Miu Jenny, Mitchell Andrew J, Müller Marcus, Carter Sally L, Manders Peter M, McQuillan James A, Saunders Bernadette M, Ball Helen J, Lu Bao, Campbell Iain L, Hunt Nicholas H
Molecular Immunopathology Unit, Bosch Institute, School of Medical Sciences, University of Sydney, New South Wales, Australia.
J Immunol. 2008 Jan 15;180(2):1217-30. doi: 10.4049/jimmunol.180.2.1217.
Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3-/- mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-gamma and lymphotoxin-alpha in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.
脑型疟疾（CM）可能是恶性疟原虫感染的一种致命表现形式。利用疟疾小鼠模型，我们发现，在致命性小鼠脑型疟疾（FMCM）期间，大脑中包括CXCR3及其配体在内的多种趋化因子mRNA的上调程度，比非脑型疟疾模型中要大得多。CXCL9和CXCL10 RNA的表达主要定位于脑微血管及相邻的神经胶质细胞，而CCL5的表达则主要局限于浸润的淋巴细胞。发现大多数缺乏CXCR3的小鼠可免受FMCM侵害，这种保护作用与脑血管中CD8 + T细胞数量减少以及穿孔素和FasL mRNA表达降低有关。将患有FMCM的C57BL / 6小鼠的CD8 +细胞过继转移，消除了CXCR3 - / -小鼠中的这种保护作用。此外，在免受FMCM侵害的小鼠大脑中，促炎细胞因子IFN-γ和淋巴毒素-α的mRNA水平降低。这些数据表明，CXCR3通过募集和激活致病性CD8 + T细胞，在FMCM的发病机制中发挥作用。
