Sex in Myocarditis

描述（由申请人提供）：心肌炎是一种通常由微生物感染引起的心脏炎症。男性比女性更容易患心肌炎。这种疾病中性别偏见的原因尚不完全清楚，然而，我们已经表明，骑车的年轻女性在腐烂加速因子（DAF; CD55）的表达中表现出自然波动，这是一种已知的柯萨奇病毒受体。此外，当DAF在卵巢周期的黄体期表达最高时，B淋巴细胞更容易受到柯萨奇病毒感染。我们建立了柯萨奇病毒B3 （CVB3）诱导的小鼠心肌炎模型。雄性老鼠极易患炎症性心脏病。处于卵巢周期发情期和发情期的雌鼠具有较高的抵抗力，而处于发情期和发情期的雌鼠易患此病。感染后24小时胰腺病毒滴度与心肌炎易感性相关。已发表的研究表明，只有在胰腺中迅速感染并复制到高滴度的CVB3变异才能诱导心肌炎。我们假设这种早期胰腺感染会升高循环TNFa水平，从而上调心脏中的DAF并促进心脏感染。雌激素抑制全身肿瘤坏死因子- α (TNFa)反应，这可能解释了CVB3在该性别中的致病性降低。我们还发现TNFa上调CD1d的表达，CD1d是一种参与先天免疫的主要组织相容性复合体l类分子。CD1d是激活表达Vy4+ T细胞受体的T细胞所必需的。vy4+细胞浸润CVB3感染的雄性小鼠的心脏，而不是雌性小鼠的心脏，并且是致病性所必需的。在病毒感染增强后（由于DAF表达增强），心脏中循环TNFa或细胞因子的增加可能是导致CD1d水平升高的原因。本提案的具体目的是：1)确定心脏特异性TNFa促进感染雌性小鼠心肌炎的能力；与心脏CD1d表达的关系；2)评价DAF在心肌炎中的作用及激素对DAF表达和感染的影响。通过了解控制病毒感染的因素和先天免疫的诱导，为更好的控制病毒疾病的机制提供可能。

DESCRIPTION (provided by applicant): Myocarditis is an inflammation of the heart which usually follows microbial infections. Men are more likely to develop myocarditis than women. The reasons for the gender bias in this disease are not completely clear, however, we have shown that young cycling women show natural fluctuations in expression of decay accelerating factor (DAF; CD55) which is a known receptor for coxsackieviruses. Furthermore, B lymphocytes are more susceptible to coxsackievirus infection when DAF expression is highest in the luteal phase of the ovarian cycle. We have established a murine model of coxsackievirus B3 (CVB3) induced myocarditis. Male mice are highly susceptible to inflammatory heart disease. Female mice in estrus and metestrus phases of the ovarian cycle are highly resistant, but females in diestrus and proestrus phases are suscceptible to the disease. Virus titers in the pancreas 24 hours after infection correlate to myocarditis susceptibility. Published studies have shown that only CVB3 variants which rapidly infect and replicate to high titers in the pancreas are able to induce myocarditis. We hypothesize that this early pancreatic infection elevates circulating TNFa levels which up-regulate DAF in the heart and promote cardiac infection. Estrogen suppresses systemic tumor necrosis factor-alpha (TNFa) responses which may explain the reduced pathogenicity of CVB3 in this sex. We have also shown that TNFa up-regulates expression of CD1d, a major histocompatibility complex class l-like molecule involved in innate immunity. CD1d is required for activation of T cells expressing the Vy4+ T cell receptor. vy4+ cells infiltrate the hearts of CVB3 infected male but not female mice and are required for pathogenicity. Increased circulating TNFa or cytokine produced in the heart after augmented virus infection (due to enhanced DAF expression) may be responsible for the increased CD1d levels. The Specific Aims of this proposal are to: 1) determine the ability of heart-specific TNFa to promote myocarditis in infected female mice; and the relationship to CD1d expression in the heart; and 2) evaluate the role of DAF in myocarditis and hormonal influence on DAF expression and infection. By understanding the factors controlling virus infection and induction of innate immunity, better mechanism for controlling viral disease should be possible.