Chronic ethanol, B cell competence and lymphoid integrity

长期饮酒会逐渐导致多种免疫缺陷。慢性酒精中毒显示 先天性和适应性免疫的损伤，并经历细菌和病毒感染率增加。 特别令人感兴趣的是，长期的酒精摄入导致B细胞区室内的异常， B细胞数量减少、抗体（Ab）应答差和调节异常。除了免疫 由于长期摄入乙醇引起的缺乏，患有胎儿酒精综合征（FAS）的儿童也表现出 免疫缺陷和更高的感染率。鉴于研究酗酒患者的固有困难 和FAS儿童，利用动物模型是必要的，以了解免疫的程度， 酒精暴露后的功能障碍，以及乙醇介导损伤的方式。为了更好 模拟慢性酒精中毒，以及胎儿酒精暴露，我们已经开发了饮用水中的乙醇 一种允许长期饮酒而无营养剥夺或全身应激的小鼠模型 重要的是，在摄入酒精数月后，小鼠表现出多种免疫异常，包括B减少 外周淋巴器官中的细胞数量和受损的Ab应答。有趣的是，这些病变 伴随着脾脏淋巴完整性的进行性破坏，表明酒精诱导 次级淋巴组织内的结构损伤。使用饮用水中的乙醇模型， 还成功地培育出小鼠，并使它们在最小的幼崽损失下足月分娩。当仍然使用乙醇时， 在整个妊娠期和新生儿期， 期成年后，这些胎儿/新生儿乙醇小鼠表现出身体和功能 免疫损伤利用这个模型，本提案中的研究将探索乙醇损害的方式 外周淋巴器官，停药后适应性免疫是否恢复，如果是胎儿/新生儿 乙醇暴露导致永久性免疫损伤。因此，目标1将研究哪些机制 在长期摄入乙醇后，次级淋巴组织所必需的蛋白质被破坏。目标2将测试 酒精诱导的氧化应激引发次级淋巴组织损伤的假说。目标3将 检验在长期消费后停止使用乙醇只会导致部分恢复的假设 免疫功能。目标4将检验以下假设：发育期间的酒精暴露导致 次级淋巴器官内的永久性损伤和终身免疫缺陷。四个目标将 主要关注淋巴完整性和B细胞能力的状态。长期酗酒会导致 适应性免疫中的显著病变，伴随着发病率和死亡率。FAS儿童同样 免疫缺陷和感染率增加。拟议的研究将提供新的见解 长期酒精暴露损伤适应性免疫系统的机制，以及 可以设计潜在的治疗方法来帮助逆转损伤和恢复免疫功能。

Long-temn alcohol consumption progressively leads to multiple immune defects. Chronic alcoholics display lesions in both innate and adaptive immunity, and experience increased rates of bacterial and viral infection. Of particular interest, extended alcohol intake leads to abnormalities within the B cell compartment with reduced B cell numbers, poor antibody (Ab) responses and aberrant regulation. In addition to immune deficiency caused by extended ethanol intake, children with fetal alcohol syndrome (FAS) also display immunologic deficits and higher infection rates. Given the inherent difficulties in studying alcoholic patients and FAS children, the utilization of animal models is essential to understand the extent of immune dysfunction after alcohol exposure, and the means by which ethanol mediates damage. In order to better mimic chronic alcoholism, as well as fetal alcohol exposure, we have exploited the ethanol-in-drinking-water mouse model that allows for long-term alcohol consumption without nutritional deprivation or systemic stress Importantly, after months of ethanol intake, mice exhibit multiple immune abnormalities including reduced B cell numbers in the peripheral lymphoid organs and compromised Ab responses. Of interest, these lesions are accompanied by progressive disruption of lymphoid integrity in the spleen, suggesting alcohol to induce structural damage within secondary lymphoid tissues. Using the ethanol-in-drinking-water model we have also successfully bred mice and brought them to term with minimal loss of pups. While remaining on ethanol, the females nursed the same pups allowing for alcohol exposure during the entire gestational and neonatal period. After reaching adulthood, these fetal/neonatal ethanol mice exhibited both physical and functional immune lesions. Using this model, studies in this proposal will explore the means by which ethanol damages peripheral lymphoid organs, whether adaptive immunity recovers after withdrawal arid if fetal/neonatal ethanol exposure leads to permanent immune lesions. Aim 1 will therefore investigate which mechanisms essential for secondary lymphoid organization are disrupted after long-term ethanol intake. Aim 2 will test the hypothesis that oxidative stress induced by alcohol triggers damage in secondary lymphoid tissue. Aim 3 will test the hypothesis that withdrawal from ethanol after extended consumption will lead to only partial recovery of immune function. Aim 4 will test the hypothesis that alcohol exposure during development leads to pemnanent damage within secondary lymphoid organs and life-long immune deficiency. All four Aims will primarily focus on the status of lymphoid integrity and B cell competence. Chronic alcohol abuse leads to significant lesions in adaptive immunity with accompanying mortiidity and mortality. FAS children likewise experience immune deficiency and increased rates of infection. The proposed studies will offer novel insights into the mechanisms by which long-term alcohol exposure injures the adaptive immune system, and whether potential therapies can be designed to help reverse damage and recover immune function.