Mechanisms Regulating Neutrophil Activation in Pregnancy

描述(由申请人提供)：本申请于 对请求应用程序识别和表征的RFA的响应 不同性别之间先天免疫反应和获得性免疫反应的差异 具体呼吁进行跨学科的临床和基础研究 可能对了解和治疗自身免疫性疾病具有重要意义。 中性粒细胞是动态平衡发展的关键细胞 病理性炎症反应。这些细胞在体内起着核心作用 自身免疫性疾病(即类风湿)中组织损伤的产生 (关节炎)以及包括败血症在内的传染病。这些研究 在本应用程序中概述的内容旨在研究 中性粒细胞在非孕妇、孕妇和男性中的功能。研究 在我们实验室进行的研究已经证实，正常的中性粒细胞 孕妇有一种独特的免疫状态，这是 以前认识到的。这种状态表现出同时表达 反映在细胞钙离子中的激活和抑制的中性粒细胞特性 信号、新陈代谢和氧化剂的产生。我们已经证明了 这些属性在交付后不久就会反转，因此可以解释 在一些自身免疫性疾病中，产后疾病活跃度增加。我们的 初步研究已经确定了这些变化的生化基础 正常妊娠中性粒细胞生理学观察及其与己糖的关系 单磷酸分流和脂筏在钙调节中的作用 信号、新陈代谢和氧化剂的产生。引人注目的是，我们已经确定了 滋养层细胞(与母体中性粒细胞直接接触) 在绒毛间隙)具有逆转中性粒细胞激活的能力 在接触时。使用超快显微镜，我们已经能够证明 对正常钙信号和活性氧代谢产物的干扰 (Rom)电池与电池接触时的生产。更重要的是，我们有 确定滋养层细胞的这一特性存在于糖萼和 可以溶解的形式释放。这一因素可能解释了临床上 妊娠期某些自身免疫性疾病的改善及其恶化 在送货后。此外，我们的发现和建议的策略可能会提供一个 识别内生影响机制的独特机会 妇女健康。我们建议在怀孕期间研究中性粒细胞生物学 将导致对临床因素的机械性理解 妊娠期间某些自身免疫性疾病的改善，也将导致 开发新的治疗方法来控制炎症和 自身免疫力。

DESCRIPTION (provided by applicant): This application is submitted in response to an RFA that requested applications to identify and characterize differences in the innate and adaptive immune response between genders, with a specific call for interdisciplinary clinical and basic research studies that may be important in the understanding and treatment of autoimmune diseases. Neutrophils are key cells in the development of homeostatic as well as pathologic inflammatory responses. These cells play a central role in the generation of tissue damage in autoimmune diseases (i.e., rheumatoid arthritis) as well as in infectious diseases, including sepsis. The studies outlined in this application are designed to study the differences in neutrophil function in non-pregnant women, pregnant women, and men. Studies conducted in our laboratory have established that neutrophils of normal pregnant women have a unique immunological state, which has not been previously recognized. This state exhibits the simultaneous expression of activated and inhibited neutrophil properties as reflected in cell calcium signaling, metabolism, and oxidant production. We have demonstrated that these properties reverse shortly after delivery and, thus, may account for the increase in postpartum disease activity in some autoimmune disorders. Our preliminary studies have identified biochemical bases for the changes in neutrophil physiology observed in normal pregnancy and implicated the hexose monophosphate shunt (HMS) and lipid rafts in the regulation of calcium signaling, metabolism and oxidant production. Strikingly, we have identified that trophoblast cells (which are in direct contact with maternal neutrophils in the intervillous space) have the capacity to reverse neutrophil activation upon contact. Using ultra-fast microscopy, we have been able to demonstrate interference with normal calcium signaling and reactive oxygen metabolite (ROM) production upon cell-to-cell contact. More importantly, we have determined that this property of trophoblasts resides in the glycocalyx and can be released in soluble form. This factor may account for the clinical improvement of some autoimmune diseases during pregnancy and their worsening after delivery. Moreover, our findings and proposed strategy may offer a unique opportunity for the identification of endogenous mechanisms affecting women's health. We propose that studying neutrophil biology during pregnancy will result in a mechanistic understanding of factors responsible for clinical improvement in certain autoimmune diseases during pregnancy and will also lead to the development of novel therapeutic approaches to control inflammation and autoimmunity.