Campanella Gabriele S V, Tager Andrew M, El Khoury Joseph K, Thomas Seddon Y, Abrazinski Tabitha A, Manice Lindsay A, Colvin Richard A, Luster Andrew D
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4814-9. doi: 10.1073/pnas.0801544105. Epub 2008 Mar 17.
Cerebral malaria is a significant cause of global mortality, causing an estimated two million deaths per year, mainly in children. The pathogenesis of this disease remains incompletely understood. Chemokines have been implicated in the development of cerebral malaria, and the IFN-inducible CXCR3 chemokine ligand IP-10 (CXCL10) was recently found to be the only serum biomarker that predicted cerebral malaria mortality in Ghanaian children. We show that the CXCR3 chemokine ligands IP-10 and Mig (CXCL9) were highly induced in the brains of mice with murine cerebral malaria caused by Plasmodium berghei ANKA. Mice deficient in CXCR3 were markedly protected against cerebral malaria and had far fewer T cells in the brain compared with wild-type mice. In competitive transfer experiments, CXCR3-deficient CD8(+) T cells were 7-fold less efficient at migrating into the infected brains than wild-type CD8(+) T cells. Adoptive transfer of wild-type CD8(+) effector T cells restored susceptibility of CXCR3-deficient mice to cerebral malaria and also restored brain proinflammatory cytokine and chemokine production and recruitment of T cells, independent of CXCR3. Mice deficient in IP-10 or Mig were both partially protected against cerebral malaria mortality when infected with P. berghei ANKA. Brain immunohistochemistry revealed Mig staining of endothelial cells, whereas IP-10 staining was mainly found in neurons. These data demonstrate that CXCR3 on CD8(+) T cells is required for T cell recruitment into the brain and the development of murine cerebral malaria and suggest that the CXCR3 ligands Mig and IP-10 play distinct, nonredundant roles in the pathogenesis of this disease.
脑型疟疾是全球死亡的一个重要原因，估计每年导致200万人死亡，主要是儿童。这种疾病的发病机制仍未完全了解。趋化因子与脑型疟疾的发展有关，最近发现干扰素诱导的CXCR3趋化因子配体IP-10（CXCL10）是预测加纳儿童脑型疟疾死亡率的唯一血清生物标志物。我们发现，由伯氏疟原虫ANKA引起的鼠脑型疟疾小鼠脑中，CXCR3趋化因子配体IP-10和Mig（CXCL9）被高度诱导。与野生型小鼠相比，CXCR3缺陷小鼠对脑型疟疾有明显的抵抗力，并且脑中的T细胞数量少得多。在竞争性转移实验中，CXCR3缺陷的CD8(+) T细胞迁移到受感染大脑中的效率比野生型CD8(+) T细胞低7倍。野生型CD8(+)效应T细胞的过继转移恢复了CXCR3缺陷小鼠对脑型疟疾的易感性，也恢复了脑内促炎细胞因子和趋化因子的产生以及T细胞的募集，且与CXCR3无关。当感染伯氏疟原虫ANKA时，IP-10或Mig缺陷的小鼠对脑型疟疾死亡率均有部分抵抗力。脑免疫组织化学显示Mig在内皮细胞中有染色，而IP-10染色主要见于神经元。这些数据表明，CD8(+) T细胞上的CXCR3是T细胞募集到脑中以及鼠脑型疟疾发展所必需的，并表明CXCR3配体Mig和IP-10在这种疾病的发病机制中发挥着不同的、非冗余的作用。
