Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province 510080, China.
Parasitol Res. 2013 Jul;112(7):2713-9. doi: 10.1007/s00436-013-3442-z. Epub 2013 May 8.
Cerebral malaria (CM) is a serious and often fatal complication of Plasmodium falciparum infections; however, the precise mechanisms leading to CM is poorly understood. Mouse malaria models have provided insight into the key events in pathogenesis of CM. T-cell immune response is known to play an important role in malaria infection, and members of the T-cell immunoglobulin- and mucin-domain-containing molecule (Tim) family have roles in T-cell-mediated immune responses. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim family proteins in Plasmodium infection remains unclear. In the present study, the mRNA levels of Tim-1, Tim-3, and some key Th1 and Th2 cytokines in the spleen of Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) were determined using real-time polymerase chain reaction (qRT-PCR). Compared with uninfected controls, Tim-1 expression was significantly decreased in infected mice with CM at day 10 postinfection (p.i.) but significantly increased in infected mice with non-CM at day 22 p.i.; in contrast, Tim-3 expression was significantly increased in infected mice both with CM at day 10 p.i. and with non-CM at day 22 p.i. The expressions of IFN-γ, TNF-α, IL-10, and IL-12 were significantly increased but IL-4 was significantly decreased in infected mice with CM at days 10 p.i., whereas the expressions of IFN-γ, TNF-α, IL-4, IL-10, and TGF-β were significantly increased but IL-12 was significantly decreased in infected mice with non-CM at days 22 p.i. Furthermore, the expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response in the spleen of PbANKA-infected mice, respectively. Our data suggest that PbANKA infection could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response in the early infective stage, whereas the infection could promote Th2 cell differentiation and induce Th2-biased immune response in the late infective stage. Our data indicate that both Tim-1 and Tim-3 may play a role in the process of PbANKA infection, which may represent a potential therapeutic target.
脑型疟疾（CM）是恶性疟原虫感染的严重且常常致命的并发症；然而，导致 CM 的具体机制尚未完全明了。鼠疟模型为 CM 发病机制的关键事件提供了深入的了解。众所周知，T 细胞免疫反应在疟疾感染中发挥重要作用，而 T 细胞免疫球蛋白和粘蛋白结构域包含分子（Tim）家族成员在 T 细胞介导的免疫反应中发挥作用。Tim-1 和 Tim-3 分别表达在终末分化的 Th2 和 Th1 细胞上，并参与 Th 免疫反应的调节。到目前为止，Tim 家族蛋白在疟原虫感染中的作用仍不清楚。在本研究中，通过实时聚合酶链反应（qRT-PCR）测定昆明近交系小鼠感染伯氏疟原虫 ANKA（PbANKA）后脾脏中 Tim-1、Tim-3 和一些关键 Th1 和 Th2 细胞因子的 mRNA 水平。与未感染对照相比，CM 感染后第 10 天（感染后）感染小鼠的 Tim-1 表达显著降低，但非 CM 感染后第 22 天感染小鼠的 Tim-1 表达显著升高；相反，Tim-3 在第 10 天感染 CM 和第 22 天感染非 CM 的感染小鼠中的表达均显著升高。在第 10 天感染 CM 的感染小鼠中，IFN-γ、TNF-α、IL-10 和 IL-12 的表达显著增加，但 IL-4 的表达显著降低，而在第 22 天感染非 CM 的感染小鼠中，IFN-γ、TNF-α、IL-4、IL-10 和 TGF-β的表达显著增加，但 IL-12 的表达显著降低。此外，Tim-1 和 Tim-3 的表达可以分别反映出 PbANKA 感染小鼠脾中的 Th2 和 Th1 免疫反应。我们的数据表明，PbANKA 感染可抑制 T 淋巴细胞向 Th2 细胞的分化，促进 Th1 细胞分化，并在早期感染阶段诱导 Th1 偏倚的免疫反应，而在晚期感染阶段，感染可促进 Th2 细胞分化并诱导 Th2 偏倚的免疫反应。我们的数据表明，Tim-1 和 Tim-3 可能在 PbANKA 感染过程中发挥作用，这可能是一个潜在的治疗靶点。
