Mercury Induced Autoimmunity

汞引起的自身免疫

基本信息

批准号：
7054646
负责人：
Kenneth Michael Pollard
金额：
$ 39.18万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7054646
关键词：
autoantibody autoimmune disorder cytokine cytokine receptors environmental exposure environmental toxicology gene expression hyperglobulinemia immunomodulators interferon gamma laboratory mouse leukocyte activation /transformation lymphocyte proliferation mercury poisoning molecular pathology receptor expression tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): Exposure to xenobiotics can produce aberrant immune reactions, including autoimmunity. Exposure of mice to the heavy metal mercury leads to systemic autoimmunity with characteristic lymphadenopathy, hypergammaglobulinemia, autoantibodies and immune complex disease. In both idiopathic and mercury-induced autoimmunity (mHglA) reductions in IFN-gamma levels are associated with reductions in both autoantibody levels and immune-complex mediated pathology. Prior studies have revealed that genes, which control IFN-gamma expression, such as IL-4, IL-12, STAT4 and ICE, do not significantly influence the development of mHglA. However absence of genes involved in IFN-gamma function (IFN-gamma, IFN-gamma receptor, IRF-1) suppresses development of mHglA, suggesting that specific defects in signaling pathways and gene expression subsequent to IFN-gamma/IFN-gamma receptor interaction control disease expression. These observations underlie the hypothesis that mHgIA is dependent upon IFN-gamma and that the severity of disease is regulated by molecular and cellular events downstream of IFN-gamma expression. This hypothesis will be addressed by four specific aims:- 1) Determination of the Site and Kinetics of IFN-gamma Production in mHglA, 2) Determination of the Cellular Requirements Leading to IFN-gamma Dependent mHglA, 3) Determination of the Genetic Requirements Leading to lFN-gamma Dependent mHglA, and 4) Examination of the Suppression of the IFN-gamma Response as a Therapy for IFN-gamma Dependent mHglA. Identification of the role that IFN-gamma plays in the development of induced murine systemic autoimmunity should prove applicable to murine models of idiopathic systemic autoimmunity and to human lupus.

描述（由申请人提供）：对异种生物的接触会产生异常的免疫反应，包括自身免疫性。小鼠暴露于重金属汞中会导致系统性自身免疫性，具有特征性的淋巴结病，高γ-球蛋白血症，自身抗体和免疫复杂疾病。在特发性和汞诱导的自身免疫性（MHGLA）中，IFN-GAMMA水平的降低与自身抗体水平和免疫复合介导的病理学的降低有关。先前的研究表明，控制IFN-GAMMA表达（例如IL-4，IL-12，STAT4和ICE）的基因不会显着影响MHGLA的发展。然而，缺乏IFN-GAMMA功能的基因（IFN-GAMMA，IFN-GAMMA受体，IRF-1）抑制了MHGLA的发展，这表明信号通路中的特定缺陷和IFN-GAMMA/IFN-GAMMA/IFN-GAMMA受体相互作用相互作用相互作用控制疾病的基因表达中的特定缺陷。这些观察结果是MHGIA取决于IFN-GAMMA的假设是疾病的严重程度，并由IFN-GAMMA表达下游的分子和细胞事件调节。 This hypothesis will be addressed by four specific aims:- 1) Determination of the Site and Kinetics of IFN-gamma Production in mHglA, 2) Determination of the Cellular Requirements Leading to IFN-gamma Dependent mHglA, 3) Determination of the Genetic Requirements Leading to lFN-gamma Dependent mHglA, and 4) Examination of the Suppression of the IFN-gamma Response as a Therapy for IFN-gamma Dependent mhgla。鉴定IFN-gamma在诱导的鼠系统自身免疫的发展中所发挥的作用应证明适用于特发性全身自身免疫性和人类狼疮的鼠模型。