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: 8896850
• 负责人: DeLisa Fairweather
• 金额: $ 13.38万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896850
• 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; 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; personalized medicine; 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.

描述（由申请人提供）：大多数慢性炎症性疾病（例如心血管和自身免疫性疾病）存在性别/性别差异。男性的心血管疾病（CVD）的发病率和严重程度更高，包括心肌炎/扩张性心肌病（DCM）和心力衰竭。男性从心肌炎转向DCM的频繁进展的原因尚不清楚。在心肌炎/DCM患者中观察到心脏中补体激活和免疫复合物沉积的明确证据，最近的一项蛋白质组学研究发现，心肌炎/DCM患者的前三个途径中有2个涉及经典和替代补体途径。 在初步研究中，我们表明，在男性的小鼠和人类的心肌炎/DCM期间，经典和替代补体途径被激活，但患有心肌炎/DCM的男性在其血清中具有比女性的促炎的补体C3水平更高，而与女性相比，性别差异在抗炎症的受体（CR）中（CR）/cr3 reducir rycry（CR）中存在性别差异（cr）。 （CVB3）心肌炎导致雌性小鼠的Th1，C3，C3，C311b/Cr3炎症，DCM和心力衰竭，以及在雌性小鼠中CVB3心肌炎期间CVB3心肌炎期间，白介素（IL）-4/TH2在心脏巨噬细胞和T细胞上增加了CR1/2的表达。据我们所知，这是第一个报告，是性激素驱动的补体差异和CR表达会影响患者和小鼠对心肌/DCM的敏感性。考虑到自身免疫性和心血管疾病期间补体在激活和调节炎症以及抗体/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的认识，以深刻和持久的方式。创新我们的CVB3诱导的心肌炎的自身免疫模型，它使用了心脏刺激的CVB3，其中包含感染性病毒和心脏蛋白质，它提供了一个独特的模型，可以更好地了解调节慢性炎症和心脏重塑的补体途径中的性别差异。我们知道，包括自身免疫性和心血管疾病在内的所有主要慢性炎症性疾病都表现出明显的性别差异，表现，症状和对治疗的反应，但这些性别差异的原因并不是研究的优先级。我们有望根据性激素的作用来看待慢性炎症的方式范式转变。随着对发展个性化医学的兴趣，CVD性别差异的生物学基础将需要更好地理解，并且仍然是发现的重要领域。基于小鼠模型的发现的具体目的，我们假设雌激素通过Th2细胞因子（例如IL-4）提高CR1水平，例如IL-4允许调节女性心肌炎，而睾丸激素会增加TH1型细胞因子，并抑制CR1的CR1，从而增加互补的CD11B+炎症，导致CD11b+炎症增加。为了研究这一假设，我们将在目标1）确定雌激素和睾丸激素如何改变补体/Cr途径表达以及目标2）确定在小鼠和人类和人类中，在心肌/dcm炎期间，在心肌炎期间，性激素是否通过Th1和Th2细胞因子（例如IL-4，IFN-）间接调节补体途径。总的来说，这些研究将有助于确定在心肌/DCM期间调节炎症和重塑的补体和CR中的性别差异。这项研究将进一步了解适用于受性别/性别影响的其他心血管和自身免疫性疾病的补体途径功能。