Pathogenesis of Chagas Heart Disease

恰加斯心脏病的发病机制

• 批准号: 6999368
• 负责人: David M. Engman
• 金额: $ 28.49万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999368
• 关键词: Trypanosoma cruzi; autoantigens; autoimmune disorder; cross immunity; disease /disorder model; idiopathic dilated cardiomyopathy; laboratory mouse; male; microorganism antigen; microorganism immunology; myosins; pathologic process; trypanosomiasis

DESCRIPTION (provided by the applicant): The protozoan parasite Trypanosoma cruzi is the etiologic agent of Chagas' disease, an illness that causes severe morbidity and death among millions of Latin Americans. The most common, and most serious, adverse effect of chronic infection with this parasite is Chagas heart disease (CHD), a dilated cardiomyopathy of uncertain etiology. A number of mechanisms have been proposed for the pathogenesis of CHD, two of which are the subject of considerable controversy. Because parasites are scarce in or absent from the heart tissues of Chagas' patients who succumb to heart failure, autoimmunity has been proposed to be responsible for disease pathogenesis. More sensitive techniques, such as in situ PCR and immunohistochemistry, have been used to analyze these hearts and, indeed, parasite DNA and antigen are present. These findings support the hypothesis that parasite-induced damage plus host immunity to parasite antiqens is the inflammatory stimulus. Another confounding factor is that different combinations of parasite and animal strains give different outcomes, which, in actuality, is reflective of the human disease. To test the autoimmunity hypothesis for CHD pathogenesis, while simultaneously considering the parasite immunity hypothesis, we developed a mouse model of CHD (T. cruzi Brazil strain infection of male A/J mice) in which strong cardiac autoimmunity and parasite-specific immunity rapidly develop upon infection. Our research during the past several years indicates that (i) cardiac autoimmunity develops upon infection that is of similar magnitude and quality as that induced by immunization with cardiac proteins in adjuvant (purely autoimmune), (ii) autoimmunity involving a number of cardiac antigens develops in infected animals, (iii) autoimmunity to cardiac myosin may develop via the mechanisms of molecular mimicry and bystander activation, and (iv) selective suppression of myosin autoimmunity does not eliminate tissue inflammation in infected animals, suggesting that other autoimmune responses may be significant and/or that parasite-specific immunity hypothesis is sufficient to give tissue inflammation. The Specific Aims of our research are (i) to investigate the molecular mimicry mechanism of myosin autoimmunity in CHD, (ii) to identify additional cardiac auto-antigens and determine their roles in CHD pathogenesis and (iii) to test the autoimmune and parasite immune hypotheses for CHD pathogenesis.

描述（由申请人提供）：原生动物寄生虫克氏锥虫是恰加斯病的病原体，这种疾病导致数百万拉丁美洲人严重发病和死亡。这种寄生虫慢性感染最常见、最严重的不良反应是恰加斯心脏病 (CHD)，这是一种病因不明的扩张型心肌病。对于CHD的发病机制，人们提出了多种机制，其中两种机制存在相当大的争议。由于死于心力衰竭的查加斯病患者的心脏组织中寄生虫很少或不存在，因此自身免疫被认为是疾病发病机制的原因。更灵敏的技术，例如原位 PCR 和免疫组织化学，已被用来分析这些心脏，并且确实存在寄生虫 DNA 和抗原。这些发现支持这样的假设：寄生虫引起的损伤加上宿主对寄生虫抗原的免疫是炎症刺激。另一个混杂因素是寄生虫和动物菌株的不同组合会产生不同的结果，这实际上反映了人类疾病。为了检验冠心病发病机制的自身免疫假说，同时考虑寄生虫免疫假说，我们开发了一种冠心病小鼠模型（雄性A/J小鼠的克氏锥虫巴西株感染），其中强烈的心脏自身免疫和寄生虫特异性免疫迅速发展感染后。我们过去几年的研究表明（i）心脏自身免疫 感染的程度和质量与佐剂中的心脏蛋白免疫诱导的感染相似（纯自身免疫），（ii）在受感染的动物中产生涉及多种心脏抗原的自身免疫，（iii）对心肌肌球蛋白的自身免疫可能通过分子拟态和旁观者激活机制，以及（iv）选择性抑制肌球蛋白自身免疫并不能消除受感染动物的组织炎症，表明其他自身免疫反应可能也很重要和/或寄生虫特异性免疫假说足以引起组织炎症。我们研究的具体目标是（i）研究冠心病肌球蛋白自身免疫的分子模拟机制，（ii）识别其他心脏自身抗原并确定它们在冠心病发病机制中的作用，以及（iii）测试自身免疫和寄生虫免疫CHD 发病机制的假设。