Sex in Myocarditis

描述（由申请人提供）：心肌炎是一种心脏炎症，通常发生在微生物感染之后。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，年轻的骑自行车的女性表现出衰变加速因子（CD 55）表达的自然波动，这是一种已知的柯萨奇病毒受体。此外，当卵巢周期的黄体期表达最高时，B淋巴细胞对柯萨奇病毒感染更敏感。我们建立了柯萨奇病毒B_3（CVB_3）诱导的小鼠心肌炎模型。雄性小鼠对炎症性心脏病非常敏感。处于卵巢周期的发情期和动情后期的雌性小鼠对该疾病具有高度抵抗性，但处于间情期和动情前期的雌性小鼠对该疾病易感。感染后24小时胰腺中的病毒滴度与心肌炎易感性相关。已发表的研究表明，只有快速感染并在胰腺中复制到高滴度的CVB 3变体才能诱导心肌炎。我们假设这种早期胰腺感染升高了循环TNF α水平，其上调了心脏中的TNF α并促进心脏感染。雌激素抑制全身肿瘤坏死因子-α（TNF α）反应，这可能解释了该性别中CVB 3致病性降低的原因。我们还表明，TNF α上调CD 1d的表达，CD 1d是一种参与先天免疫的主要组织相容性复合物I类分子。CD 1d是活化表达V γ 4 + T细胞受体的T细胞所必需的。vy 4+细胞浸润CVB 3感染的雄性而不是雌性小鼠的心脏，并且是致病性所需的。增强病毒感染后心脏中产生的循环TNF α或细胞因子增加（由于增强的TNF α表达）可能是导致CD 1d水平升高的原因。本提案的具体目的是：1）确定心脏特异性TNF α促进感染雌性小鼠心肌炎的能力;以及与心脏中CD 1d表达的关系;以及2）评价TNF α在心肌炎中的作用以及激素对TNF α表达和感染的影响。通过了解控制病毒感染和诱导先天免疫的因素，控制病毒性疾病的更好机制应该是可能的。

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.