Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2<sup>h4</sup>Mice

Kolypetri, Panayota; King, Justin J.; Larijani, Mani; Carayanniotis, George

doi:10.3109/08830185.2015.1065828

Cited by 20 publications

(21 citation statements)

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“…A common concern with studies of autoimmune thyroid diseases in NOD.H-2h4 mice is the requirement for supraphysiologic concentrations of iodine for early development of autoimmune disease (45–48). Although NaI supplementation facilitates early development of severe TEC H/P in CD28 −/− mice, many mice develop severe TEC H/P without iodine supplementation (Fig.…”

Section: Discussionmentioning

confidence: 99%

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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60–70 % of IFN-γ−/− NOD.H-2h4 mice given NaI-supplemented water develop a slow onset autoimmune thyroid disease, characterized by thyrocyte epithelial cell hyperplasia/ proliferation (TEC H/P). TEC H/P develops much earlier in CD28−/− mice and nearly 100 % (both sexes) have severe TEC H/P at 4 months of age. Without NaI supplementation, 50% of 5–6 month old CD28−/−IfFN-γ−/− mice develop severe TEC H/P, and 2–3 weeks of NaI is sufficient for optimal development of severe TEC H/P. Mice with severe TEC H/P are hypothyroid and normalization of serum thyroxine (T4) levels does not reduce TEC H/P. Activated CD4+ T cells are sufficient to transfer TEC H/P to SCID recipients. Thyroids of mice with TEC H/P have infiltrating T cells and expanded numbers of proliferating thyrocytes that highly express CD40. CD40 facilitates, but is not required for development of severe TEC H/P, as CD40−/−IFN-γ−/−CD28−/− mice develop severe TEC H/P. Accelerated development of TEC H/P in IFN-γ−/− CD28−/− mice is a result of reduced Treg numbers as CD28−/− mice have significantly fewer Tregs, and transfer of CD28-positive Tregs inhibits TEC H/P. Essentially all female IFN-γ−/− CD28−/−NOD.H-2h4 mice have substantial lymphocytic infiltration of salivary glands and reduced salivary flow by 6 months of age, thereby providing an excellent new model of autoimmune exocrinopathy of the salivary gland. This is one of very few models where autoimmune thyroid disease and hypothyroidism develop in most mice by 4 months of age. This model will be useful for studying the effects of hypothyroidism on multiple organ systems.

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Section: Discussionmentioning

confidence: 99%

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

Kayes

Weisman

Camden

et al. 2016

The Journal of Immunology

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“…Interestingly, the original authors also noted that addition of sodium iodide to the drinking water accelerated the incidence and severity of thyroiditis in the NOD-H2 h4 but not the parental NOD strain (8), an observation later confirmed and expanded by others (9,10). More specifically, once iodine-rich water supplementation is started (typically done at two months of age), thyroiditis ensues within two weeks and becomes fully prevalent at about five months of age (5). This anticipation and worsening of thyroiditis by iodine has been the subject of numerous studies and hypotheses (4,5).…”

Section: Introductionmentioning

confidence: 89%

“…The authors noted that the congenic NOD-H2 h4 strain (K ) but acquired thyroiditis, as assessed by the appearance of mononuclear cell infiltration in the thyroid gland and circulating thyroglobulin antibodies. It is now well established that thyroiditis in NOD-H2 h4 mice first emerges at about four months of age and becomes fully prevalent at 12 months (4,5). In contrast to the human counterpart (Hashimoto thyroiditis), in NOD-H2 h4 mice thyroperoxidase antibodies develop only later (6), thyroxine remains normal (7), and males are as equally affected as females (4,5).…”

Section: Introductionmentioning

confidence: 99%

“…It is now well established that thyroiditis in NOD-H2 h4 mice first emerges at about four months of age and becomes fully prevalent at 12 months (4,5). In contrast to the human counterpart (Hashimoto thyroiditis), in NOD-H2 h4 mice thyroperoxidase antibodies develop only later (6), thyroxine remains normal (7), and males are as equally affected as females (4,5). Interestingly, the original authors also noted that addition of sodium iodide to the drinking water accelerated the incidence and severity of thyroiditis in the NOD-H2 h4 but not the parental NOD strain (8), an observation later confirmed and expanded by others (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…More specifically, once iodine-rich water supplementation is started (typically done at two months of age), thyroiditis ensues within two weeks and becomes fully prevalent at about five months of age (5). This anticipation and worsening of thyroiditis by iodine has been the subject of numerous studies and hypotheses (4,5). One view is that incorporation of iodine in thyroglobulin renders this autoantigen more immunogenic, and thus more easily recognizable by autoreactive T cells.…”

Section: Introductionmentioning

confidence: 99%

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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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Development of Targeted Therapies Based on Gene Modification

Benson

Leti

DiStefano

2018

Methods in Molecular Biology

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With the advent of next-generation sequencing (NGS) and the demand for a personalized healthcare system, the fields of precision medicine and gene therapy are advancing in new directions. There is a push to identify genes that contribute to disease development, either alone or in conjunction with other genes or environmental factors, and then design targeted therapies based on this knowledge, rather than the traditional approach of treating generalized symptoms with pharmaceuticals in a one-size-fits-all manner. Identification of genes that contribute to disease pathogenesis and progression is critical for the maturation of the precision medicine field. Concomitant with a better understanding of disease pathology, precision medicine approaches can be adopted with greater confidence and are expected to lead to a new standard for clinical practice. In this chapter, we provide a brief introduction to precision medicine, discuss the importance of identifying genes and genetic variants that contribute to disease development and progression, offer examples of approaches that can be applied to treat specific diseases, and present some of the current challenges and limitations of precision medicine.

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Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2^h4Mice

Cited by 20 publications

References 95 publications

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

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

Development of Targeted Therapies Based on Gene Modification

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Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2h4Mice

Cited by 20 publications

References 95 publications

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

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

Development of Targeted Therapies Based on Gene Modification

Contact Info

Product

Resources

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Genes and Environment as Predisposing Factors in Autoimmunity: Acceleration of Spontaneous Thyroiditis by Dietary Iodide in NOD.H2^h4Mice