Understanding the connection between exposure to mercury, auto-immunity and tolerance in B cells

摘要 汞(Hg)是一种广泛存在于环境中的外来生物。汞也是一种有效的免疫调节剂， 已经被认为是导致动物模型和人类自身免疫性疾病的一个因素。最近 流行病学研究现在令人信服地表明，在原本健康的人中，只有 通过典型的环境暴露暴露于低水平的汞，在 汞的血液水平和血液中出现的双链DNA抗体。这表明 在适当的情况下，暴露在环境汞中会促进自身免疫，这是一种先兆 自身免疫性疾病。自从B细胞被发现以来，免疫学家们已经认识到，鉴于 克隆选择理论，在B细胞正常发育过程中，大量未成熟B细胞 细胞必须产生对许多自身抗原(自身抗体)有反应的免疫球蛋白。 然而，在正常发育过程中，绝大多数未成熟的自身反应性B细胞 通过统称为容忍的过程防止成熟。自身免疫性疾病在以下情况下发生 这些容忍机制被打乱了。在B细胞中，耐受性取决于 B细胞受体(BCR)产生的信号。我们的初步实验表明，汞会干扰 BCR通过可能涉及酪氨酸激酶Lyn的机制产生信号，而 酪氨酸磷酸酶SHP-1和CD45。我们的假设是，暴露在与环境相关的低浓度环境中 汞水平，通过干扰bcr信号干扰未成熟B细胞耐受性的发展， 导致成熟的自身反应性B细胞的出现，这种细胞有可能导致自身免疫 疾病。我们建议通过利用抗鸡蛋溶菌酶(HEL)/鸡蛋来检验这一假设 溶菌酶双转基因小鼠。我们还建议扩大我们的初步实验，以便 阐明汞干扰bcr信号的分子机制。我们将使用鼠标 具有不同但明确的汞中毒遗传易感性的菌株，并采用互补 蛋白质组学和多色荧光流式细胞术直接研究汞的干扰能力 与LYN、SHP-1和CD45在BCR信号转导中的作用有关。

ABSTRACT Mercury (Hg) is a xenobiotic that is widespread in the environment. Hg is also a potent immunomodulator that has been implicated as a factor contributing to autoimmune disease in animal models and humans. A recent epidemiological study has now convincingly shown that in otherwise healthy individuals who were only exposed to low levels of mercury through typical environmental exposures, that there is a correlation between mercury blood levels and the appearance in the blood of antibodies to double stranded DNA. This indicates that under the proper circumstances exposure to environmental mercury promotes autoimmunity, a precursor to autoimmune disease. Since the discovery of B cells it has been appreciated by immunologists that in light of the Clonal Selection Theory, during the normal course of B cell development, large numbers of immature B cells must be generated that produce immunoglobulin reactive to many self- antigens (auto-antibodies). However, in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when these mechanisms of tolerance are disrupted. In B cells, it is firmly established that tolerance depends upon signals generated by the B Cell Receptor (BCR). Our preliminary experiments have shown that Hg interferes with signal generation by the BCR through mechanisms that may involve the tyrosine kinase Lyn, and the tyrosine phosphatases SHP-1 and CD45. It is our hypothesis that exposure to low, environmentally relevant levels of Hg, disrupts the development of tolerance in immature B cells by interfering with BCR signaling, leading to the appearance of mature auto-reactive B cells which have the potential to cause auto-immune disease. We propose to test this hypothesis through the utilization of anti-hen egg lysozyme (HEL)/hen egg lysozyme double transgenic mice. We also propose to expand upon our preliminary experiments in order to elucidate molecular mechanisms behind the ability of Hg to interfere with BCR signaling. We will utilize mouse strains with different, but well defined genetic susceptibilities to Hg intoxication, and employ complementary proteomic and multicolor phosphoflow cytometric approaches to directly investigate the ability of Hg to interfere with the function of Lyn, SHP-1 and CD45 during BCR signaling.