Gazzinelli R T, Eltoum I, Wynn T A, Sher A
Immunology and Cell Biology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1993 Oct 1;151(7):3672-81.
C57BL/6 mice infected with the ME-49 strain of Toxoplasma gondii develop a progressive encephalitis culminating in 100% mortality between 12 and 15 wk after intraperitoneal inoculation of the parasite. Moreover, when injected at 4 wk after infection with anti-IFN-gamma mAb, progression of toxoplasmic encephalitis is markedly accelerated, resulting in death of the animals by 9 to 12 days posttreatment. In this study, we investigated the expression of mRNAs encoding cytokines as well as lymphocyte and macrophage markers during the development of toxoplasmic encephalitis. High levels of lymphocyte CD4 and CD8 surface Ag transcript were detected in the brains of mice throughout the infection. In addition from 2 to 4 wk we found elevations of Th1 (IFN-gamma and IL-2) but not of Th2 (IL-4 and IL-5) cytokine mRNAs. The elevation in Th1 cytokines was accompanied by increases in the expression of monokine (IL-1, IL-6, IL-10, granulocyte macrophage-colony stimulating factor [GM-CSF], and TNF-alpha) mRNAs, as well as markers expressed by activated macrophages (major histocompatibility class II [Ia], inducible nitric oxide synthase [iNOS] and macrophage activation gene 1 [Mag-1]). Interestingly, after 8 wk of infection with T. gondii we observed a dramatic decrease of Th1 cytokine and most monokine (IL-1, IL-6, GM-CSF, and TNF-alpha) as well as Mag-1 and iNOS mRNA levels. This down-regulation was associated with enhanced necrosis and neutrophilic infiltrates in the brain accompanied by increased expression of genes expressed specifically by the tachyzoite stage of T. gondii (T. gondii surface antigen 1 [SAG-1] and T. gondii surface antigen 2 [SAG-2]). Similarly, in mice chronically infected with T. gondii and treated with anti-IFN-gamma mAb the resulting pathology was associated with decreased expression of TNF-alpha and iNOS and increased expression of SAG-1 and SAG-2. Moreover, treatment with anti-TNF-alpha mAb also resulted in enhanced pathology, which correlated with low levels of iNOS mRNA and high levels of tachyzoite-specific mRNAs. Together these results suggest that reactivation of T. gondii results from a down-regulation of IFN-gamma and TNF-alpha expression leading to decreased macrophage or microglial cell activation, release of parasite growth, and subsequent tissue damage.
感染刚地弓形虫ME-49株的C57BL/6小鼠会发生进行性脑炎，在腹腔接种该寄生虫后12至15周内死亡率达100%。此外，在感染后4周注射抗IFN-γ单克隆抗体时，弓形虫脑炎的进展会显著加速，导致动物在治疗后9至12天死亡。在本研究中，我们调查了弓形虫脑炎发展过程中细胞因子以及淋巴细胞和巨噬细胞标志物编码mRNA的表达情况。在整个感染过程中，在小鼠大脑中均检测到高水平的淋巴细胞CD4和CD8表面抗原转录本。此外，在感染后2至4周，我们发现Th1（IFN-γ和IL-2）细胞因子mRNA水平升高，但Th2（IL-4和IL-5）细胞因子mRNA水平未升高。Th1细胞因子的升高伴随着单核因子（IL-1、IL-6、IL-10、粒细胞巨噬细胞集落刺激因子[GM-CSF]和TNF-α）mRNA表达的增加，以及活化巨噬细胞表达的标志物（主要组织相容性复合体II类[Ia]、诱导型一氧化氮合酶[iNOS]和巨噬细胞活化基因1[Mag-1]）表达的增加。有趣的是，在感染刚地弓形虫8周后，我们观察到Th1细胞因子以及大多数单核因子（IL-1、IL-6、GM-CSF和TNF-α）以及Mag-1和iNOS mRNA水平显著下降。这种下调与大脑中坏死增加和嗜中性粒细胞浸润增强有关，同时伴随着刚地弓形虫速殖子阶段特异性表达基因（刚地弓形虫表面抗原1[SAG-1]和刚地弓形虫表面抗原2[SAG-2]）表达的增加。同样，在慢性感染刚地弓形虫并用抗IFN-γ单克隆抗体治疗的小鼠中，所产生的病理变化与TNF-α和iNOS表达降低以及SAG-1和SAG-2表达增加有关。此外，用抗TNF-α单克隆抗体治疗也导致病理变化加剧，这与iNOS mRNA水平低和速殖子特异性mRNA水平高相关。这些结果共同表明，刚地弓形虫的再激活是由于IFN-γ和TNF-α表达下调导致巨噬细胞或小胶质细胞活化降低、寄生虫生长释放以及随后的组织损伤所致。
