Sex in Viral Myocarditis

描述（由申请人提供）：心肌炎是一种炎症性疾病 心肌层大约65%的病例是由最近的肠道病毒引起的 感染和发生在男性。与人类一样，CVB 3感染会导致严重的 心肌炎的雄性，但不是处女雌性小鼠。雄激素（孕酮和 睾酮）增加心肌细胞上病毒受体表达，而17- β-雌二醇治疗则不然。由于淋巴细胞也表达CVB 3， 受体，我们假设激素可能调节淋巴细胞的表达 这些分子也是如此。此外，肠道病毒受体通常属于 免疫球蛋白和整合素超家族，它们具有重要的信号传导作用， 转导功能。病毒直接与正常淋巴细胞结合， 病毒暴露4小时内快速钙流和细胞因子释放。 男性和女性淋巴细胞与男性细胞之间的细胞因子释放不同 产生干扰素（IFN）γ的雌性细胞和产生白细胞介素（IL）的雌性细胞- 10.我们假设病毒，具有重复对称性的病毒 衣壳，交联淋巴细胞上的重要细胞表面分子， 快速非抗原特异性淋巴细胞活化。这种初始激活 与相关的细胞因子释放决定随后的先天和适应性 对病毒的免疫应答，如CD 4 + T辅助（Th）细胞应答， 自身免疫性CD 8 + T细胞在体内的发育/存活。的具体目标 该应用是：1）确定病毒受体表达，结合 对雄性和雌性动物的亲和力、激活潜力和细胞因子产生 暴露于非感染性病毒的淋巴样细胞; 2）确定以下因素的影响： CD 8 + α，β T细胞上的直接病毒相互作用和激素信号传导 受体（TCR）+和γ，δ TCR+效应细胞功能和存活 体内;和3）确定直接病毒相互作用和激素 病毒特异性CD 4 + α，β TCR+应答和体内存活的信号传导。 这些研究可能为病毒如何影响发育提供新的见解 宿主防御反应以及激素如何调节这种初始反应。

DESCRIPTION (provided by applicant): Myocarditis is an inflammatory disease of the myocardium. Approximately 65% of cases follow recent enterovirus infections and occur in males. As in humans, CVB3 infections cause severe myocarditis in male, but not virgin female mice. Androgens (progesterone and testosterone) increase virus receptor expression on cardiac myocytes while 17- beta-estradiol treatment does not. Since lymphocytes also express CVB3 receptors, we hypothesize that hormones might modulate lymphocyte expression of these molecules as well. Furthermore, enterovirus receptors often belong to immunoglobulin and integrin superfamilies, which have important signal transduction functions. Direct virus binding to normal lymphocytes causes rapid calcium flux and cytokine release within four hours of virus exposure. Cytokine release differs between male and female lymphocytes with male cells producing interferon (IFN)gamma and female cells producing interleukin (IL)- 10. We hypothesize that viruses, which have repetitive symmetry of the virus capsid, cross-link important cell surface molecules on lymphocytes and cause rapid non-antigen-specific lymphocyte activation. This initial activation with associated cytokine release determines subsequent innate and adaptive immune responses to the virus, such as CD4+ T helper (Th) cell response and development/survival of autoimmune CD8+ T cells in vivo. The Specific Aims of this application are to: 1) Determine virus receptor expression, binding avidity, activation potential and cytokine production on male and female lymphoid cells exposed to non-infectious virus; 2) Determine the effects of direct virus interaction and hormone signaling on CD8+alpha,beta T cell receptor (TCR)+ and gamma,delta TCR+ effector cell function and survival in vivo; and 3) Determine the effects of direct virus interaction and hormone signaling on virus-specific CD4+alpha,beta TCR+ response and survival in vivo. These studies may provide new insights as to how viruses affect developing host defense responses and how hormones can modulate this initial response.