Role of innate immunity in autoimmune myocarditis

描述（由申请人提供）：心肌炎是青少年和年轻人心衰的重要原因。虽然大约33%的心肌炎患者康复，但其余患者可能发展为慢性扩张型心肌病，占北美所有心力衰竭的25%。柯萨奇病毒B3 （CB3）感染与约40%的心肌炎病例有关。抗病毒药物和免疫抑制疗法的结果好坏参半，需要进一步研究以开发有效的治疗方法。对小鼠CB3诱导的心肌炎的研究为CB3在自身免疫性心肌炎发展中的适应性、获得性免疫反应提供了有价值的信息。虽然已知适应性T细胞对CB3的反应在心肌炎的发展中发挥作用，但对CB3感染的早期先天免疫反应如何影响自身免疫性疾病的发展知之甚少。本提案的目的是表征CB3感染的先天免疫反应，以确定导致自身免疫性疾病的因素。我们假设早期对CB3感染的先天免疫反应决定了后来的适应性免疫反应，从而导致自身免疫性心肌炎的发展。为了研究这一假设，我们提出了三个具体目标：(i)检查早期先天免疫细胞因子的作用，（ii）早期先天免疫细胞的作用，以及（iii）补体在自身免疫性心肌炎发展中的作用。这些研究结果将有助于理解由感染引发的自身免疫性疾病的发展。

DESCRIPTION (provided by applicant): Myocarditis is an important cause of heart failure among adolescents and young adults. While about 33% of myocarditis patients recover, the remainder may develop chronic dilated cardiomyopathy which accounts for 25% of all heart failures in North America. Coxsackievirus B3 (CB3) infections have been implicated in around 40% of myocarditis cases. Antiviral drugs and immunosuppressive therapies have given mixed results, requiring further research in order to develop effective therapies. Studies of CB3-induced myocarditis in mice have provided valuable information about the role of the adaptive, acquired immune response to CB3 in the development of autoimmune myocarditis. Although the adaptive T cell response to CB3 is known to play a role in the development of myocarditis, little is understood on how the early, innate immune response to CB3 infection effects the development of autoimmune disease. The aim of this proposal is to characterize the innate immune response to CB3 infection in order to determine the factors that lead to autoimmune disease. We hypothesize that the early innate immune response to CB3 infection determines the later adaptive immune response leading to the development of autoimmune myocarditis. To investigate this hypothesis, we propose three specific aims: (i) to examine the role of early innate immune cytokines, (ii) the role of early innate immune cells, and (iii) the role of complement in the development of autoimmune myocarditis. The findings generated by these studies will aid in understanding the development of autoimmune disease initiated by infection.