FEASIBILITY STUDY--AUTOIMMUNE CARDIOMYOPATHY/AUTOANTIGENS IN CHAGAS' DISEASE

可行性研究--自身免疫性心肌病/恰加斯病中的自身抗原

• 批准号: 3792022
• 负责人: David M. Engman
• 金额: --
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3792022
• 关键词: T lymphocyte; Trypanosoma cruzi; antigen antibody reaction; autoantigens; autoimmune disorder; cellular immunity; cellular pathology; cross immunity; delayed hypersensitivity; fusion gene; genetic strain; humoral immunity; immunoregulation; laboratory mouse; leukocyte activation /transformation; medical complication; molecular cloning; myocarditis; trypanosomiasis; western blottings

Various human autoimmune diseases, including the rheumatologic diseases ankylosing spondylitis and rheumatoid arthritis, have been associated with etiologies triggered by infectious processes. Unfortunately, there are few animal models useful for the study of autoimmunity resulting directly from an infectious disease. Infection of mice with the protozoan parasite Trypanosoma cruzi, the agent of human Chagas' disease, constitutes a particularly good system because the acute and chronic pathology is virtually identical to that seen in the human. The most common (and most serious) adverse effect of chronic infection with this parasite is the development of cardiomyopathy. Because parasites are rarely found at autopsy in the heart tissues of chagasic patients who succumb to heart failure, an autoimmune basis has been proposed to be responsible for disease pathogenesis. This hypothesis has been supported by extensive experimentation in which cross-reactive T. cruzi and mammalian antigens have been identified, and the development of chagasic pathology has been induced by the transfer of T cells from infected mice to naive recipients. Although we and others have identified T. cruzi antigens potentially involved in autoimmune pathogenesis, the approaches used have been indirect. Using an immunologic screening strategy, we propose to identify mammalian heart antigens that are targets of the immune response during T. cruzi infection by directly cloning the genes that encode them. The humoral and cellular immune responses to these putative autoantigens will be investigated and their potential roles in Chagas' disease pathogenesis determined. If these studies implicate antigen-specific autoimmune responses in disease pathogenesis, we will attempt to induce disease in naive recipients via the transfer of autoantigen-specific antibodies or T cells - the ultimate confirmatory test for antigen-specific autoimmunity.

各种人类自身免疫性疾病，包括风湿病 强直性脊柱炎和类风湿性关节炎都与 由感染过程引发的病因。 不幸的是，很少有 可用于研究直接引起的自身免疫的动物模型 一种传染病。 小鼠感染原生动物寄生虫 克氏锥虫是人类恰加斯病的病原体， 特别好的系统，因为急性和慢性病理学是 与在人类身上看到的几乎相同。 最常见（也是最 慢性感染这种寄生虫的严重）副作用是 心肌病的发展。 因为寄生虫很少见 对死于心脏病的恰加斯病患者的心脏组织进行尸检 失败，已提出自身免疫基础负责 疾病发病机制。 这一假说得到了广泛的支持 克氏锥虫与哺乳动物抗原发生交叉反应的实验 已被确定，恰加斯病病理学的发展已 由受感染小鼠的 T 细胞转移至初始受体诱导。 尽管我们和其他人已经潜在地鉴定出克氏锥虫抗原 参与自身免疫发病机制，所使用的方法已被 间接。 我们建议使用免疫筛选策略来识别 哺乳动物心脏抗原是 T 期间免疫反应的目标。 通过直接克隆编码它们的基因来感染 cruzi。 这 对这些假定的自身抗原的体液和细胞免疫反应将 进行研究及其在恰加斯病发病机制中的潜在作用 决定。 如果这些研究表明抗原特异性自身免疫 疾病发病机制中的反应，我们将尝试诱发疾病 通过转移自身抗原特异性抗体或 T 细胞 - 抗原特异性自身免疫的最终确认测试。