Effect of Ethanol on the Murine B Cell Compartment

说明(申请人提供)：长期饮酒会逐渐导致多种免疫缺陷。慢性酗酒者表现出先天免疫和获得性免疫损伤，细菌和病毒感染率增加。特别有趣的是，长期饮酒会导致B细胞室内的异常。在许多酒精滥用者中，循环中的总B细胞受到抑制，接种疫苗后抗体效价很低。除了肱骨缺乏外，B细胞活动的调节被破坏，导致血清Ig水平升高和自身抗体的存在。总而言之，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，以及酒精影响这些变化的方式，利用实验模型是必不可少的。大量研究采用了啮齿动物模型，在这种模型中，短期内在流质饮食中给予乙醇。尽管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酗酒后出现的异常，因为饮酒持续时间较短，并引发了压力反应。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，其中饮用水中提供乙醇。使用这个系统，我们发现几个月的酒精摄入会导致成熟的脾B细胞丢失，并降低T细胞依赖(TD)抗体(Ab)的反应。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，这些缺陷的发展没有系统性压力的证据。利用这一模型，拟议的实验将充分证明乙醇对B细胞室的影响，以及导致肱骨功能障碍的潜在机制。目标1中的研究将测试一些假说，以解释长期酒精摄入后B细胞的磨损，包括成熟、半衰期和支持性趋化因子和细胞因子的产生方面的缺陷。目的2将询问乙醇是否诱导B细胞的自主性损伤，从而导致异常的激活和分化。AIMS 3和AIMS 4中的实验将评估饮酒小鼠分别用非T细胞抗原和TD抗原免疫后产生抗体的能力。重要的是，目标4将深入研究乙醇对T细胞驱动的B细胞分化的影响，包括亲和力成熟、体细胞突变、记忆细胞的生成和长寿浆细胞的形成。总而言之，这些研究将扩大我们对慢性酗酒者常见的肱骨缺陷的理解，并为设计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.