Erythrocytes, immuno-modulation and G6PD deficiency

描述（由申请人提供）： 遗传多态性对炎症反应具有重要影响，这一点已被广泛认识。葡萄糖-6-磷酸脱氢酶（G6 PD）缺乏症是已知最常见的人类遗传多态性。G6 PD缺陷对宿主对创伤和感染的反应有重大影响，并可防止疟疾感染。负责G6 PD缺乏的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，在G6 PD缺乏的红细胞和活化的白色血细胞中，受损的抗氧化防御改变了感染期间巨噬细胞的活化和随后的T细胞反应。研究将在G6 PD缺陷小鼠中采用脓毒症啮齿动物模型（盲肠结扎和穿孔）。在最常见形式的人G6 PD缺陷的背景下，所提出的小鼠系是相关的，因为缺陷小鼠中的残留细胞G6 PD活性与非洲人A型G6 PD缺陷相似。所提出的假设将测试（一般而言）G6 PD缺陷型和非缺陷型动物之间（1）巨噬细胞活化和T淋巴细胞极化是否不同。将使用盲肠结扎和穿刺模型在体外和体内对这些进行测试。(2)我们还将研究脓毒症诱导的红细胞损伤是否在G6 PD缺乏症中更明显。还将测试G6 PD缺乏对脓毒症诱导的器官炎症反应和损伤以及死亡率的影响。此外，我们将研究（3）抗氧化剂和抗一氧化氮治疗是否对脓毒症期间的G6 PD缺陷有益。鉴于众所周知的早期氧化应激和红细胞损伤在感染和巨噬细胞和T细胞反应的重要性，在炎症反应的调查问题是新的和重要的，可能有利于所有创伤患者。在G6 PD缺乏症的背景下阐明这些问题带来了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和先天免疫应答调节之间的关系。阐明巨噬细胞和T细胞细胞因子对G6 PD缺乏症感染的反应也可能是重要的，在提供一种机制，疟疾保护替代目前接受的概念。

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.