Analysis of B Cell Receptor Signals Modified by Mercury

描述（由申请人提供）：世界范围内自身免疫性疾病的患病率约为3%。自身免疫性疾病可以是器官特异性的，也可以是全身性的，但无论哪种情况，其最显著的特点是其病因是多因素的，包括遗传和环境影响。在过去的几年中，在阐明与自身免疫性疾病相关的潜在遗传病变方面取得了很大进展，但令人惊讶的是，相对而言，很少有人致力于理解环境因素的影响。我们的长期研究目标是纠正这种不平衡，并通过揭示环境因素，特别是毒物，与免疫系统相互作用以促进自身免疫性疾病的机制，进一步了解自身免疫性疾病的病因。这一领域的一个主要问题是难以将接触特定环境因素，特别是毒物与自身免疫性疾病联系起来。少数例外之一是环境汞。因此，本提案的重点将放在无机汞（Hg2+）的免疫毒理学上。在许多不同的系统中，Hg2+已被证明可促进自身免疫性疾病。因此，Hg2+自然成为探测环境-自身免疫轴的工具。最近，人们对B细胞在自身免疫性疾病中的作用重新产生了兴趣。我们实验室的初步和最近发表的结果支持了我们的假设，即Hg2+ < 0.01 pg/细胞的低毒性和无毒性负荷通过干扰未成熟过渡性1 (T1) B细胞的B细胞受体（BCR）信号转导，直接损害B细胞室的中枢耐受性。现有的知识支持这一概念，即通过BCR在T1B细胞上的信号强度是形成体液免疫库和建立对自身抗原耐受性的主要决定因素。基于我们的初步研究，我们提出BCR信号强度会受到环境相关水平的Hg2+的衰减。该建议将解决全球假设，即暴露于hg与未暴露的B淋巴细胞的BCR信号谱不同。我们计划采用基于流式细胞术的技术来绘制单个细胞中的信号网络（即单细胞蛋白质组学），以及基于质谱的技术，旨在快速调查hg暴露和非暴露细胞中的B细胞蛋白质组。

DESCRIPTION (provided by applicant): World wide the prevalence of autoimmune disease is about 3%. Autoimmune diseases can be either organ specific or systemic, but in either case their most notable quality is that their cause is multifactorial, including both genetic and environmental influences. Over the past several years much progress has been made in elucidating underlying genetic lesions associated with autoimmune disease, but surprisingly comparatively little effort has been directed towards understanding the influences of environmental factors. Our long term research goal is to correct this imbalance and further our understanding of the etiology of autoimmune disease by uncovering the mechanisms by which environmental factors, and toxicants in particular, interact with the immune system to promote autoimmune disease. A major problem in this field has been the difficulty in linking exposure to specific environmental factors, especially toxicants, with autoimmune disease. One of the few exceptions is environmental mercury. Accordingly, the focus of this proposal will be on the immunotoxicology of inorganic mercury (Hg2+). In a number of different systems Hg2+ has been shown to promote autoimmune disease. Thus Hg2+ naturally lends itself as a tool with which to probe the environment- autoimmunity axis. Recently there has been renewed interest in the role that B cells play in autoimmune diseases. Preliminary and recently published results from our laboratory support our hypothesis that low and non toxic burdens of Hg2+ < 0.01 pg/cell directly impair central tolerance in the B cell compartment by interfering with B Cell Receptor (BCR) signal transduction in immature transitional 1 (T1) B cells. Existing knowledge supports the concept that signal strength through the BCR on T1B cells is a major determinant that shapes the humoral immune repertoire and establishes tolerance to self antigens. Based on our preliminary studies, we propose that BCR signal strength is attenuated by environmentally relevant levels of Hg2+. This proposal will address the global hypothesis that BCR signaling profiles of Hg-exposed versus non-exposed B lymphocytes differ. We plan to employ flow cytometric-based techniques to map signaling networks in individual cells (i.e., single cell proteomics) as well as mass spectrometry based techniques designed to rapidly survey the B cell proteome in Hg-exposed and non-exposed cells. PUBLIC HEALTH RELEVANCE: The etiology of most autoimmune diseases is unknown, but most investigators believe that environmental and genetic factors are involved. While in recent years there has been much progress in understanding the genetic factors involved in autoimmune diseases, there has been much less progress in understanding the impact of environment. The purpose of this research is to investigate how low levels of the environmental toxicant mercury, might interact with the immune system in such a way as to promote autoimmune disease.