Gill R, McCabe M J, Rosenspire A J
Department of Immunology, Microbiology and Biochemistry, Wayne State University, Detroit, MI, United States.
Department of Environmental Medicine, University of Rochester, Rochester, NY, United States.
Toxicol Appl Pharmacol. 2017 Sep 1;330:22-29. doi: 10.1016/j.taap.2017.06.022. Epub 2017 Jun 28.
Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to 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 the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transduction pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease.
在动物模型和人类中，汞（Hg）被认为是导致自身免疫性疾病的一个因素。然而，其发生机制仍不清楚。自从发现B细胞以来，免疫学家已经认识到，在B细胞正常发育过程中，必须产生一些对自身抗原具有反应性的免疫球蛋白（自身抗体）的未成熟B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细胞会通过统称为耐受的过程而被阻止成熟。当这些耐受机制被破坏时，自身免疫性疾病就会出现。在B细胞区室中，已经确定耐受部分取决于对自身反应性未成熟（过渡1型）B细胞的阴性选择。在这些细胞中，阴性选择取决于B细胞受体（BCR）产生的信号，即那些BCR与自身抗原结合最强烈并因此产生最强信号的T1 B细胞会被中和。在本报告中，我们利用多色磷酸化流式细胞术表明，在未成熟的T1 B细胞中，汞通过可能涉及Lyn（BCR信号转导途径中的关键酪氨酸激酶）的机制减弱BCR产生的信号。我们认为，暴露于环境中低水平的汞会干扰未成熟B细胞中的BCR信号传导，从而破坏耐受，可能导致具有导致自身免疫性疾病能力的成熟自身反应性B细胞出现。
