Interferon gamma in autoimmune thyroiditis & thyroid function

干扰素γ在自身免疫性甲状腺炎中的作用

• 批准号: 7265107
• 负责人: PATRIZIO CATUREGLI
• 金额: $ 27.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7265107
• 关键词: Adipocytes; Apoptosis; Appearance; Askenazy Cells; Autoimmune Diseases; Autoimmune Process; Autoimmune thyroiditis; Autoimmunity; Cells; Cessation of life; Coculture Techniques; Conflict (Psychology); Disease; Epithelium; Fatty acid glycerol esters; Gene Expression; Genetic; Grant; Growth; Hashimoto Disease; Histocompatibility Antigens Class II; Human; Hypothyroidism; IRF1 gene; In Situ; Incidence; Intercellular Adhesion Molecules; Intercellular adhesion molecule 1; Interferon Type II; Interleukin-12; Knockout Mice; Leptin; Lesion; Link; Lymphocyte; Mediating; Monitor; Morphology; Mus; Nature; Numbers; Pathogenesis; Patients; Phenotype; Research Personnel; Role; Severities; Signal Transduction; T-Lymphocyte; Testing; Thyroid Function Tests; Thyroid Gland; Thyroiditis; Thyrotropin Receptor; Transgenic Mice; Transgenic Organisms; autoreactive T cell; base; caspase-8; design; human SLC5A5 protein; in vivo; leptin receptor; macrophage; programs; protective effect; transcription factor

Interferon gamma (IFNgamma) has been implicated in the pathogenesis of autoimmune (Hashimoto's) thyroiditis. We have generated transgenic mice that express IFNg specifically in the thyroid gland, and shown that IFNgamma a) directly induces primary hypothyroidism with decreased NIS expression; b) induces Hurthle cells-like and increase thyroidal fat; c) protects from autoimmune thyroiditis. Specific aim 1 is to test the hypothesis that the IFNg-driven activation of the immunoproteasome is critical to the ontogeny of Hurthle cells. We will: i) test whether pharmacologic or genetic blocks of the immunoproteasome inhibit the appearance of Hurthle cells; ii) evaluate in situ immunoproteasome expression in thyroids from thyr-IFNgamma transgenic mice, as well as from patients with Hurthle cell lesions. Specific aim 2 is to unravel the mechanism through which IFNgamma protects from autoimmune thyroiditis. We hypothesize that this protective effect is mediated by a caspase-8 dependent activation of apoptosis, which results in death of autoreactive, thyroid-specific lymphocytes. We will transduce autoreactive T cells with an inactive form of caspase-8 and adoptively transfer T cells to wild type or thyr-IFNgamma transgenic hosts, assessing thereafter the incidence and severity of thyroiditis. We wil also cross thyr-IFNgamma transgenics to knockout mice that lack IRF-1 or IRF-4, two critical transcription factors linking IFNgamma signaling with caspase-8 dependent apoptosis. Specific aim 3 is to study the interaction between IFNg interleukin-12 (IL-12) on thyroid autoimmunity and function. We have generated transgenic mice that express IL-12 specifically in the thyroid gland. The mice develop spontaneously lymphocytic thyroiditis and primary hypothyroidism with increased NIS expression. We will cross thyr-IL-12 transgenics to thyr-IFNg transgenics to assess whether the disease suppressive effect of IFNgamma prevails on the disease-promoting effect of IL-12, and whether IFNg and IL-12 synergistically induce a more severe form of hypothyroidism. Specific aim 4 is to investigate why thyroids from thyr-IFNg transgenic contain an increased number of adipocytes, and to assess whether this increase influences thyroid function. We hypothesize that thyroid macrophages primed in vivo by IFNg promote differentiation of stromal preadipocytes into mature adipocytes. We will co-culture thyroid macrophages from transgenics and controls with syngeneic pre-adipocytes, monitoring acquisition of morphological features typical of adipocytes. We also hypothesize that augmented TSH signaling is required to induce the adipocyte-rich phenotype, and cross thyr-IFNg transgenics to TSH receptor knockout mice.

干扰素γ (IFNgamma)与自身免疫性（桥本氏）甲状腺炎的发病机制有关。我们已经产生了在甲状腺中特异性表达IFNg的转基因小鼠，并表明IFNgamma a)直接诱导原发性甲状腺功能减退，并降低NIS的表达；b)诱导Hurthle细胞样细胞，增加甲状腺脂肪；C)预防自身免疫性甲状腺炎。具体目的1是验证ifng驱动的免疫蛋白酶体激活对Hurthle细胞的个体发生至关重要的假设。我们将：i)测试免疫蛋白酶体的药理学或遗传阻滞是否抑制Hurthle细胞的外观；ii)评估thyr-IFNgamma转基因小鼠和Hurthle细胞病变患者甲状腺中免疫蛋白酶体的原位表达。具体目的2是揭示IFNgamma保护自身免疫性甲状腺炎的机制。我们假设这种保护作用是由caspase-8依赖性的细胞凋亡激活介导的，细胞凋亡导致自身反应性甲状腺特异性淋巴细胞死亡。我们将用无活性的caspase-8转导自身反应性T细胞，并过继性地将T细胞转移到野生型或thyr-IFNgamma转基因宿主中，随后评估甲状腺炎的发病率和严重程度。我们还将交叉使用thyr-IFNgamma转基因基因敲除缺乏IRF-1或IRF-4的小鼠，IRF-1或IRF-4是连接IFNgamma信号与caspase-8依赖性凋亡的两个关键转录因子。具体目的3是研究IFNg白细胞介素-12 （IL-12）在甲状腺自身免疫和功能中的相互作用。我们已经产生了在甲状腺中特异性表达IL-12的转基因小鼠。小鼠出现自发性淋巴细胞性甲状腺炎和原发性甲状腺功能减退，并伴有NIS表达增加。我们将把thyr-IL-12转基因与thyr-IFNg转基因杂交，以评估IFNgamma的疾病抑制作用是否优于IL-12的疾病促进作用，以及IFNg和IL-12是否协同诱导更严重形式的甲状腺功能减退。具体目的4是研究为什么thyr-IFNg转基因的甲状腺含有更多的脂肪细胞，并评估这种增加是否影响甲状腺功能。我们假设IFNg在体内激活的甲状腺巨噬细胞促进基质前脂肪细胞向成熟脂肪细胞的分化。我们将转基因和对照的甲状腺巨噬细胞与同源前脂肪细胞共培养，监测脂肪细胞典型形态特征的获取。我们还假设需要增强的TSH信号来诱导富含脂肪细胞的表型，并将thyr-IFNg转基因到TSH受体敲除小鼠中。

项目成果

Studies on murine thyroiditis: new insights from organ flow cytometry.

小鼠甲状腺炎研究：器官流式细胞术的新见解。

• DOI: 10.1089/105072503322021070
• 发表时间: 2003
• 期刊: Thyroid : official journal of the American Thyroid Association
• 作者: Caturegli,Patrizio;Rose,NoelR;Kimura,Miho;Kimura,Hiroaki;Tzou,Shey-Cherng
• 通讯作者: Tzou,Shey-Cherng

Excess iodide decreases transcription of NIS and VEGF genes in rat FRTL-5 thyroid cells.

• DOI: 10.1016/j.bbrc.2010.01.123
• 发表时间: 2010-03-05
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Suzuki, Koichi;Kimura, Hiroaki;Wu, Huhehasi;Kudo, Naoko;Kim, Won Bae;Suzuki, Sayuri;Yoshida, Akio;Caturegli, Patrizio;Kohn, Leonard D.
• 通讯作者: Kohn, Leonard D.

Immunoproteasome overexpression underlies the pathogenesis of thyroid oncocytes and primary hypothyroidism: studies in humans and mice.

• DOI: 10.1371/journal.pone.0007857
• 发表时间: 2009-11-17
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kimura HJ;Chen CY;Tzou SC;Rocchi R;Landek-Salgado MA;Suzuki K;Kimura M;Rose NR;Caturegli P
• 通讯作者: Caturegli P

Oncocytic mania: a review of oncocytic lesions throughout the body.

嗜酸细胞躁狂：对全身嗜酸细胞病变的回顾。

• DOI: 10.1007/bf03347464
• 发表时间: 2011
• 期刊: Journal of endocrinological investigation
• 影响因子: 5.4
• 作者: Guaraldi,F;Zang,G;Dackiw,AP;Caturegli,P
• 通讯作者: Caturegli,P

Autoimmune hypophysitis of SJL mice: clinical insights from a new animal model.

SJL 小鼠的自身免疫性垂体炎：来自新动物模型的临床见解。

• DOI: 10.1210/en.2007-1692
• 发表时间: 2008
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Tzou,Shey-Cherng;Lupi,Isabella;Landek,Melissa;Gutenberg,Angelika;Tzou,Ywh-Min;Kimura,Hiroaki;Pinna,Giovanni;Rose,NoelR;Caturegli,Patrizio
• 通讯作者: Caturegli,Patrizio