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

了解汞暴露、自身免疫和 B 细胞耐受性之间的联系

• 批准号: 9539264
• 负责人: ALLEN J ROSENSPIRE
• 金额: $ 19.25万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9539264
• 关键词: Address; Affect; Animal Model; Antibodies; Antigens; Appearance; Attenuated; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B cell repertoire; B-Cell Development; B-Lymphocytes; Binding; Biochemical; Blood; Cell membrane; Cells; Complex; Cytoskeleton; Data; Development; Elements; Environment; Environmental Exposure; Exposure to; F-Actin; Female; Flow Cytometry; Generations; Genetic; Genetic Predisposition to Disease; Goals; Hen Egg Lysozyme; Human; Image; Immune; Immune response; Immunogenetics; Immunoglobulins; Immunologist; Immunomodulators; Individual; Intoxication; Light; Link; Maps; Mass Spectrum Analysis; Measures; Mediating; Membrane Proteins; Mercury; Modeling; Molecular; Molecular Abnormality; Molecular Target; Mouse Strains; Mus; Nature; PTPN6 gene; PTPRC gene; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Population; Predisposition; Process; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Proteome; Proteomics; Receptor Signaling; Receptors, Antigen, B-Cell; Reporting; Shapes; Signal Pathway; Signal Transduction; Sulfhydryl Compounds; Surface; Surveys; Techniques; Technology; Testing; Transgenic Mice; Western Blotting; Xenobiotics; attenuation; autoreactive B cell; base; cofilin; design; drinking water; ds-DNA; environmental agent; epidemiology study; experimental study; immunogenic; meetings; molecular dynamics; mouse model; novel; prevent; sex; theories

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.

摘要 汞（Hg）是一种广泛存在于环境中的外源性物质。汞也是一种有效的免疫调节剂， 在动物模型和人类中被认为是导致自身免疫性疾病的一个因素。最近的一 流行病学研究现在令人信服地表明，在其他方面健康的人中， 通过典型的环境暴露接触低水平的汞， 血液中的汞含量和血液中出现的双链DNA抗体。这表明 在适当的情况下，暴露于环境汞促进自身免疫， 自身免疫性疾病自从B细胞被发现以来，免疫学家已经认识到，鉴于 根据克隆选择理论，在B细胞发育的正常过程中，大量未成熟的B细胞被克隆选择。 必须产生产生对许多自身抗原（自身抗体）反应的免疫球蛋白的细胞。 然而，在正常发育过程中，绝大多数未成熟的自身反应性B细胞是 被统称为宽容的过程所阻止。自身免疫性疾病发生时， 这些耐受机制被破坏。在B细胞中，已经确定耐受性依赖于 由B细胞受体（BCR）产生的信号。我们的初步实验表明，汞干扰 BCR通过可能涉及酪氨酸激酶林恩的机制产生信号， 酪氨酸磷酸酶SHP-1和CD 45。我们的假设是，暴露于低，环境相关的， 汞水平，通过干扰BCR信号传导，破坏未成熟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，其具有引起自身免疫的潜力 疾病我们建议通过利用抗鸡蛋溶菌酶（HEL）/鸡蛋来验证这一假设 溶菌酶双转基因小鼠。我们还建议扩大我们的初步实验， 阐明汞干扰BCR信号传导能力背后的分子机制。我们将使用鼠标 菌株不同，但明确定义的遗传易感性汞中毒，并采用互补 蛋白质组学和流式细胞术直接研究汞的干扰能力 在BCR信号转导过程中发挥林恩、SHP-1和CD 45的作用。