Sex in Myocarditis

描述(申请人提供)：心肌炎是一种心脏炎症，通常伴随着微生物感染。男性比女性更容易患上心肌炎。这种疾病存在性别偏见的原因尚不完全清楚，然而，我们已经发现，年轻骑自行车的女性表现出衰退加速因子(DAF；CD55)的自然波动，该因子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淋巴细胞更容易感染柯萨奇病毒。我们建立了柯萨奇B3病毒(CVB3)诱导的小鼠心肌炎模型。雄性小鼠极易患炎症性心脏病。处于卵巢周期动情期和动情期的雌性小鼠具有高度的抵抗力，但处于动情间期和动情前期的雌性小鼠对这种疾病易感。感染后24小时胰腺中的病毒滴度与心肌炎的易感性相关。已发表的研究表明，只有在胰腺中快速感染并复制到高滴度的CVB3变体才能诱发心肌炎。我们推测，这种早期的胰腺感染提高了循环中的TNFa水平，从而上调了心脏中的DAF，并促进了心脏感染。雌激素抑制全身肿瘤坏死因子-α(TNFa)反应，这可能解释了CVB3在两性中致病性降低的原因。我们还发现，TNFa上调CD1d的表达，CD1d是一种主要的组织相容性复合体，类似L的分子，参与先天性免疫。CD1d是激活表达Vy4+T细胞受体的T细胞所必需的。Vy4+细胞渗透到感染CVB3的雄性小鼠的心脏，而不是雌性小鼠的心脏，是致病所必需的。在病毒感染增强后(由于DAF表达增强)，循环中的TNFa或心脏中产生的细胞因子的增加可能是CD1d水平增加的原因。这项建议的具体目的是：1)确定心脏特异的TNFa在感染的雌性小鼠中促进心肌炎的能力；以及与心脏中CD1d表达的关系；2)评估DAF在心肌炎中的作用以及激素对DAF表达和感染的影响。通过了解控制病毒感染的因素和诱导天然免疫，应该有可能更好地控制病毒疾病的机制。

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.