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

Xue, Haibo; Wang, Weiwei; Shan, Zhongyan; Li, Yuanbin; Li, Yushu; Teng, Xiaochun; Gao, Yun; Fan, Chenling; Wang, Teng

doi:10.1007/s12011-010-8815-x

Cited by 14 publications

(16 citation statements)

References 21 publications

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“…MHC class II expression is clearly induced by iodine treatment in thyrocytes, especially in those near the focal lymphocytic infiltrations [71]. Thyroid autoantibody titers are significantly upregulated along with the progression of lymphocytic infiltration [72]. Both thyroiditis and autoantibody generation can be abolished by depleting the populations of CD4 + T-cells, CD8 + T-cells or B-cells [73,74,75], indicating a critical role of lymphocytic infiltration in the development of iodine-induced AIT.…”

Section: Mechanisms Involved In Iodine-induced Autoimmune Thyroiditismentioning

confidence: 99%

“…CD4 + /CD25 + /Foxp3 + regulatory T-cells and Foxp3 gene expression were reduced in mice with iodine-induced thyroiditis [72], and the number of regulatory T-cells was negatively related to the severity of thyroiditis [82]. Iodine-induced thyroiditis was inhibited, at least in part, by the increased number of regulatory T-cells in NOD.H-2h4 mice expressing transgenic transforming growth factor (TGF)-β on thyrocytes [83]; while depletion of regulatory T-cells by anti-CD25 antibody before iodine treatment significantly exacerbated iodine-induced thyroiditis and increased anti-thyroglobulin antibody titers [84].…”

Section: Mechanisms Involved In Iodine-induced Autoimmune Thyroiditismentioning

confidence: 99%

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Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

Luo

Kawashima

Ishido

et al. 2014

IJMS

148

101

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The global effort to prevent iodine deficiency disorders through iodine supplementation, such as universal salt iodization, has achieved impressive progress during the last few decades. However, iodine excess, due to extensive environmental iodine exposure in addition to poor monitoring, is currently a more frequent occurrence than iodine deficiency. Iodine excess is a precipitating environmental factor in the development of autoimmune thyroid disease. Excessive amounts of iodide have been linked to the development of autoimmune thyroiditis in humans and animals, while intrathyroidal depletion of iodine prevents disease in animal strains susceptible to severe thyroiditis. Although the mechanisms by which iodide induces thyroiditis are still unclear, several mechanisms have been proposed: (1) excess iodine induces the production of cytokines and chemokines that can recruit immunocompetent cells to the thyroid; (2) processing excess iodine in thyroid epithelial cells may result in elevated levels of oxidative stress, leading to harmful lipid oxidation and thyroid tissue injuries; and (3) iodine incorporation in the protein chain of thyroglobulin may augment the antigenicity of this molecule. This review will summarize the current knowledge regarding excess iodide as an environmental toxicant and relate it to the development of autoimmune thyroid disease.

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Section: Mechanisms Involved In Iodine-induced Autoimmune Thyroiditismentioning

confidence: 99%

Section: Mechanisms Involved In Iodine-induced Autoimmune Thyroiditismentioning

confidence: 99%

Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

Luo

Kawashima

Ishido

et al. 2014

IJMS

148

101

View full text Add to dashboard Cite

show abstract

“…To investigate whether BID can cooperate with other thyroiditis risk factors to facilitate the development of autoimmune thyroiditis, we treated mice with iodine, a known risk factor for thyroiditis [10,12,13]. Mice treated with 0.3% iodine begin to show an increase in anti-Tg antibody at Week 4 in Tg-BID transgenic mice compared with wild type CBA/J (H-2 k) mice, and the level of anti-Tg antibody was significantly higher at Week 8 (* p < 0.01, Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…Among these elements, iodine is able to exert pleiotropic effects on either metabolic or immunological processes of thyroid. While iodine is an indispensable constituent of the two major thyroid hormones T3 and T4 [24], it contributes to the development of autoimmune thyroiditis by enhancing the antigenicity of thyroglobulin and reducing regulatory T cells [13,25]. Though iodine is known to contribute to the development of autoimmune thyroiditis [8-10], it may not be able to do so without other co-factors.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of BID in thyroids of transgenic mice increases sensitivity to iodine-induced autoimmune thyroiditis

Wang

Fan²,

Baker

2014

J Transl Med

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BackgroundBID functions as a bridge molecule between death-receptor and mitochondrial related apoptotic pathways to amplify apoptotic signaling. Our previous studies have demonstrated a substantial increase in BID expression in primary normal thyroid epithelia cells treated with inflammatory cytokines, including the combination of IFNγ and IL-1β or IFNγ and TNFα. The aim of this study was to determine whether an increase in BID expression in thyroid can induce autoimmune thyroiditis.MethodsA transgenic mouse line that expresses human BID in thyroid cells was established by fusing a mouse thyroglobulin (Tg) promoter upstream of human BID (Tg-BID). We tested whether the increased expression of pro-apoptotic BID in thyroid would induce autoimmune thyroiditis, both in the presence and absence of 0.3% iodine water.ResultsOur data show that Tg-BID mice in a CBA/J (H-2 k) background do not spontaneously develop autoimmune thyroiditis for over a year. However, upon ingestion of iodine in the drinking water, autoimmune thyroiditis does develop in Tg-BID transgenic mice, as shown by a significant increase in anti-Tg antibody and mononuclear cell infiltration in the thyroid glands in 30% of mice tested. Serum T4 levels, however, were similar between iodine-treated Tg-BID transgenic mice and the wild type mice.ConclusionsOur data demonstrate that increased thyroid expression of BID facilitates the development of autoimmune thyroiditis induced by iodine uptake. However, the overexpression of BID itself is not sufficient to initiate thyroiditis in CBA/J (H-2 k) mice.

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“…In fact, iodine feeding decreases the proportion of CD4 + CD25 + Foxp3 + T regs in the spleen (12,13) and thyroid glands (14) of NOD-H2 h4 mice. In addition, NOD-H2 h4 mice lacking the T cell costimulatory molecule CD28 develop a more severe form of iodine-accelerated thyroiditis and have fewer T regs in spleen and cervical lymph nodes (15).…”

Section: Introductionmentioning

confidence: 96%

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

Sharma

Dalmazi

Caturegli

2016

Thyroid

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Background: Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a negative regulator of immune responses that suppresses the activity of effector T cells and contributes to the maintenance of self tolerance. When blocked therapeutically, CTLA-4 leads to an overall activation of T cells that has been exploited for cancer control, a control associated however with a variety of immune-related side effects such as autoimmune thyroiditis. To investigate the mechanism(s) underlying this form of thyroiditis, we used the NOD-H2h4 mouse, a model that develops thyroiditis at very high incidence after addition of iodine to the drinking water. Methods: NOD-H2 h4 mice were started on drinking water supplemented with 0.05% sodium iodide when 8 weeks old and then injected with a hamster monoclonal antibody against mouse CTLA-4, polyclonal hamster immunoglobulins, or phosphate buffered saline when 11 weeks old. One month later (15 weeks of age), mice were sacrificed to assess thyroiditis, general immune responses in blood and spleen, and expression of indoleamine 2, 3-dioxygenase (IDO) in the thyroid and in isolated antigen-presenting cells after stimulation with interferon gamma. The study also analyzed IDO expression in four autopsy cases of metastatic melanoma who had received treatment with a CTLA-4 blocking antibody, and six surgical pathology Hashimoto thyroiditis controls. Results: CTLA-4 blockade worsened autoimmune thyroiditis, as assessed by a greater incidence, a more aggressive mononuclear cell infiltration in thyroids, and higher thyroglobulin antibody levels when compared to the control groups. CTLA-4 blockade also expanded the proportion of splenic CD4+ effector T cells, as well as the production of interleukin (IL)-2, interferon gamma, IL-10, and IL-13 cytokines. Interestingly, CTLA-4 blockade induced a strong expression of IDO in mouse and human thyroid glands, an expression that could represent a counter-regulatory mechanism to protect against the inflammatory environment. Conclusions: This study shows that CTLA-4 blockade exacerbates the iodine-accelerated form of thyroiditis typical of the NOD-H2 h4 mouse. The study could also have implications for cancer patients who develop thyroiditis as an immune-related adverse event after CTLA-4 blockade.

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

Cited by 14 publications

References 21 publications

Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

Iodine Excess as an Environmental Risk Factor for Autoimmune Thyroid Disease

Overexpression of BID in thyroids of transgenic mice increases sensitivity to iodine-induced autoimmune thyroiditis

Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase

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