Sex Differences in Complement during Myocarditis/DCM

心肌炎/扩张型心肌病期间补体的性别差异

• 批准号: 8370119
• 负责人: DeLisa Fairweather
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8370119
• 关键词: Acute; Agonist; Alternative Complement Pathway; Androgen Receptor; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigen-Antibody Complex; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological; Bone Marrow; Cardiac; Cardiovascular Diseases; Cells; ChIP-seq; Chimera organism; Chronic; Clinical; Collaborations; Complement; Complement 3b; Complement 4b; Complement Activation; Complement Receptor; Coxsackie Viruses; Cytokine Gene; Data; Deposition; Dilated Cardiomyopathy; Diphtheria Toxin; Disease; Estrogen Receptors; Estrogens; Female; Gender; Gene Targeting; Gonadal Steroid Hormones; Heart; Heart Diseases; Heart Transplantation; Heart failure; Hormones; Human; ITGAM gene; Immune; Immunoglobulins; Incidence; Individual; Inflammation; Inflammatory; Interferons; Interleukin-4; Knowledge; Macrophage-1 Antigen; Mediating; Medicine; Modeling; Mus; Myocardial; Myocarditis; Myocardium; Orchiectomy; Outcome; Pathogenesis; Pathway interactions; Patients; Predisposition; Prevalence; Proteins; Proteomics; Publications; Radiation; Regulation; Reporting; Research; Research Personnel; Research Priority; Role; Serum; Severities; Sex Characteristics; Source; Staging; Symptoms; T-Lymphocyte; Techniques; Testosterone; Time; Tissues; Treatment Efficacy; Ventricular Dysfunction; Virus; Woman; base; cofactor; complement pathway; cytokine; frontier; innovation; insight; interest; macrophage; male; men; mouse model; receptor expression; response; sex

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. PUBLIC HEALTH RELEVANCE: Men have a higher incidence and severity of cardiovascular diseases including myocarditis, dilated cardiomyopathy and heart failure than women. The reason why men progress more frequently from myocarditis to dilated cardiomyopathy is unclear. This project will define sex differences in complement pathways that regulate inflammation and heart failure.

描述（由申请人提供）：大多数慢性炎症性疾病（如心血管和自身免疫性疾病）存在性别/性别差异。男性心血管疾病（CVD）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。为什么男性更频繁地从心肌炎进展到DCM的原因尚不清楚。在心肌炎/DCM患者中观察到心脏中补体激活和免疫复合物（IC）沉积的明确证据，最近的蛋白质组学研究发现，心肌炎/DCM患者中前3种途径中的2种涉及经典和替代补体途径。 在初步研究中，我们表明，经典和替代补体途径在小鼠和两性人类的心肌炎/DCM期间被激活，但心肌炎/DCM男性血清中的促炎补体C3水平高于女性，在柯萨奇病毒B3（CVB 3）感染过程中，抗炎性补体受体（CR）1表达存在性别差异，睾酮降低CR 1/2，心肌炎导致雄性小鼠Th 1、C3、CD 11b/CR 3炎症、扩张型心肌病和心力衰竭增加，而雌性小鼠CVB 3心肌炎/扩张型心肌病期间，白细胞介素（IL）-4/Th2增加心脏巨噬细胞和T细胞上CR 1/2的表达。据我们所知，这是第一份报告，性别差异驱动的补体和CR表达的差异影响患者和小鼠对心肌炎/扩张型心肌病的易感性。考虑到补体在自身免疫性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，性激素如何影响补体介导的炎症和IC沉积的知识将极大地影响我们对这些疾病的发病机制的理解。创新我们的CVB 3诱导的心肌炎的自身免疫模型，使用含有感染性病毒和心脏蛋白的心脏传代CVB 3，提供了一个独特的模型，以更好地了解调节心脏慢性炎症和重塑的补体途径的性别差异。我们已经知道，所有主要的慢性炎症性疾病，包括自身免疫性疾病和心血管疾病，在患病率，表现，症状和对治疗的反应方面都显示出明显的性别差异，但这些性别差异的原因并不是研究的重点。我们正准备在如何看待基于性激素影响的慢性炎症方面进行范式转变。随着人们对开发个性化药物的兴趣越来越大，需要更好地理解CVD性别差异的生物学基础，这仍然是一个重要的发现前沿。具体目的基于我们的小鼠模型的发现，我们假设雌激素通过Th 2细胞因子如IL-4增加CR 1水平，从而调节女性的心肌炎，而睾酮增加Th 1型细胞因子并抑制CR 1，导致男性补体诱导的CD 11b+炎症增加。为了研究这一假设，我们将在目的1）中确定雌激素和睾酮如何改变补体/CR途径表达，并在目的2）中确定性激素是否通过Th 1和Th 2细胞因子（例如IL-4，IFN-γ）间接调节小鼠和人类心肌炎/DCM期间的补体途径。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CR的性别差异。这项研究将进一步深入了解补体途径的功能，适用于受性别影响的其他心血管和自身免疫性疾病。 公共卫生相关性：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、扩张型心肌病和心力衰竭。男性心肌炎发展为扩张型心肌病的原因尚不清楚。该项目将定义调节炎症和心力衰竭的补体途径的性别差异。