Pathogenesis of Chagas Heart Disease

描述(申请人提供)：原生动物寄生虫克氏锥虫是查加斯病的病原体，这种疾病在数百万拉丁美洲人中造成严重的发病率和死亡。慢性感染这种寄生虫最常见也是最严重的副作用是查加斯心脏病(CHD)，这是一种病因不明的扩张型心肌病。对于CHD的发病机制已经提出了很多种，其中有两种引起了相当大的争议。由于Chagas死于心力衰竭的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的原因。更敏感的技术，如原位聚合酶链式反应和免疫组织化学，已经被用来分析这些心脏，确实存在寄生虫DNA和抗原。这些发现支持这样的假设，即寄生虫诱导的损伤加上宿主对寄生虫抗原剂的免疫是炎症刺激。另一个令人困惑的因素是，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。为了验证CHD发病机制的自身免疫假说，同时考虑寄生虫免疫假说，我们建立了一种CHD小鼠模型(克鲁兹毛滴虫巴西株感染雄性A/J小鼠)，在感染后迅速产生强大的心脏自身免疫和寄生虫特异性免疫。我们在过去几年的研究表明：(I)心脏自身免疫 (I)在感染的动物中发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模仿和旁观者激活的机制发展，以及(Iv)选择性地抑制肌球蛋白自身免疫并不能消除感染动物的组织炎症，这表明其他自身免疫反应可能是显著的和/或寄生虫特异性免疫假说足以引起组织炎症。本研究的具体目的是：(1)研究CHD中肌球蛋白自身免疫的分子模拟机制；(2)鉴定其他心脏自身抗原并确定其在CHD发病机制中的作用；(3)验证CHD发病机制中的自身免疫和寄生虫免疫假说。

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.