van der Meide P H, Groenestein R J, de Labie M C, Aten J, Weening J J
Biomedical Primate Research Centre (BPRC) TNO, Rijswijk, The Netherlands.
Cell Immunol. 1995 Apr 15;162(1):131-7. doi: 10.1006/cimm.1995.1060.
The repeated administration of low-dose HgCl2 to brown Norway (BN) rats induces an autoimmune syndrome which is characterized by polyclonal B cell activation, high-level synthesis of IgE and IgG1, and massive proteinuria. Data have been presented suggesting that during disease development there is a preferential expansion of CD4+ T cells belonging to the TH2 subset. In the present study it was found that aged BN rats are far less susceptible to the immunopathological effects of HgCl2 compared to their younger counterparts. Whereas rats at 10 weeks of age develop high-level proteinuria upon three repeated injections with HgCl2, animals at 18 to 24 months of age do not release urinary protein under these conditions and develop low-level proteinuria with a delayed onset after five repeated injections with HgCl2. FACScan analysis of splenocytes from old and young rats revealed a defined increase in the frequency of CD45RB(RC)+/CD4+ T cells in the splenocyte population of older rats, suggesting an age-related shift to a more TH1-like phenotype. Moreover, splenocytes of aged rats generated a threefold higher number of IFN-gamma-producing cells than those of young rats upon polyclonal activation in vitro. The administration of neutralizing anti-rat IFN-gamma mono- and/or polyclonal antibodies to aged BN rats just prior to HgCl2 exposure significantly augmented IgE and IgG1 serum levels and exerted a small but significant stimulatory effect on proteinuria in the initial stage but not in the more advanced stages of the renal disease. When antibodies were given 7 days after the beginning of HgCl2 exposure no stimulatory effect on both IgE/IgG1 levels and proteinuria was observed. The data indicate that splenic T cells of aged BN rats possess a higher capacity to release IFN-gamma than those of young rats and that this cytokine functions to downregulate IgG1 and IgE synthesis in HgCl2-exposed BN rats. The findings further suggest that IFN-gamma plays a regulatory role in the development of glomerulonephritis.
给棕色挪威（BN）大鼠反复注射低剂量的HgCl₂会诱发一种自身免疫综合征，其特征为多克隆B细胞活化、高水平合成IgE和IgG1以及大量蛋白尿。已有数据表明，在疾病发展过程中，属于TH2亚群的CD4⁺T细胞会优先扩增。在本研究中发现，与年轻的BN大鼠相比，老年BN大鼠对HgCl₂的免疫病理作用的易感性要低得多。10周龄的大鼠在三次反复注射HgCl₂后会出现高水平蛋白尿，而18至24月龄的动物在这些条件下不会释放尿蛋白，在五次反复注射HgCl₂后会出现延迟发作的低水平蛋白尿。对老年和年轻大鼠脾细胞的FACScan分析显示，老年大鼠脾细胞群体中CD45RB(RC)⁺/CD4⁺T细胞的频率有明确增加，表明与年龄相关的向更类似TH1表型的转变。此外，在体外多克隆激活后，老年大鼠的脾细胞产生的产生IFN-γ的细胞数量比年轻大鼠多三倍。在HgCl₂暴露前给老年BN大鼠注射中和抗大鼠IFN-γ单克隆和/或多克隆抗体，可显著提高IgE和IgG1血清水平，并在肾脏疾病的初始阶段对蛋白尿产生小但显著的刺激作用，但在疾病更晚期则无此作用。当在HgCl₂暴露开始7天后给予抗体时，未观察到对IgE/IgG1水平和蛋白尿的刺激作用。数据表明，老年BN大鼠的脾T细胞比年轻大鼠的脾T细胞具有更高的释放IFN-γ的能力，并且这种细胞因子在暴露于HgCl₂的BN大鼠中发挥下调IgG1和IgE合成的作用。这些发现进一步表明，IFN-γ在肾小球肾炎的发展中起调节作用。
