Kosuda L L, Whalen B, Greiner D L, Bigazzi P E
Department of Pathology, University of Connecticut Health Center, Farmington 06030, USA.
Toxicology. 1998 Feb 6;125(2-3):215-31. doi: 10.1016/s0300-483x(97)00180-7.
Repeated exposure to mercury causes various autoimmune effects in rats of the Brown Norway (BN) strain. Previous studies from our laboratory have shown that on day 15 of HgCl2 treatment BN rats exhibit a relative decrease in RT6.2+ T cells. At the same time, they produce high levels of autoantibodies to renal antigens and experience a membranous glomerulonephropathy. In contrast, Lewis (LEW) rats are resistant to autoimmunity caused by mercury and do not demonstrate a decrease in RT6+ cells after administration of HgCl2. In the present paper we provide novel information on the correlation between changes in RT6.2+ lymph node T cells and the production of autoantibodies to laminin 1, obtained by detailed kinetic studies of HgCl2-treated BN rats. We have confirmed a decrease in the percentage of RT6.2+ lymphocytes on day 15 of mercury treatment, despite a significant increase in the number of peripheral lymphocytes. No such changes were observed in LEW rats. We have determined that on day 15 the percentage decrease in RT6+ cells is evident in both RT6.2+CD4+ and RT6.2+CD8+ T cell subsets. Kinetic studies demonstrated that significant changes in the percentage of RT6.2+ cells are first observed by day 8 and continue through days 11 and 15. We have also observed a significant percent decrease in CD4+ T lymphocytes as well as an increase in CD4-CD8- cells. The dramatic increase in the percentage of these double negative cells at the level of peripheral lymphoid tissues does not appear to be due to higher thymic output, since there was a decrease in the percentage of TCR+Thy1+ cells, a phenotype that is associated with recent thymic emigrants. Finally, we have demonstrated that 100% of HgCl2-treated BN rats had circulating antibodies that reacted with both mouse and rat laminin 1, i.e. are autoantibodies to laminin 1. These autoantibodies were predominantly of the IgG1 and IgG2a isotype, possibly as the result of a polarized autoimmune response driven by Type 2 cytokines. A kinetic investigation showed that significant levels of IgG1 and IgG2a autoantibodies to laminin 1 were first presentin the circulation by day 11. The inverse correlation between levels of RT6.2+ T lymphocytes and autoantibodies to laminin 1 suggests that mercury may induce autoimmune responses in BN rats by its effects on these immunoregulatory cells.
反复接触汞会在褐挪威（BN）品系大鼠中引发各种自身免疫效应。我们实验室之前的研究表明，在氯化汞处理的第15天，BN大鼠的RT6.2⁺ T细胞相对减少。与此同时，它们会产生高水平的针对肾脏抗原的自身抗体，并患上膜性肾小球肾炎。相比之下，刘易斯（LEW）大鼠对汞引起的自身免疫具有抗性，在给予氯化汞后RT6⁺ 细胞不会减少。在本文中，我们通过对氯化汞处理的BN大鼠进行详细的动力学研究，提供了关于RT6.2⁺ 淋巴结T细胞变化与抗层粘连蛋白1自身抗体产生之间相关性的新信息。我们证实，在汞处理的第15天，尽管外周淋巴细胞数量显著增加，但RT6.2⁺ 淋巴细胞的百分比仍有所下降。在LEW大鼠中未观察到此类变化。我们确定，在第15天，RT6⁺ 细胞的百分比下降在RT6.2⁺CD4⁺ 和RT6.2⁺CD8⁺ T细胞亚群中均很明显。动力学研究表明，RT6.2⁺ 细胞百分比的显著变化在第8天首次观察到，并持续到第11天和第15天。我们还观察到CD4⁺ T淋巴细胞百分比显著下降以及CD4⁻CD8⁻ 细胞增加。在外周淋巴组织水平上，这些双阴性细胞百分比的急剧增加似乎并非由于胸腺输出增加，因为与近期胸腺迁出细胞相关的TCR⁺Thy1⁺ 细胞百分比有所下降。最后，我们证明，100% 经氯化汞处理的BN大鼠循环抗体与小鼠和大鼠层粘连蛋白1都发生反应，即这些是抗层粘连蛋白1的自身抗体。这些自身抗体主要为IgG1和IgG2a同种型，这可能是由2型细胞因子驱动的极化自身免疫反应的结果。动力学研究表明，到第11天，循环中首次出现显著水平的抗层粘连蛋白1的IgG1和IgG2a自身抗体。RT6.2⁺ T淋巴细胞水平与抗层粘连蛋白1自身抗体之间的负相关表明，汞可能通过其对这些免疫调节细胞的作用在BN大鼠中诱导自身免疫反应。
