Increased survival in B-cell-deficient mice during experimental cerebral malaria suggests a role for circulating immune complexes.
Increased survival in B-cell-deficient mice during experimental cerebral malaria suggests a role for circulating immune complexes.
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DOI：
10.1128/mbio.00949-14
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发表时间：
2014-03-18
期刊：
影响因子：
6.4
通讯作者：
Golenbock DT
中科院分区：
文献类型：
--
作者：
de Oliveira RB;Wang JP;Ram S;Gazzinelli RT;Finberg RW;Golenbock DT
疟疾是一种昆虫传播的疾病，每年夺去数百万人的生命，其发病机制仍未完全了解。补体受体1(CR1)是引起人类脑型疟疾的恶性疟原虫的受体。我们研究了CR1在脑型疟疾实验模型中的作用。在红细胞上表达人CR1(hCR1+)的转基因小鼠感染伯氏疟原虫并发生脑型疟疾。感染伯氏疟原虫后，hCR1+小鼠的存活率与野生型小鼠没有差异；然而，在感染后7天和10天，红细胞上hCR1的检测显著减少。存活动物的hCR1水平在感染后第17天恢复到基线水平。免疫印迹分析显示，红细胞hCR1的总水平降低，证实与红细胞hCR1相关的免疫复合物可能在体内通过免疫黏附清除而从红细胞中移除。HCR1的减少完全依赖于C3的表达，因为眼镜蛇毒素(消耗和消耗C3)处理的小鼠在C3耗竭期间直到第7天红细胞上保留了hCR1；只有当C3水平在第9天恢复时，红细胞hCR1才观察到减少。B细胞缺陷小鼠在感染伯氏疟原虫后存活率显著增加，这表明免疫复合体在实验性脑疟疾的发病机制中发挥了核心作用。总之，我们的发现强调了补体和免疫复合体在实验性脑型疟疾中的重要性。脑型疟疾是感染恶性疟原虫的致命并发症。尽管其发病率很高，但对其发病机制了解相对较少。我们已经确定，在脑型疟疾的小鼠模型中，免疫复合体被产生并沉积在红细胞上，特异性地表达人类补体受体1。我们还提供了证明免疫球蛋白在小鼠脑疟疾发病机制中的重要性的证据。这些发现可能对人类脑型疟疾有重要意义。
The pathogenesis of malaria, an insect-borne disease that takes millions of lives every year, is still not fully understood. Complement receptor 1 (CR1) has been described as a receptor for Plasmodium falciparum, which causes cerebral malaria in humans. We investigated the role of CR1 in an experimental model of cerebral malaria. Transgenic mice expressing human CR1 (hCR1+) on erythrocytes were infected with Plasmodium berghei ANKA and developed cerebral malaria. No difference in survival was observed in hCR1+ mice compared to wild-type mice following infection with P. berghei ANKA; however, hCR1 detection was significantly diminished on erythrocytes between days 7 and 10 postinfection. hCR1 levels returned to baseline by day 17 postinfection in surviving animals. Immunoblot assays revealed that total erythrocyte hCR1 levels were diminished, confirming that immune complexes in association with erythrocyte hCR1 were likely removed from erythrocytes in vivo by clearance following immune adherence. Decreases in hCR1 were completely dependent on C3 expression, as mice treated with cobra venom factor (which consumes and depletes C3) retained hCR1 on erythrocytes during C3 depletion through day 7; erythrocyte hCR1 decreases were observed only when C3 levels recovered on day 9. B-cell-deficient mice exhibit a marked increase in survival following infection with P. berghei ANKA, which suggests that immune complexes play a central role in the pathogenesis of experimental cerebral malaria. Together, our findings highlight the importance of complement and immune complexes in experimental cerebral malaria. Cerebral malaria is a deadly complication of infection with Plasmodium falciparum. Despite its high prevalence, relatively little is understood about its pathogenesis. We have determined that immune complexes are generated and deposited on erythrocytes specifically expressing human complement receptor 1 in a mouse model of cerebral malaria. We also provide evidence demonstrating the importance of immunoglobulins in the pathogenesis of cerebral malaria in mice. These findings may have important implications in human cerebral malaria.