High Iodine Diet Research Articles

Vitamin D3 attenuates autoimmune thyroiditis by regulating Th17/Treg cell differentiation via YAP/JAK1/STAT1 axis

BackgroundAutoimmune thyroiditis (AITD) is an organ-specific autoimmune disease. Substantial evidence suggests that Vitamin D (VitD) deficiency is closely associated with an increased risk of AITD. However, the effects of VitD3 on immune cells, especially Th17/Treg cell subsets, and the underlying molecular mechanism in AITD have not yet been investigated. MethodsAn experimental autoimmune thyroiditis (EAT) mouse model was established with a high-iodine diet. After 8 weeks, thyroid injury was assessed using hematoxylin and eosin (H&E) staining. ELISA was employed to measure serum levels of thyroxine (T3 and T4), thyroid autoimmune antibodies (Tg-Ab and TPO-Ab), and inflammatory cytokines. Flow cytometry and multiplex fluorescence immunohistochemical (mIHC) assays were used to analyze Th17/Treg cell subsets. The CCK-8 and flow cytometry assays were used to determine cell viability and apoptosis. ResultsAdministration of VitD3 reduced thyroid follicle destruction, decreased lymphocyte infiltration, and lowered T3, T4, Tg-Ab, and TPO-Ab serum levels in EAT mice. VitD3 treatment also reduced the frequency of Th17 cells while promoting the Treg cell subset both in the thyroid tissue and in the splenocytes cultured in vitro. Furthermore, VitD3 administration suppressed the production of inflammatory cytokines in EAT mice. VitD3 was also found to regulate Treg cells' differentiation, viability, and apoptosis. Mechanistically, we discovered that VitD3 treatment upregulated YAP expression and activated the JAK/STAT pathway. Rescue assays confirmed that depletion of YAP counteracted the effects of VitD3 on Treg cell differentiation and function. ConclusionVitamin D3 attenuates AITD by modulating Th17/Treg cell balance via regulating the YAP/JAK1/STAT1 axis.

LncRNA MALAT1-miR-339-5p-NIS axis is involved in the increased level of thyroid stimulating hormone (TSH) induced by combined exposure of high iodine and hyperlipidemia

Hypothyroidism and subclinical hypothyroidism were both characterized by elevated levels of thyroid stimulating hormone (TSH). Previous studies had found that high iodine or hyperlipidemia alone was associated with increased TSH level. However, their combined effects on TSH have not been elucidated. In this study, combination of high iodine and hyperlipidemia was established through the combined exposure of high-water iodine and high fat diet in Wistar rats. The results showed that combined exposure of high iodine and high fat can induce higher TSH level. The mRNA and protein levels of sodium iodide transporters (NIS) and type 1 deiodinase (D1) in thyroid tissues, which were crucial genes in the synthesis of thyroid hormones, decreased remarkably in combined exposure group. Mechanistically, down-regulated long non-coding RNA (lncRNA) metastasis associated in lung denocarcinoma transcript 1 (MALAT1) may regulate the expression of NIS by increasing miR-339-5p, and regulating D1 by increasing miR-224-5p. Then, the above findings were explored in subjects exposed to high water iodine and hyperlipidemia. The results indicated that in population combined with high iodine and hyperlipidemia, TSH level increased to higher level and lncRNA MALAT1-miR-339-5p-NIS axis was obviously activated. Collectively, this study found that combined exposure of high iodine and hyperlipidemia induced a higher level of TSH, and lncRNA MALAT1-miR-339-5p-NIS axis may play important role.

Selenium regulates T cell differentiation in experimental autoimmune thyroiditis in mice

Selenium (Se) is an essential trace element that plays an important role in thyroid physiology. Se supplementation can reduce levels of autoimmune thyroid antibodies, which may be beneficial in Hashimoto's thyroiditis (HT). However, the long-term benefits of Se supplementation for HT patients are controversial and there is no clear clinical evidence to support it, so further basic and clinical research is needed. The effect of Se on immune cells, especially T cells, in autoimmune thyroiditis (AIT) has not been elucidated. Here, we replicated a mouse model of experimental autoimmune thyroiditis (EAT) on a high-iodine diet and treated it with Se supplementation. At week 8 of the experiment, Se supplementation reduced the destruction of thyroid follicles and the infiltration rate of lymphocytes in EAT mice, and reversed the disturbance of peripheral blood thyroxine and thyroid autoantibody levels. Further examination revealed that Se had broad effects on T-cell subsets. Its effects include reducing the production of pro-inflammatory cytokines by Th1 cells, inhibiting the differentiation and production of cytokines by Th2 and Th17 cells, and upregulating the differentiation and production of cytokines by Treg cells. These changes help alleviate thyroid follicle damage during EAT. In conclusion, selenium supplementation has the potential to improve the prognosis of AIT by altering the subset differentiation and/or function of CD4+ T cells.

High dietary iodine intake may contribute to the low death rate from COVID-19 infection in Japan with activation by the lactoperoxidase system.

We draw the attention of readers and governments to the death rate from coronavirus disease 2019 in Japan, continuing as a fraction of that experienced by many other developed nations. We think this is due to the activity of the powerful, protective lactoperoxidase system (LPO) which prevents serious airborne infections. The LPO system requires iodine, which is liberally provided by the typical Japanese diet but lacking in many others. One might consider the Japanese experience an incredibly large, open-label study exhibiting the preventative power of a high-iodine diet. We predict this favourable trend will continue for Japan because deadly variants of the severe, acute respiratory syndrome coronavirus 2 will be with us, forever.

Application of oral inorganic iodine in the treatment of Graves' disease.

Iodine is a crucial trace element for the human body and the basic raw material for the synthesis of thyroid hormones. Oral inorganic iodine includes dietary iodine and therapeutic iodine, both of which are closely associated with thyroid immunity and metabolism. Graves' disease (GD), also known as diffuse toxic goiter, is characterized by hyperthyroidism and high iodine metabolism. Clinically, patients diagnosed with GD are often asked to limit iodine intake or even avoid iodine in their diet. The latest research has demonstrated that the interference of dietary iodine with antithyroid drugs (ATDs) treatment may be overestimated. In addition, as a medication for GD treatment, the administration of inorganic iodine has shown positive results in patients with mild hyperthyroidism, a low thyroid autoantibody concentration, a small thyroid volume, a high iodine diet and so on. Inorganic iodine may also be used as an alternative when patients experience side effects with traditional ATDs and for those who still prefer conservative treatment. Due to its low teratogenicity, blood toxicity and bone marrow toxicity, inorganic iodine plays a unique role in special populations, such as pregnant or lactating patients and patients receiving tumor radiotherapy or chemotherapy. In this review, the research progress, biological function, doses and effects, applicable populations and specific applications of dietary iodine and therapeutic iodine are summarized to provide references for the diagnosis and treatment of GD, thus improving the quality of life of GD patients.

Leptin receptor antagonist attenuates experimental autoimmune thyroiditis in mice by regulating Treg/Th17 cell differentiation.

Leptin has been found to be involved in the development and progression of many autoimmune diseases. As an organ-specific autoimmune disease, the pathogenesis of Hashimoto's thyroiditis has not been fully elucidated. It has been reported that serum leptin level is increased in Hashimoto's thyroiditis, but other studies have not shown any difference. We replicated a mouse model of experimental autoimmune thyroiditis (EAT) with a high-iodine diet and found that injection of the leptin receptor antagonist Allo-aca reduced thyroid follicle destruction and inflammatory cell infiltration in EAT mice, and thyroxine and thyroid autoimmune antibody levels. Further investigation revealed that Allo-aca promotes the differentiation of Treg cells and inhibits the differentiation of Th17 cells. We believe that Allo-aca can alter the differentiation of Treg/Th17 cells by inhibiting the leptin signaling pathway, thereby alleviating thyroid injury in EAT mice. Interfering with the leptin signaling pathway may be a novel new approach to treat treating and ameliorating Hashimoto's thyroiditis.

XB130 Deficiency Causes Congenital Hypothyroidism in Mice due to Disorganized Apical Membrane Structure and Function of Thyrocytes.

Background: Congenital hypothyroidism is often caused by genetic mutations that impair thyroid hormone (TH) production, resulting in growth and development defects. XB130 (actin filament associated protein 1 like 2) is an adaptor/scaffold protein that plays important roles in cell proliferation, migration, intracellular signal transduction, and tumorigenesis. It is highly expressed in thyrocytes, however, its function in the thyroid remains largely unexplored. Methods:Xb130-/- mice and their littermates were studied. Postnatal growth and growth hormone levels were measured, and responses to low or high-iodine diet, and levothyroxine treatment were examined. TH and thyrotropin in the serum and TH in the thyroid glands were quantified. Structure and function of thyrocytes in embryos and postnatal life were studied with histology, immunohistochemistry, immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction. Results:Xb130-/- mice exhibited transient growth retardation postnatally, due to congenital hypothyroidism with reduced TH synthesis and secretion, which could be rescued by exogenous thyroxine supplementation. The thyroid glands of Xb130-/- mice displayed diminished thyroglobulin iodination and release at both embryonic and early postnatal stages. XB130 was found mainly on the apical membrane of thyroid follicles. Thyroid glands of embryonic and postnatal Xb130-/- mice exhibited disorganized apical membrane structure, delayed folliculogenesis, and abnormal formation of thyroid follicle lumina. Conclusion: XB130 critically regulates folliculogenesis by maintaining apical membrane structure and function of thyrocytes, and its deficiency leads to congenital hypothyroidism.

Comparison of Knowledge and Behavior of High-Iodine Food Consumption Among Patients With Graves’ Disease and Healthy Adults in Iodine-Sufficient Area

Background: Iodine is a required dietary supplement to solve iodine deficiencies; however, many food products may now have an excessive amount of iodine. This excess may be causing unexpected iodine-induced Graves’ disease.
 Objective: To investigate the impact of high-iodine diets on adults diagnosed with Graves’ disease and healthy adults.
 Methods: A case-control study was performed among 200 patients with Graves’ disease and 200 healthy participants in Chon Buri, Thailand, using cluster random sampling from November 2019 to March 2020. Data on iodine-rich food consumption were collected using a questionnaire. Data were analyzed using a chi-square test and multiple logistic regression.
 Results: Patients with Graves’ disease significantly less knew of high-iodine food than the control group (P < .05), particularly in eggs, processed foods, ready-to-eat food, cod liver oil, and high-iodine vegetables. A frequent consumption of high-iodine food items, including fermented food (OR, 2.20; 95% CI, 1.20 - 4.02), ready-to-eat food (OR, 2.08; 95% CI, 1.02 - 4.22), high-iodine vegetables (OR, 1.72; 95% CI, 1.13 - 2.61), bakery (OR, 1.99; 95% CI, 1.10 - 3.64), iodine-supplemented sauces (OR, 1.79; 95% CI, 1.18 - 2.72), and iodized salts (OR, 1.62; 95% CI, 1.02 - 2.56) was higher in Graves’ disease patients.
 Conclusions: In iodine sufficiency area, patients with Graves’ disease less knew and more frequently consumed high-iodine foods than healthy participants.

Effect of excessive iodine intake on the 99Tcm-pertechnetate uptake function of thyroid and the related mechanism

Objective To study the influence of excessive iodine intake on the 99Tcm-pertechnetate uptake function of thyroid and explore the related mechanism. Methods A total of 150 male Wistar rats were divided into normal iodine group (NI group) and 4 high iodine (HI) groups (10HI, 50HI, 100HI and 500HI group) with completely random method. Each group included 30 rats. Rats in HI groups were intragastrically administrated with different concentrations of KIO3, and rats in NI group were administrated with the same amount of distilled water. After a 7 d HI diet, each group was randomly divided into 3 subgroups: 7 d group (HI diet for 7 d), 10 d group (HI diet for 7 d + limiting iodine for 3 d) and 14 d group (HI diet for 7 d + limiting iodine for 7 d). All rats were given 1.85 MBq 99TcmO4-, then the thyroid glands were isolated and weighed 20 min post-injection. The radioactive counts were measured and the thyroid uptake percentage activity of injected dose per gram of tissue (%ID/g) of 99TcmO4- for each sample was calculated. Sodium-iodide symporter (NIS) expression level was analyzed by Western blot. One-way analysis of variance or Welch test was used to compare the differences among groups, and Spearman rank correlation analysis was also used. Results At the same observation time, the %ID/g of 99TcmO4- and NIS expression among different HI groups were statistically significant (F values: 48.825-119.219, all P 0.05). Significant differences of %ID/g of 99TcmO4- and NIS expression were found among different time subgroups in 50HI, 100HI and 500HI groups (F values: 10.442-90.408, all P<0.01). Spearman correlation analysis showed that the concentration of iodine correlated negatively with %ID/g of 99TcmO4- and NIS expression (rs values: -0.853 and -0.950, both P<0.01), while the %ID/g of 99TcmO4- and NIS expression was positively correlated (rs=0.925, P<0.01). Conclusions Excessive iodine intake can inhibit thyroid uptake of 99TcmO4- in rats, which is associated with the down-regulation of NIS expression. The degree of inhibition correlates positively with iodine concentration, and correlates negatively with NIS expression. The degree of recovery of NIS and %ID/g of 99TcmO4- may relate to the time of limiting the iodine intake. Key words: Thyroid gland; Sodium pertechnetate Tc 99m; Iodine; Rats; Sodium/iodide symporter

Hashimoto’s thyroiditis presenting as cerebellar stroke

Hashimoto’s thyroiditis (HT) or autoimmune hypothyroidism is the most common form of primary hypothyroidism, characterized by lymphocytic infiltration of the thyroid gland thereby leading to its destruction. It is more common in females. Genetic factors and chronic exposure to high iodine diet also play an important role. Hypertension, in these patients, is the result of increased peripheral resistance and arterial stiffness. The patient being reported is a 54 year old female with uncontrolled hypertension who presented with cerebellar infarct and was diagnosed to have HT. Following therapy with levothyroxine, her blood pressure was well controlled. This case emphasises the need for thyroid evaluation in all patients with uncontrolled hypertension.Asian Journal of Medical Sciences Vol.7(4) 2016 101-103

Effect of Iodine Intake on p14ARF and p16INK4a Expression in Thyroid Papillary Carcinoma in Rats.

BackgroundIodine intake is related to thyroid disease. This study investigated the effect of the amount of iodine intake on p14ARF and p16INK4a expression of thyroid papillary carcinoma in rats.Material/MethodsA cohort of 240 SD rats were randomly divided into control group, low iodine, normal iodine, and high iodine groups (n=60 per group). We inoculated 2×105 papillary thyroid carcinoma (PTC) cells on the left side of the thyroid gland. After 6 and 12 weeks, serum thyroid hormone level and urine iodine level were measured in addition to morphological observations of tumor tissues. Expression of p14ARF, p16INK4a was detected by immunohistochemical staining.ResultsThe expression of p14ARF, p16INK4a, FT3, and FT4 levels in all iodine-treated animals were significantly lower than in the control group, while TSH level was significantly higher (P<0.05). Compared to the normal iodine group, the low and high groups had lower p14ARF and p16INK4a expression, lower FT3 and FT4 levels, higher TSH levels, and heavier tumors (P<0.05). In a further between-group comparison, p14ARF and p16INK4a expression and FT3 and FT4 levels at 12 weeks were lower than at 6 weeks. Expression of p14ARF and p16INK4a were positively correlated with FT3 and FT4, and negatively correlated with TSH and tumor weight.ConclusionsLow and high iodine diet intake could reduce p14ARF and p16INK4a expressions and promote tumor development.

Excess dietary iodine differentially affects thyroid gene expression in diabetes, thyroiditis‐prone versus ‐resistant BioBreeding (BB) rats

To identify genes involved in the susceptibility to iodine-induced autoimmune thyroiditis. Diabetes, thyroiditis-prone (BBdp) and -resistant (BBc) rats were fed either a control or a high-iodine diet for 9 wk. Excess iodine intake increased the incidence of insulitis and thyroiditis in BBdp rats. BBdp rats fed the high-iodine diet that did not develop thyroiditis had higher mRNA levels of Fabp4, Cidec, perilipin, Pparγ and Slc36a2 than BBdp rats fed the control diet and BBc rats fed either the control or the high-iodine diet. BBdp rats fed the high-iodine diet that did develop thyroiditis had higher mRNA levels of Cidec, Icam1, Ifitm1, and Slpi than BBdp rats fed the control diet and BBc rats fed either the control or the high-iodine diet. BBdp rats that did develop thyroiditis had lower mRNA levels of Fabp4, perilipin and Slc36a2 but higher mRNA levels of Icam1, Ifitm1 and Slpi than BBdp that did not develop thyroiditis. Excess dietary iodine also increased the protein levels of Fabp4, Cidec and perilipin in BBdp rats. Differential expression of thyroid genes in BBdp versus BBc rats caused by excess dietary iodine may be implicated in autoimmune thyroiditis and insulitis pathogenesis.

Iodide excess exerts oxidative stress in some target tissues of the thyroid hormones

Environmental iodine deficiency continues to be a significant public health problem worldwide. On the other hand, iodide excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. For this reason we intended to explore iodide excess impairment on prooxidant/antioxidant balance of the thyroid gland, hepatic tissue and in blood and the effect of selenium administration on oxidative stress markers under the same circumstances. Experiments were performed for 10 days with white, male, Wistar rats, as follows: group 1: control-normal iodine supply group; 2: high iodine diet, group; 3: high iodine diet and selenium; group 4: high iodine diet and Carbimasole. Oxidative stress markers such as lipid peroxides were determined in thyroid gland, hepatic tissue and in blood. Measuring H+ donor ability of the sera and catalase activity in thyroid gland and in hepatic tissue assessed antioxidant defense. Iodide excess had prooxidant effects, leading to an increased lipid peroxides level and catalase activity in target tissues and in blood and to a decreased H+ donor ability of the sera. Selenium supplementation had opposite effects. Present data allow us to conclude that the alterations due to iodide excess in thyroid gland, hepatic tissue and in blood are mediated through oxidative stress.

A high dietary iodine increases thyroid iodine stores and iodine concentration in blood serum but has little effect on muscle iodine content in pigs

There is still iodine deficiency in many populations, which justifies efforts to increase this trace element in food such as milk, eggs and meat by fortifying compound animal feeds with extra iodine. The iodine requirement of growing pigs is in the order of 100–200 μg/kg feed (as a supplement) and the effects of this dosage range or higher on pork iodine concentration should be determined including the action of relevant iodine antagonists in feed, e.g., rapeseed. In three experiments on a total of 208 pigs [Pietrain × (Landrace × Large White)] the iodine concentration of meat (m. longissimus) – 71 samples –, blood serum – 100 samples – and of the thyroid – 100 samples – was analysed by intracoupled plasma-MS. In Experiment 1, 4 × 10 pigs received diets without or with rapeseed cake (0 and 3.2 mmol glucosinolates/kg diet) either with 125 or with 250 μg iodine/kg. In Experiment 2, the three groups with 46 pigs each were fed high iodine diets (1200 μg supplementary iodine/kg) without or with 100 or 150 g solvent extracted rapeseed meal/kg diet (0; 0.8 and 1.2 mmol glucosinolates/kg). In Experiment 3, 3 × 10 pigs received either 600 μg iodine/kg feed (1) or the 5-fold dosage (600 + 2400 μg iodine/kg diet) administered 7 days (2) or 18 days (3) before slaughtering. The group means of pork iodine content were in the relatively small range from 3 to 16 μg/kg, which contrasted to the enormously varying dosage range from 125 to 3000 μg iodine/kg diet. There was a certain iodine dosage effect in Experiment 3 when – in comparison to the control – a 3-fold higher meat iodine concentration resulted from a 5-fold higher diet iodine concentration. In Experiment 1 with the low iodine offer, rapeseed cake with glucosinolates decreased the serum iodine level whereas in Experiment 2 this did not happen due to higher iodine fed and lower glucosinolates exposure. The thyroid iodine reflected the dietary iodine better than blood serum iodine and the serum better than muscle. However, in Experiment 2, 1200 μg iodine/kg diet produced only half the serum iodine concentration than half as much dietary iodine in Experiment 3 (600 μg iodine/kg diet), which may result from rapid elimination of blood iodine and a higher urinary excretion by longer duration of feed withdrawal before blood sampling. The muscle of pigs has to be classified as a low iodine food. Thus, there are no possibilities to concentrate this trace element reproducibly in amounts relevant for human nutrition in pork.

Dietary Soybean Enhances Pit-1 Dependent Pituitary Hormone Production in Iodine Deficient Rats

Reports have shown that soybeans are goitrogenic. In the present study, we investigated the effects of a high soybean diet in rats that were fed normal or iodine-deficient chow on the regulation of anterior pituitary hormone production. Iodine deficiency alone resulted in thyroid hyperplasia, reduced serum thyroxine levels, and a tendency towards an increase in serum thyroid stimulating hormone (TSH). The combination of a high soybean and low iodine diet (ID + DS) acted synergistically to induce thyroid hypertrophy, reduce serum thyroxine and tri-iodothyronine, and markedly increase serum TSH. Immunohistochemical analysis revealed that rats fed the ID + DS diet exhibited a marked increase in their number of pituitary TSH, prolactin (PRL), and growth hormone (GH) producing cells. Pituitary transcription factor-1 (Pit-1) which is involved in the expression of the TSH, PRL, and GH genes was also increased in ID + DS fed rats. These results suggest that a diet high in soybean products modulates anterior pituitary hormone production by regulating Pit-1 induction, in iodine-deficient animals.

The effects of alpha interferon on the development of autoimmune thyroiditis in the NOD H2h4 mouse.

Alpha interferon (αIFN) therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD-H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units) or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%). Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN-injected group, 6/13 (46.2%) developed thyroiditis and/or thyroid antibodies while in the saline-injected group, only 4/13 (30.8%) developed thyroiditis and/or thyroid antibodies (p=0.4). The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non-genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching.

Animal models of endocrine/organ-specific autoimmune diseases: do they really help us to understand human autoimmunity?

Organ-specific or endocrine autoimmune diseases are complex, polygenic afflictions the penetrance of which is heavily dependent on various environmental influences. Important target tissues are the thyroid, the islets of Langerhans, gastric parietal cells and steroid-producing cells in the adrenal and ovary. The etiology of these diseases remains to be clarified. The pathogenesis is strongly associated with autoimmune phenomena. None of the current treatment approaches provides a cure; rather they represent replacement therapy. An important objective in the treatment of endocrine/organ-specific autoimmune diseases is the detection of individuals at risk for the development of such diseases and the development of interventions to prevent an outbreak of the diseases. This requires an exquisite knowledge of the early etio-pathogenic stages of these diseases. This review concentrates on the usefulness of animal models for a precise understanding of these very early stages. It must be emphasized that studying animal models cannot answer all the problems presented by endocrine/organ-specific autoimmune diseases as seen in the clinic. It must be expected - considering the different etiologies in the different animal models (see below) - that the causes of the diseases in the human and the involvement of various genes and environmental factors may also vary. Yet, particularly in the study of the pre-autoimmune phases of the diseases, there is hardly any alternative to the study of animal models. Only limited series of experiments can be carried out in human subjects at risk to develop such diseases. Moreover, a general semblance (blueprint) of the etio-pathogenesis found in the animal models can lead the way for human studies. Efforts to understand the patho-physiology of the early stages of endocrine/organ-specific autoimmune diseases have mainly involved animal models that "spontaneously" develop such diseases. Of these the bio-breeding diabetes-prone (BB-DP) rat and the non-obese diabetes (NOD) mouse are the most well studied, yet many studies have also been carried out in the obese strain (OS) chicken. Apart from these spontaneous models there are animal models that are induced by environmental perturbations (viruses, toxic substances), by thymectomy procedures or by genetic manipulations, e.g., the RIP-LCMV model and the BDC 2.5 TCR mouse model. A general blueprint has emerged from the studies into the early stages of the pathogenesis of endocrine/organ-specific autoimmune diseases in these animal models: animals at risk to develop endocrine/organ-specific autoimmune diseases show various pre-autoimmune aberrancies in their target glands, T cells, macrophages (Mphi) and dendritic cells (DC). The presumably aberrant target cells, T cells, DC and Mphi need to interact abnormally before autoimmune disease can fully develop. In this abnormal interaction additional aberrancies in other regulatory systems may play a role in a further exacerbation of the self-directed immune response, such as defects in the hypothalamus pituitary adrenal (HPA) axis system. The various aberrancies are partly genetically determined by a variety of separate genes, particularly MHC-related genes, but they may also be environmentally induced (e.g., via viruses, high iodine diet, and other experimental manipulations). Recently evidence has been gathered for pre-autoimmune aberrancies similar to the animal models in the DC/ Mphi compartment and the HPA axis in humans at risk to develop endocrine/organ-specific autoimmune diseases. However, analogous pre-autoimmune abnormalities in human target glands or in T cell function have not yet been found with certainty. We believe that animal models of endocrine/organ-specific autoimmune disease still hold immense promise for the discovery of pathways, genes and environmental factors that determine the development of endocrine/organ-specific autoimmune diseases. Animals affected by such diseases provide a unique opportunity to uncover disease-associated pathways, which are complicated to define in man.

Histological changes in TSH-dependent tumours of the thyroid gland during serial transplantation in Fischer 344 rats.

Transplantable tumours were induced in the thyroids of Fischer 344 rats fed thiouracil (TU) in a moderately low iodine diet for 8-13 months. Pieces of hyperplastic thyroid were implanted subcutaneously into rats fed a TU containing diet. Almost all implants gave rise to very small vascularized transplants but there were three significantly larger, pieces of which were transplanted again and gave rise to the tumour lines. From the third transplantation generation on, pieces of tumours were implanted into rats treated to have elevated circulating thyrotropin and a group fed a high iodine diet. With some exceptions, the implants grew only in rats fed the TU or a low iodine diet and yielded TSH-dependent tumours. Almost all the tumours observed initially were papillary, and most of the remainder had colloid-filled follicles bounded by columnar cells. One line of tumours was of the latter type for eight generations. The others had more complex histories, in which there were sublines that were papillary for eight or nine generations, whereas, others became progressively more cellular or follicular, and more heterogeneous with respect to histological types present per section at rates that varied with the subline. The large number of population doublings necessary to make a one gram tumour from a single original tumour cell indicates that the cells of dependent papillary tumours were immortalized.

Summary of observations on transplantable tumors of the rat thyroid gland

Transplantable tumors of the thyroid gland have been produced by feeding of thiouracil (TU) to inbred Fischer 344 rats followed by the transplantation, initially, of pieces of hyperplastic thyroid gland, and in later generations, of pieces of transplanted tissue into similar rats or into rats fed a high iodine diet. In early generations, transplants grew only in the rats fed the TU diet, and this tissue was called dependent, whereas if the tissue grew in rats fed the high iodine diet in the abscence of TU, it was called independent. Dependent tumors were, initially, either papillary or of follicles distended with colloid. Later generations of some sublines were cellular or microfollicular in pattern and some became progressively more heterogeneous with later generations. Independent tumors began to appear by the third transplant generation. They were, initially, relatively uniform in pattern, and some tended to remain so, whereas other sublines exhibited some heterogeneity. Tumors had patterns that were cellular, or microfollicular, or follicular or had open follicles, etc.; there was one cellular ascites tumor subline. Other observations were made of vascular patterns, connective tissue, necrosis, and metastases.

The neuropeptides, VIP and NPY, that are present in the thyroid nerves are not released into the thyroid vein.

In the present study, we tested the hypothesis that the neuropeptides, vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), which are present in the thyroid nerves, act as physiological neurotransmitters involved in the regulation of thyroid hormone secretion and thyroid blood flow. Specifically, we examined whether these neuropeptides can be released into thyroid blood vessels by electrical stimulation of the major thyroid nerves or whether their expression is altered by changes in iodine intake. Sprague-Dawley rats were used in this study. The cervical sympathetic trunk or the superior laryngeal nerve was stimulated by bipolar electrodes in anesthetized rats. During nerve stimulation, blood samples were withdrawn from the thyroid vein. Thyroid blood flow was monitored by laser Doppler blood flowmetry. Sympathetic stimulation caused a marked decrease in thyroid blood flow, which was associated with a significant increase in release of norepinephrine. However, these effects were not accompanied by any change in NPY release into the thyroid vein. Stimulation of the superior laryngeal nerve was not associated with changes in thyroid blood flow or VIP release into the thyroid vein. In a separate experiment, rats were fed a diet containing low-, high-, or normal iodine concentrations. Triiodothyronine (T3) and thyroxine (T4) levels in thyroid venous plasma were significantly reduced in rats fed a low-iodine diet but not in a separate group of rats fed a high iodine diet. However, these treatments had no effect on VIP or NPY concentrations in thyroid venous plasma or in thyroid ganglia. Thus, our results indicate that VIP and NPY, which are present in the thyroid nerves, may not be directly involved in the regulation of thyroid function.