Sex Differences in Complement during Myocarditis/DCM

描述(申请人提供)：大多数慢性炎症性疾病，如心血管疾病和自身免疫性疾病，存在性别/性别差异。男性心血管疾病的发病率和严重程度高于女性，包括心肌炎/扩张型心肌病(DCM)和心力衰竭。男性更频繁地从心肌炎进展为扩张型心肌炎的原因尚不清楚。在心肌炎/DCM患者中观察到明显的补体激活和免疫复合物(IC)沉积的证据，最近的一项蛋白质组学研究发现，在心肌炎/DCM患者中，前3条途径中有2条涉及经典和替代补体途径。在初步研究中，我们发现经典和替代补体途径在心肌炎/DCM期间被激活，但男性心肌炎/DCM患者血清中促炎症补体C3的水平高于女性，抗炎补体受体(CR)1的表达存在性别差异，在柯萨奇病毒B3(CVB3)心肌炎期间睾酮减少CR1/2，导致雄性小鼠Th1、C3、CD11b/CR3炎症、DCM和心力衰竭增加，而白介素4/Th2增加了雌性CVB3心肌炎/DCM小鼠心脏巨噬细胞和T细胞上CR1/2的表达。据我们所知，这是第一份报告，性激素驱动的补体和CR表达的差异会影响患者和小鼠患心肌炎/DCM的易感性。考虑到补体在自身免疫和心血管疾病中激活和调节炎症和抗体/自身抗体水平的重要性，了解性激素如何影响补体介导的炎症和IC沉积将极大地影响我们对这些疾病发病机制的深刻和持久的理解。创新我们的CVB3诱导心肌炎的自身免疫模型，该模型使用心脏传递的含有感染病毒和心脏蛋白的CVB3，提供了一种独特的模型，可以更好地了解补体途径中的性别差异，补体途径调节心脏的慢性炎症和重塑。我们已经知道，所有主要的慢性炎症性疾病，包括自身免疫和心血管疾病，在患病率、表现、症状和对治疗的反应方面都显示出显著的性别差异，但造成这些性别差异的原因并不是研究的重点。我们正准备改变我们对慢性炎症的看法，这是基于性激素的影响。随着人们对开发个性化药物的兴趣越来越大，心血管疾病性别差异的生物学基础将需要得到更好的理解，并仍然是发现的一个重要前沿。根据我们的小鼠模型的研究结果，我们假设雌激素通过Th2细胞因子(如IL-4)增加CR1水平，从而调节女性心肌炎，而睾酮增加Th1型细胞因子并抑制CR1，导致男性补体诱导的CD11b+炎症增加。为了研究这一假说，我们将在目标1)确定雌激素和睾酮如何改变补体/CR途径的表达，并在目的2)确定性激素是否通过Th1和Th2细胞因子(如IL-4、干扰素-)间接调节小鼠和人类心肌炎/DCM过程中的补体途径。总的来说，这些研究将有助于确定在心肌炎/DCM期间调节炎症和重塑的补体和CRS的性别差异。这项研究将进一步深入了解补体途径的功能，这些途径适用于受性别/性别影响的其他心血管和自身免疫性疾病。

DESCRIPTION (provided by applicant): Sex/gender differences exist for most chronic inflammatory diseases such as cardiovascular and autoimmune diseases. Men have a higher incidence and severity of cardiovascular diseases (CVDs) including myocarditis/dilated cardiomyopathy (DCM) and heart failure than women. The reason why men progress more frequently from myocarditis to DCM is unclear. Clear evidence for complement activation and immune complex (IC) deposition in the heart is observed in myocarditis/DCM patients, and a recent proteomics study found that 2 of the top 3 pathways in myocarditis/DCM patients involved the classical and alternative complement pathways. In preliminary studies we show that the classical and alternative complement pathways are activated during myocarditis/DCM in mice and humans of both sexes but that men with myocarditis/DCM have higher levels of proinflammatory complement C3 in their sera than women, that sex differences exist in anti-inflammatory complement receptor (CR)1 expression with testosterone reducing CR1/2 during coxsackievirus B3 (CVB3) myocarditis resulting in increased Th1, C3, CD11b/CR3 inflammation, DCM and heart failure in male mice, and that interleukin (IL)-4/Th2 increases CR1/2 expression on cardiac macrophages and T cells during CVB3 myocarditis/DCM in female mice. This is the first report, to our knowledge, that sex hormone-driven differences in complement and CR expression influence susceptibility to myocarditis/DCM in patients and mice. Considering the importance of complement in activating and regulating inflammation and antibody/autoantibody levels during autoimmune and cardiovascular diseases, knowledge of how sex hormones influence complement-mediated inflammation and IC deposition will greatly impact our understanding of the pathogenesis of these diseases in profound and lasting ways. Innovation Our autoimmune model of CVB3-induced myocarditis, which uses heart-passaged CVB3 containing infectious virus and heart proteins, provides a unique model to gain better insight into sex differences in complement pathways that regulate chronic inflammation and remodeling in the heart. We have known that all major chronic inflammatory diseases, including autoimmune and cardiovascular diseases, display marked sex differences in prevalence, presentation, symptoms and response to therapy, but the reason for these sex differences has not been a research priority. We are poised for a paradigm shift in how we view chronic inflammation based on the effect of sex hormones. With an increased interest in developing personalized medicine, the biological basis for sex differences in CVD will need to be better understood and remains an important frontier for discovery. Specific Aims Based on findings from our mouse model, we hypothesize that estrogen increases CR1 levels via Th2 cytokines like IL-4 allowing regulation of myocarditis in females, while testosterone increases Th1-type cytokines and inhibits CR1 resulting in increased complement-induced CD11b+ inflammation in males. To investigate this hypothesis we will determine in Aim 1) how estrogen and testosterone alter complement/CR pathway expression and in Aim 2) determine whether sex hormones regulate complement pathways indirectly via Th1 and Th2 cytokines (e.g. IL-4, IFN- ) during myocarditis/DCM in mice and humans. Collectively, these studies will help define sex differences in complement and CRs that regulate inflammation and remodeling during myocarditis/DCM. This research will provide further insight into the function of complement pathways that applies to other cardiovascular and autoimmune diseases that are influenced by sex/gender.