Dynamic Changes of CD4<Superscript>+</Superscript>CD25<Superscript>+</Superscript> Regulatory T Cells in NOD.H-2<Superscript>h4</Superscript> Mice with Iodine-Induced Autoimmune Thyroiditis

Iodine is an essential trace element for thyroid hormone synthesis and metabolism, either low or high intake may lead to thyroid disease, but the pathogenetic mechanisms by which iodine interacts with the thyroid autoimmune are poorly understood. We investigated the dynamic changes of CD4⁺CD25⁺ regulatory T cells in NOD.H-2^h4 mice with iodine-induced autoimmune thyroiditis (AIT), and explore potential immune mechanism of AIT induced by iodine. NOD.H-2^h4 mice were randomly divided into two groups, and received plain water or water containing 0.005% sodium iodide. Eight weeks after iodine provision, the incidences of thyroiditis, relative weights of thyroids, and serum thyroglobulin antibody titers in the iodine-supplied groups were significantly increased compared to the control groups (p < 0.05). The AIT mice had fewer CD4⁺CD25⁺Foxp3⁺ T cells and reduced Foxp3 mRNA expression in splenocytes compared with the controls (p < 0.01), and maintained relatively low levels during the development of thyroiditis. The changes described above aggravated gradually with the extension of iodine treatment. These data suggest that CD4⁺CD25⁺ regulatory T cells may be involved in the pathogenesis and development of AIT induced by iodine.     

Phagocytosis Deficiency of Macrophages in NOD.H-2h4 Mice Accelerates the Severity of Iodine-Induced Autoimmune Thyroiditis

Apoptosis occurs in many autoimmune diseases. Excess iodine induces thyrocyte apoptosis and increases the incidence and prevalence of autoimmune thyroiditis (AIT). However, the sequence of events between the appearance of thyrocyte apoptosis and the occurrence of thyroiditis remains uncharacterized. Furthermore, few studies have investigated the role of macrophage phagocytosis in the development of AIT. Therefore, we evaluated the relationship between apoptosis and inflammatory infiltration in NOD.H-2^h4 mouse thyroids by comparing the sequence of events in tissue samples. We also investigated the role of macrophages by comparing macrophage phagocytosis function in BALB/c, C57BL/6, and NOD.H-2^h4 mice treated with different levels of iodine. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays and thyroid inflammatory scores revealed that apoptosis (2 weeks) occurred before inflammatory infiltration (4 weeks). Phosphatidylserine (PS) expression on the extracellular surface of the cell membrane and double-stranded DNA fragments associated with apoptosis appeared at 2 and 8 weeks, respectively. Additionally, although apoptosis was enhanced in the thyroids of mice supplemented with excess iodine (0.05 ± 0.12 vs 1.63 ± 0.82% for BALB/c, 0.09 ± 0.14 vs 1.51 ± 0.34% for C57BL/6, and 0.07 ± 1.11 vs 4.72 ± 0.62% for NOD.H-2^h4 mice), only NOD.H-2^h4 mouse thyroids presented with inflammation. Furthermore, macrophages from NOD.H-2^h4 mice (44.46 ± 1.79%) exhibited decreased phagocytotic activity relative to that in BALB/c (54.21 ± 4.58%) and C57BL/6 (58.96 ± 4.04%) mice. There were no differences in phagocytosis function between NOD.H-2^h4 mice supplemented with excess iodine or left untreated (24.50 ± 2.66 vs 21.71 ± 1.79%, p = 0.06). In conclusion, deficiencies in the apoptosis clearance of macrophages in NOD.H-2^h4 mice may constitute an early pathogenic mechanism in AIT that is not influenced by iodine intake.

     

Both CD4(+) T cells and CD8(+) T cells are required for iodine accelerated thyroiditis in NOD mice

The nonobese diabetic (NOD) mouse, a spontaneous animal model for insulin-dependent diabetes mellitus, displays a tendency in common with human diabetic populations to develop autoimmune thyroiditis although incidence and severity of thyroid lesions vary widely among different colonies around the world. A congenic strain of NOD mice bearing I-Ak on a NOD background (NOD-H2(h4)) has recently been derived and displays a much greater tendency to develop thyroiditis and autoantibodies to mouse thyroglobulin (MTg) although it is free of diabetes. Both thyroid infiltrates and autoantibody formation are accelerated and enhanced in NOD-H2(h4) mice by increased iodine intake. The effect of increased iodine intake on NOD mice themselves has not been directly investigated although a recent study of these animals given high or low doses of iodine showed no follicular destruction unless the mice were first rendered goitrous by iodine deprivation. We found that dietary iodine increased both the incidence and the severity of thyroid lesions in our NOD mice although autoantibodies to MTg were absent. NOD background genes appear to be essential for the development of these lesions, which were maximal after 4 weeks of iodine administration and showed no significant regression when the iodine was stopped. Furthermore, our studies show for the first time that both CD4(+) and CD8(+) T cells are necessary for the development of this accelerated but essentially spontaneous murine thyroid disease.     

Early requirement for B cells for development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice

B cells are known to play an important role in the pathogenesis of several autoimmune diseases. NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and anti-mouse thyroglobulin (MTg) autoantibodies, the levels of which correlate closely with the severity of thyroid lesions. NOD.H-2h4 mice genetically deficient in B cells (NOD.Kmu(null)) or rendered B cell-deficient by treatment from birth with anti-IgM develop minimal SAT. B cells were required some time in the first 4-6 wk after birth, because NOD.Kmu(null) or NOD.H-2h4 mice did not develop SAT when they were reconstituted with B cells as adults. The requirement for B cells was apparently not solely to produce anti-MTg autoantibodies, because passive transfer of anti-MTg Ab did not enable B cell-deficient mice to develop SAT, and mice given B cells as adults produced autoantibodies but did not develop SAT. B cell-deficient mice developed SAT if their T cells developed from bone marrow precursors in the presence of B cells. Because B cells are required early in life and their function cannot be replaced by anti-MTg autoantibodies, B cells may be required for the activation or selection of autoreactive T cells. These autoreactive T cells are apparently unable to respond to Ag if B cells are absent in the first 4-6 wk after birth.     

Role of TGFbeta in development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice.

Nearly 100% of NOD.H-2h4 mice develop spontaneous autoimmune thyroiditis (SAT) and produce anti-mouse thyroglobulin autoantibodies when they receive 0.05% NaI in their drinking water beginning at 8 wk of age. Our previous studies showed that TGFbeta1 mRNA was constitutively expressed in thyroids and spleens of normal NOD.H-2h4 mice but not other strains of mice. To determine whether TGFbeta might have a role in SAT, mice were given anti-TGFbeta mAb at various times during development of SAT. Anti-TGFbeta markedly inhibited development of SAT and production of anti-mouse thyroglobulin IgG1 autoantibodies. Anti-TGFbeta was most effective in inhibiting SAT when given during the time thyroid lesions were developing, i.e., starting 4 wk after administration of NaI water. The active form of the TGFbeta1 protein was present in thyroids of mice with SAT but not in normal NOD.H-2h4 thyroids. However, thyrocytes of normal NOD.H-2h4 thyroids did express latent TGFbeta1. TGFbeta1 protein expression in the thyroid correlated with SAT severity scores, and administration of anti-TGFbeta inhibited TGFbeta1 protein expression in both the thyroid and spleen. TGFbeta1 was produced primarily by inflammatory cells and was primarily localized in areas of the thyroid containing clusters of CD4(+) T and B cells. Depletion of CD8(+) T cells had no effect on TGFbeta1 protein expression. Activation of splenic T cells was apparently not inhibited by anti-TGFbeta, because up-regulation of mRNA for cytokines and other T cell activation markers was similar for control and anti-TGFbeta-treated mice. TGFbeta1 may function by promoting migration to, or retention of, inflammatory cells in the thyroid.     

Syngeneic sensitization of mouse lymphocytes on monolayers of thyroid epithelial cells: IV. Correlation with H-2 haplotypes

In vitro primary syngeneic sensitization on monolayers of thyroid epithelial cells was performed with 21 inbred strains of mice representing 11 original H-2 haplotypes. Significant differences in the proliferative responses, assessed by thymidine uptake, were found to be related to the major histocompatibility complex haplotype. This result was further confirmed using congenic resistant strains of mice. In comparison with the experimental autoimmune thyroiditis induced by syngeneic thyroglobulin and adjuvant, primary syngeneic sensitization on monolayers of thyroid epithelial cells appeared to be under the same genetic control (H-2^k strains being good responders, while H-2^b mice are poor responders).     

A Comparative Study on the Effects of Excess Iodine and Herbs with Excess Iodine on Thyroid Oxidative Stress in Iodine-Deficient Rats

This study aimed to compare the effect of excess iodine and herbs with excess iodine on treating iodine deficiency-induced goiter from the perspective of oxidative stress and to measure selenium values in Chinese herbs. One hundred twenty 4-week-old Wistar rats were selected and randomly divided into four groups after inducing iodine-deficiency goiter: normal control group (NC), model control group (MC), iodine excess group (IE), and herbs with iodine excess group (HIE). The activities of oxidative enzymes and levels of oxidative products were measured using biochemical tests. The expression of 4-hydroxynonenal (4-HNE) in the thyroid was detected by immunohistochemistry and the expression of peroxiredoxin 5 (PRDX5) by the Western blot and immunohistochemistry. Selenium values in iodine-excessive herbs were measured by hydride generation-atomic fluorescence spectrometry. The herbs with iodine excess were tested to contain rich selenium. The activities of superoxide dismutase (SOD) and PRDX5 increased markedly, and the values of malondialdehyde (MDA) and 4-HNE decreased significantly in the HIE group. In conclusion, compared with excess iodine, herbs with excess iodine damaged thyroid follicular cells less, which may be related to the increase of antioxidant capacity and rich selenium values in iodine-excessive herbs.     

B cell depletion inhibits spontaneous autoimmune thyroiditis in NOD.H-2h4 mice

B cells are important for the development of most autoimmune diseases. B cell depletion immunotherapy has emerged as an effective treatment for several human autoimmune diseases, although it is unclear whether B cells are necessary for disease induction, autoantibody production, or disease progression. To address the role of B cells in a murine model of spontaneous autoimmune thyroiditis (SAT), B cells were depleted from adult NOD.H-2h4 mice using anti-mouse CD20 mAb. Anti-CD20 depleted most B cells in peripheral blood and cervical lymph nodes and 50-80% of splenic B cells. Flow cytometry analysis showed that marginal zone B cells in the spleen were relatively resistant to depletion by anti-CD20, whereas most follicular and transitional (T2) B cells were depleted after anti-CD20 treatment. When anti-CD20 was administered before development of SAT, development of SAT and anti-mouse thyroglobulin autoantibody responses were reduced. Anti-CD20 also reduced SAT severity and inhibited further increases in anti-mouse thyroglobulin autoantibodies when administered to mice that already had autoantibodies and thyroid inflammation. The results suggest that B cells are necessary for initiation as well as progression or maintenance of SAT in NOD.H-2h4 mice.     

Thyroid-specific expression of IFN-gamma limits experimental autoimmune thyroiditis by suppressing lymphocyte activation in cervical lymph nodes

The role of IFN-gamma in the pathogenesis of autoimmune disease is controversial, being described as immunostimulatory in some studies and immunosuppressive in others. To determine the contribution of local expression of IFN-gamma, we derived NOD.H-2(h4) transgenic mice overexpressing IFN-gamma in a thyroid-restricted manner. Transgenic mice, which had serum IFN-gamma levels similar to wild-type littermates, showed up-regulation of MHC class II on thyrocytes, but did not develop spontaneous thyroiditis. Upon immunization with murine thyroglobulin, transgenic mice developed milder disease and reduced IgG1 responses compared with wild type. The milder disease was associated with decreased frequency of activated CD44(+) lymphocytes in the cervical lymph nodes. This suppressive effect was confirmed by showing that blockade of systemic IFN-gamma with mAb enhanced disease and increased IgG1 responses. The study supports a disease-limiting role of IFN-gamma in autoimmune thyroiditis. Furthermore, it provides the first evidence that local IFN-gamma activity in the thyroid is sufficient for disease suppression.     

Association of different pathologic processes of the thyroid gland in fine needle aspiration samples

OBJECTIVE: To evaluate the possible significant association between different pathologic processes of the thyroid gland. STUDY DESIGN: From a series of 10,039 fine needle aspiration biopsies of the thyroid gland, a total of 1,330 cases were aspirated involving two or more palpable nodules. In 103 (1%) cases, two different pathologic processes were cytologically diagnosed. Statistical analysis was performed through four two-tailed chi 2 tests to evaluate the following events: (1) mononodularity and multinodularity vs. neoplasms, (2) colloid goiter and neoplasms, and (3) all neoplasms vs. colloid goiter and lymphocytic thyroiditis. All tests were performed using < .05 as the probability level. RESULTS: Simultaneous pathologic processes observed were: goiter and chronic lymphocytic thyroiditis (32), goiter and Hashimoto's thyroiditis (21), goiter and subacute granulomatous thyroiditis (8), goiter and follicular neoplasm (9), and goiter and papillary carcinoma (14). In 12 cases we found goiter and Hürthle cell tumor, goiter and medullary thyroid carcinoma (2), papillary thyroid carcinoma and Hashimoto's thyroiditis (2), Graves' disease and lymphocytic thyroiditis (2), and follicular neoplasm and lymphocytic thyroiditis (1). Statistical analysis showed significant association between multinodularity and neoplasms (P < .001), while the association between goiter and any type of neoplasia was not statistically significant. All the neoplasms taken together were associated with lymphocytic thyroiditis and goiter (P < .005). CONCLUSION: While there may be no statistically significant associations between the individual pathologies, it seems that having one pathology increases the risk of developing another. All the palpable nodules in the same gland should be investigated by fine needle aspiration in order to improve diagnostic sensitivity and to identify occult neoplasms.     

Iodine and IFN-gamma synergistically enhance intercellular adhesion molecule 1 expression on NOD.H2h4 mouse thyrocytes

NOD.H2(h4) mice spontaneously develop autoimmune lymphocytic thyroiditis that mimics human Hashimoto's thyroiditis, a disease where iodine, IFN-gamma, and adhesion molecules have all been implicated in the pathogenesis. To study how iodine and IFN-gamma modulate the expression of ICAM-1, we analyzed NOD.H2(h4) thyrocytes in baseline conditions (day 0) and at several time points following supplementation of iodine in the drinking water. On day 0, a small percentage ( approximately 10%) of thyrocytes constitutively expressed ICAM-1. The expression gradually increased to 13, 25, and 41% on days 7, 14 and 28, respectively, returning to baseline (9%) on day 35. The initial ICAM-1 kinetics was paralleled by thyroidal infiltration of CD45(+) hemopoietic cells, which increased from an average of 4% on day 0 to an average of 13, 21, and 24% on days 14, 28, and 35, respectively. To distinguish whether the observed ICAM-1 increase was a direct effect of iodine or a consequence of the immune infiltrate, we treated mouse primary thyrocyte cultures with 0.01 mM sodium iodine and showed a 3-fold increased ICAM-1 expression. To assess interaction between IFN-gamma and iodine, we analyzed CD45 and ICAM-1expression on thyrocytes from NOD.H2(h4) wild-type and NOD.H2(h4) thyr-IFN-gamma transgenic littermates. Strikingly, IFN-gamma interacted synergistically with iodine to enhance ICAM-1 expression on thyrocytes. These findings suggest that iodine and IFN-gamma cooperate to promote thyroidal expression of ICAM-1 in this mouse model of thyroiditis, highlighting the complex interplay present in the pathogenesis of Hashimoto's thyroiditis.     

碘与甲状腺疾病

碘是人体必需的微量元素,是合成甲状腺激素（thyroid hormone,TH）的主要原料。人体内的碘主要从饮水及食物中获取。碘的摄入缺乏或过量,不仅对TH的合成及分泌有至关重要的影响,而且与甲状腺形态及多种甲状腺疾病的发生、发展及转归密切相关。加碘盐的推广有效预防了碘缺乏可能引起的相关疾病;而碘过量导致的甲状腺疾病谱和发病率的急剧变化,也引起各界高度重视。流行病学调查表明,碘的摄入量与甲状腺功能亢进、自身免疫性甲状腺炎、甲状腺功能减退、甲状腺肿大和甲状腺癌等疾病的发病率密切相关。针对碘的相关生物学问题,对近年来的基础研究和人群研究进行综述,希望借此抛砖引玉,引起相关部门的重视,提高人民群众对碘营养的科学认识水平。     

TRAIL and DR5 Promote Thyroid Follicular Cell Apoptosis in Iodine Excess-Induced Experimental Autoimmune Thyroiditis in NOD Mice

Death receptor-mediated apoptosis has been implicated in target organ destruction in patients with chronic autoimmune thyroiditis. Several apoptosis signaling pathways, such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), have been shown to be active in thyroid cells and may be involved in destructive thyroiditis. Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet, but its pathogenic role remains unclear. The effects of excessive iodine on TRAIL and its death receptor expression in thyroid were investigated. Experimental autoimmune thyroiditis (EAT) was induced by excessive iodine and thyroglobulin (Tg) in non-obese diabetic mice. The expression of TRAIL and its death receptor DR5 was detected by immunofluorescence staining. Following administration of excessive iodine alone, Tg, and excessive iodine combined with Tg, TRAIL-positive cells appear not only in follicular cells but also in lymphocytes infiltrated in the thyroid, whereas DR5-positive cells appear only in follicular cells. Large numbers of CD3-positive cells and a few CD22-positive cells were detected in thyroid. A great amount of follicular cells were labeled specifically by terminal deoxynucleotide transferase-mediated deoxynucleotide triphosphate nick-end labeling assay. Taken together, our results suggest that excessive iodine could induce TRAIL and DR5 abnormal expression in thyroid. TRAIL band with DR5 to promote follicular cells apoptosis thus mediate thyroid destruction in EAT.     

Amiodarone: a common source of iodine-induced thyrotoxicosis

Amiodarone, a iodine-rich drug widely used in the treatment of tachyarrhythmias, represents one of the most common sources of iodine-induced thyrotoxicosis. The data concerning 58 patients with amiodarone-iodine-induced thyrotoxicosis (AIIT) were analyzed in the present study. Prevalence of AIIT was higher in males than in females (M/F = 1.23/l). Thyrotoxicosis occurred either during treatment with or at various intervals after withdrawal of amiodarone. AIIT developed not only in patients with underlying thyroid disorders, but also in subjects with apparently normal thyroid gland. Classical symptoms of thyrotoxicosis were often lacking, the main clinical feature being a worsening of cardiac disorders. Biochemical diagnosis of AIIT was established by the finding of elevated serum total and free triiodothyronine levels, since elevated serum total and free thyroxine could be found also in euthyroid amiodarone-treated subjects. Twenty-four-hour thyroid radioiodine uptake was very low or undetectable in AIIT patients with apparently normal thyroid glands, while it was inappropriately elevated in patients with underlying thyroid disorders, despite iodine contamination. The role of autoimmune phenomena in the pathogenesis of AIIT appeared to be limited, because circulating thyroid autoantibodies were undetectable in AIIT patients without underlying thyroid disorders or with nodular goiter. Conversely, humoral features of thyroid autoimmunity were mostly found in AIIT patients with diffuse goiter. Treatment of AIIT appeared to be a difficult challenge. Among the 11 patients given no treatment, thyrotoxicosis spontaneously subsided in the 5 patients with apparently normal thyroid gland, whereas the 6 patients with nodular or diffuse goiter were still hyperthyroid 6-9 months after discontinuation of the drug. The administration of high doses (40 mg/day) of methimazole alone proved to be ineffective in most (14/16) patients given this treatment. Twenty-seven patients were treated by methimazole combined with potassium perchlorate (1 g/day). With one exception, euthyroidism was restored within 15-90 days in all cases with underlying thyroid abnormalities, and within 6-55 days in subjects with apparently normal thyroid gland. Thus, the combined treatment appears to be the most effective one, but, due to the potential toxicity of potassium perchlorate, it should be reserved to patients with severe thyrotoxicosis and should be carefully monitored.     

Safe Range of Iodine Intake Levels: A Comparative Study of Thyroid Diseases in Three Women Population Cohorts with Slightly Different Iodine Intake Levels

Iodine excess may lead to thyroid diseases. Our previous 5-year prospective survey showed that the prevalence and incidence of hypothyroidism or autoimmune thyroiditis increased with iodine intake. The aim of the present study was to investigate the optimal range of iodine intake by comparing the prevalence of thyroid diseases in three areas with slightly different levels of iodine intake. In 2005, 778 unselected women subjects from three areas with different iodine intake levels were enrolled. Levels of serum thyroid hormones, thyroid autoantibodies, and urinary iodine were measured, and thyroid B ultrasounds were performed. Among the subjects with mildly deficient iodine intake, those with adequate intake, and those with more than adequate intake, the prevalence of clinical and subclinical hypothyroidism was 0, 1.13, and 2.84%, respectively (P = 0.014); that of thyroid goiter was 24.88, 5.65, and 11.37%, respectively (P < 0.001); that of serum thyrotropin values was1.01, 1.25, and 1.39 mIU/l, respectively; and that of serum thyrotropin/thyroglobulin ratio was 7.98, 6.84, and 5.11, respectively (P < 0.001). In conclusion, median urinary iodine 100~200 μg/l may reflect the safe range of iodine intake levels. Serum thyrotropin/thyroglobulin ratio might be a better index of evaluating iodine status.     

Dual roles for IFN-gamma,but not for IL-4, in spontaneous autoimmune thyroiditis in NOD.H-2h4 mice

Spontaneous autoimmune thyroiditis (SAT) is an organ-specific autoimmune disease characterized by chronic inflammation of the thyroid by T and B lymphocytes. To investigate the roles of Th1 and Th2 cytokines in the pathogenesis of SAT, IFN-gamma(-/-) and IL-4(-/-) NOD.H-2h4 mice were generated. IL-4(-/-) mice developed lymphocytic SAT (L-SAT) comparable to that of wild-type (WT) mice. They produced little anti-mouse thyroglobulin (MTg) IgG1, but had levels of anti-MTg IgG2b comparable to WT mice. Compared with WT mice, IFN-gamma(-/-) mice produced significantly less anti-MTg IgG1 and IgG2b. Absence of IFN-gamma resulted in abnormal proliferation of thyroid epithelial cells with minimal lymphocyte infiltration. Thyroids of IFN-gamma(-/-) mice had markedly reduced B lymphocyte chemoattractant expression, B cell and plasma cell infiltration, and decreased MHC class II expression on thyrocytes compared with WT mice. Adoptive transfer of WT splenocytes to IFN-gamma(-/-) mice restored the capacity to develop typical L-SAT, enhanced anti-MTg IgG1 and IgG2b production, up-regulated MHC class II expression on thyrocytes and decreased thyrocyte proliferation. These results suggest that IFN-gamma plays a dual role in the development of SAT. IFN-gamma is required for development of L-SAT, and it also functions to inhibit thyroid epithelial cell proliferation.     

Therapeutic effect of human amniotic epithelial cells in murine models of Hashimoto's thyroiditis and Systemic lupus erythematosus

Background aims

The chronic inflammation of autoimmune diseases develops repetitive localized destruction or systemic disorders, represented by Hashimoto's thyroiditis (HT) and Systemic lupus erythematosus (SLE) respectively. Currently, there are no efficient ways to treat these autoimmune diseases. Therefore, it is critically important to explore new therapeutic strategies. The aim of this study was to investigate the therapeutic efficacy of human amniotic epithelial cells (hAECs) in murine models of HT and SLE.

Distinct genetic pattern of mouse susceptibility to thyroiditis induced by a novel thyroglobulin peptide

Experimental autoimmune thyroiditis (EAT), induced by thuroglobulin (Tg) and adjuvant, is major histocompatibility complex-controlled and dependent on Tg-reactive T cells, but the immunopathogenic T-cell epitopes on Tg remain mostly undefined. We report here the thyroiditogenicity of a novel rat Tg peptide (TgP2; corresponding to human Tg amino acids 2695–2713), identified by algorithms as a site of putative T-cell epitope(s). TgP2 causes EAT in SJL (H-2 ^s) but not in C3H or B10.BR (H-2 ^k), BALB/c (H-2 ^d), and B10 (H-2 ^b) mice. This reveals a new genetic pattern of EAT susceptibility, since H-2 ^k mice are known to be high reponders (susceptible) after Tg challenge. Following in vivo priming with TgP2, T cells from only SJL mice proliferated significantly and consistently to TgP2 in vitro, whereas TgP2-specific IgG was observed in all strains tested. Adoptive transfer of TgP2-primed SJL lymph node cells to naive syngeneic recipients induced a pronounced mononuclear infiltration of the thyroid, which was more extensive than that observed after direct peptide challenge. TgP2 is non-immunodominant, since priming of SJL mice with rTg did not consistently elicit T-cell responses to TgP2 in vitro and a TgP2-specific T-cell hybridoma did not respond to antigen presenting cells pulsed with rTg. The data support the notion that Tg epitopes need not be either iodinated or immunodominant in order to cause severe thyroiditis and that the genetic pattern of the disease they induce can be distinct from that of Tg-mediated EAT. Correspondence to: G. Carayanniotis.     

Analyses of the serum concentrations and antigenic determinants of thyroglobulin in chickens susceptible to autoimmune thyroiditis

These studies revealed an abnormal elevation in serum thyroglobulin (Tg) concentrations of the thyroiditis-prone OS chicks. Their serum levels, measured by a sensitive and specific RIA, remained high for the first 2 wk of age, a time preceding significant lymphoid infiltration of their thyroid glands. The elevated serum Tg levels probably resulted from, or were related to, hyperactivity of the OS thyroid gland. Reducing the activity of the OS thyroid gland by exogenous administration of T4 caused a temporary but significant reduction in thyroidal infiltration and the synthesis of Tg antibodies. In addition to the analysis of serum concentrations of Tg, a competitive binding RIA was developed to determine whether unique antigenic determinants exist on Tg isolated from OS thyroid glands. This was proved to be unlikely because OS chicks produced autoantibodies that fully cross-reacted with Tg isolated from normal chicken thyroid glands. The relationships between intrinsic thyroid hyperactivity, high serum Tg levels, the sensitization of OS thymocytes, and thyroiditis are discussed.