Effect of Ethanol on the Murine B Cell Compartment

描述（由申请人提供）：长期饮酒逐渐导致多种免疫缺陷。慢性酗酒者表现出先天免疫和适应性免疫的损害，并且经历了细菌和病毒感染率的增加。特别有趣的是，过量饮酒会导致B细胞区室的异常。在许多酒精滥用者中，总循环B细胞被抑制，免疫应答的Ab滴度较差。除了肱骨缺乏外，B细胞活性的调节被破坏，导致血清Ig水平升高和自身抗体的存在。综上所述，很明显，酒精会导致B细胞功能受损，进而导致危及生命的感染。为了更好地了解B细胞功能障碍的程度，以及乙醇影响这些变化的方式，有必要利用实验模型。大量的研究采用啮齿类动物模型，在短期内将乙醇添加到液体饮食中。尽管用这种方法已经记录了一系列免疫缺陷，但这些发现最适用于人类在短时间饮酒和诱导应激反应后出现的异常。为了更好地模拟慢性酒精中毒的情况，我们建立了一个长期的小鼠模型，其中在饮用水中提供乙醇。使用该系统，我们发现数月的乙醇摄入导致成熟脾B细胞的损失和T细胞依赖性（TD）抗体（Ab）反应的减弱。我们进一步发现了B细胞成熟和淋巴结构的异常。重要的是，这些缺陷的形成没有系统性压力的证据。利用该模型，实验将充分证明乙醇对B细胞区室的影响，以及导致肱骨功能障碍的潜在机制。Aim 1中的研究将测试一些假设，以解释B细胞在长期摄入乙醇后的损耗，包括成熟、半衰期和支持性趋化因子和细胞因子产生的缺陷。目的2将询问乙醇是否诱导B细胞的细胞自主病变，导致异常活化和分化。Aims 3和Aims 4的实验将分别评估用T细胞独立抗原和TD抗原免疫后乙醇消耗小鼠产生抗体的能力。重要的是，Aim 4将彻底研究乙醇对T细胞驱动的B细胞分化的影响，包括亲和成熟、体细胞突变、记忆细胞的产生和长寿浆细胞的形成。总的来说，这些研究将扩大我们对慢性酗酒者常见的肱骨缺损的理解，并为制定更好的治疗方法提供新的见解。

DESCRIPTION (provided by applicant): Long-term 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. In many alcohol abusers, total circulating B cells are depressed and Ab titers in response to vaccination are poor. In addition to humeral deficiency, regulation of B cell activity is disrupted leading to increased levels of serum Ig and the presence of autoantibodies. Taken together, it is clear that alcohol leads to impaired B cell function, and in turn, life-threatening infections. In order to understand better the extent of B cell dysfunction, and the means by which ethanol effects these changes, it is essential to utilize experimental models. A large number of studies have employed rodent models where ethanol is administered in liquid diets over short periods. Although a range of immune defects have been documented with this approach, these findings are best applied to abnormalities that appear after binge drinking in humans given the short duration of consumption and induction of the stress response. In order to better mimic the condition of chronic alcoholism, we have established a long-term murine model where ethanol is provided in drinking water. Using this system, we have found that months of ethanol intake result in loss of mature splenic B cells and diminished T cell-dependent (TD) antibody (Ab) responses. We have further discovered abnormalities in B cell maturation and lymphoid structure. Importantly, these defects develop without evidence of systemic stress. Using this model, proposed experiments will fully document the effects of ethanol on the B cell compartment, and the underlying mechanisms leading to humeral dysfunction. Studies in Aim 1 will test a number of hypotheses to explain the attrition of B cells after long-term ethanol intake, including defects in maturation, half-life, and production of supportive chemokines and cytokines. Aim 2 will ask whether ethanol induces cell autonomous lesions in B cells leading to abnormal activation and differentiation. Experiments in Aims 3 and 4 will assess the capacity of ethanol-consuming mice to produce Abs after immunization with T cell independent and TD antigens, respectively. Importantly, Aim 4 will thoroughly examine the effects of ethanol on T cell-driven B cell differentiation including affinity maturation, somatic mutation, generation of memory cells, and formation of long-lived plasma cells. Collectively, these studies will expand our understanding of humeral defects common to chronic alcoholics, and offer novel insights with which to fashion better therapies.