Erythrocytes, immuno-modulation and G6PD deficiency

描述(由申请人提供)： 人们越来越认识到，基因多态对炎症反应有重要影响。葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症是人类已知的最常见的遗传多态性。G6PD缺乏对宿主对创伤和感染的反应有重大影响，并对疟疾感染具有保护作用。G6PD缺乏症免疫调节作用的细胞和生化机制尚不清楚。我们的一般假设是，G6PD缺乏的红细胞和激活的白细胞中的抗氧化剂防御受损会改变感染期间巨噬细胞的激活和随后的T细胞反应。这项研究将在G6PD缺陷小鼠中采用败血症啮齿动物模型(盲肠结扎和穿孔)。在人类最常见的G6PD缺乏症的背景下，所提出的小鼠品系是相关的，因为缺陷小鼠的细胞残余G6PD活性与人类非洲A-G6PD缺乏症相似。所提出的假设将检验(总体)是否(1)巨噬细胞激活和T淋巴细胞极化在G6PD缺陷和非缺陷动物之间是不同的。这些方法将使用盲肠结扎和穿孔模型在体外和体内进行测试。(2)我们还将探讨败血症引起的红细胞损伤是否在G6PD缺乏症中更为明显。G6PD缺乏对脓毒症引起的器官炎症反应和损害以及死亡率的影响也将被测试。此外，我们还将研究(3)抗氧化剂和抗一氧化氮治疗是否对脓毒症期间G6PD缺乏症有益。鉴于感染过程中的早期氧化应激和红细胞损伤以及巨噬细胞和T细胞反应在炎症反应中的重要性，所研究的问题是新的和重要的，可能会使所有创伤患者受益。在G6PD缺乏的背景下阐明这些问题带来了一个高度相关的临床方面；此外，这也提供了一个独特的机会来测试红细胞功能障碍与先天性免疫反应调节之间的关系。阐明巨噬细胞和T细胞细胞因子对G6PD缺乏症感染的反应，对于提供一种替代目前公认的概念的疟疾保护机制也可能是重要的。

DESCRIPTION (provided by applicant): It is becoming well appreciated that genetic polymorphism has a major impact on the inflammatory response. Glucose-6-phophate dehydrogenase (G6PD) deficiency is the most common known human genetic polymorphism. G6PD deficiency has a major impact on the host response to trauma and infections and protects against malaria infection. The cellular and biochemical mechanisms responsible for the immuno-modulatory effects of G6PD deficiency are not known. Our general hypothesis is that a compromised antioxidant defense in G6PD deficient erythrocytes and in activated white blood cells alters macrophage activation and subsequent T-cell responses during infections. The studies will employ a septic rodent model (cecal ligation and puncture) in the G6PD deficient mouse. In the context of the most common forms of human G6PD deficiencies, the proposed mouse line is relevant because the residual cellular G6PD activity in the deficient mice is similar to that of the human African, type A- G6PD deficiencies. The proposed hypotheses will test (in general) whether (1) macrophage activation and T lymphocyte polarization are different between G6PD deficient and non-deficient animals. These will be tested in vitro as well as in vivo using the cecal ligation and puncture model. (2) We will also investigate wether the sepsis induced erythrocyte damage is more pronounced in G6PD deficiency. The effects of G6PD deficiency on the sepsis-induced organ inflammatory responses and damage, as well as, mortality will also be tested. Additionally, we will investigate (3) whether antioxidant and anti nitric oxide therapies will be beneficial in G6PD deficiency during sepsis. In view of the well-known early oxidative stress and erythrocyte damage during infections and the importance of macrophage and T-cell responses in the inflammatory response the investigated questions are novel and important and may benefit all trauma patients. Elucidating these questions in the context of G6PD deficiency brings in a highly relevant clinical aspect; furthermore, this also provides a unique opportunity to test the relationship between erythrocyte dysfunction and the modulation of the innate immune response. Elucidation of macrophage and T-cell cytokine responses to infection in G6PD deficiency may also be important in providing a mechanism of malaria protection alternative to currently accepted notions.