidal Dio1 and Dio2 mRNA increased in the LID rats, and Dio1 decreased in the lung, with no changes in mRNA expression in other tissues. Our data indicate that LID induces changes in deiodinase activities, especially in the thyroid, to counteract the low T4 synthesis and secretion, contributing to maintain the local T3 concentrations in the tissues with D2 activity.
Iodothyronine deiodinase
DIO2
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After the administration of estradiol benzoate (EB), testosterone propionate (TP) and progesterone (P)to Sprague-Dawley rats it was revealed that both the thyroid gland weight and the thyroxin-binding capacity of protein (TBCP) of the blood plasma were higher in the female than in the male animals. The female animals responsed to TP and P with lower values for total (TT4) and free thyrotoxin (T4)than the male animals. In the males EB elevated the level of TT4 and free T4, and in the females--the level of TT4 and TBCP. TP decreased the sensitivity of the thyroid gland to thyrotropic hormone. The stimulating effect of P on the thyroid gland resulted in its functional overstrain and exhaustion, which was stronger and more rapid in the female than in the male animals.
Testosterone propionate
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