Pathogenesis of Chagas Heart Disease

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，恰加斯病是一种导致数百万拉丁美洲人严重发病和死亡的疾病。慢性感染这种寄生虫最常见和最严重的不良反应是恰加斯心脏病（CHD），一种病因不明的扩张性心肌病。关于冠心病的发病机制，人们提出了许多机制，其中两种机制存在相当大的争议。由于死于心力衰竭的恰加斯病患者的心脏组织中很少或没有寄生虫，因此有人提出自身免疫可能是疾病发病机制的原因。更敏感的技术，如原位PCR和免疫组织化学，已经被用来分析这些心脏，确实，寄生虫DNA和抗原存在。这些发现支持了寄生虫诱导的损伤加上宿主对寄生虫抗原的免疫是炎症刺激的假设。另一个混淆因素是，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。为了验证自身免疫假说对冠心病发病机制的影响，同时考虑寄生虫免疫假说，我们建立了冠心病小鼠模型（雄性a /J小鼠巴西克氏T. cruzi菌株感染），该模型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：(1)心脏自身免疫

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.