Gill Randall F, McCabe Michael J, Rosenspire Allen J
Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA.
Department of Environmental Medicine, University of Rochester, Rochester, NY 14642, USA.
Autoimmune Dis. 2014;2014:239358. doi: 10.1155/2014/239358. Epub 2014 May 4.
It has been suggested that environmental exposures to mercury contribute to autoimmune disease. Disruption of BCR signaling is associated with failure of central tolerance and autoimmunity, and we have previously shown that low levels of Hg(2+) interfere with BCR signaling. In this report we have employed multiparametric phosphoflow cytometry, as well as a novel generalization of the Overton algorithm from one- to two-dimensional unimodal distributions to simultaneously monitor the effect of low level Hg(2+) intoxication on activation of ERK and several upstream elements of the BCR signaling pathway in WEHI-231 B cells. We have found that, after exposure to low levels of Hg(2+), only about a third of the cells are sensitive to the metal. For those cells which are sensitive, we confirm our earlier work that activation of ERK is attenuated but now report that Hg(2+) has little upstream effect on the Btk tyrosine kinase. On the other hand, we find that signaling upstream through the Syk tyrosine kinase is actually augmented, as is upstream activation of the B cell signalosome scaffolding protein BLNK.
有人提出，环境汞暴露会导致自身免疫性疾病。BCR信号传导的破坏与中枢耐受失败和自身免疫有关，我们之前已经表明，低水平的Hg(2+)会干扰BCR信号传导。在本报告中，我们采用了多参数磷酸化流式细胞术，以及将Overton算法从一维单峰分布推广到二维单峰分布的新方法，以同时监测低水平Hg(2+)中毒对WEHI-231 B细胞中ERK激活和BCR信号通路几个上游元件的影响。我们发现，在暴露于低水平的Hg(2+)后，只有约三分之一的细胞对这种金属敏感。对于那些敏感细胞，我们证实了我们早期的研究结果，即ERK的激活减弱，但现在报告Hg(2+)对Btk酪氨酸激酶几乎没有上游影响。另一方面，我们发现通过Syk酪氨酸激酶的上游信号实际上增强了，B细胞信号体支架蛋白BLNK的上游激活也是如此。
