Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen.
Malaria induces anemia through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen.
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DOI：
10.1128/mbio.02493-14
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发表时间：
2015-01-20
期刊：
影响因子：
6.4
通讯作者：
Haldar K
中科院分区：
文献类型：
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作者：
Safeukui I;Gomez ND;Adelani AA;Burte F;Afolabi NK;Akondy R;Velazquez P;Holder A;Tewari R;Buffet P;Brown BJ;Shokunbi WA;Olaleye D;Sodeinde O;Kazura J;Ahmed R;Mohandas N;Fernandez-Reyes D;Haldar K
严重疟疾贫血(SMA)在半免疫性个体中会清除感染和未感染的红细胞，是一种常见的致命并发症。它不是与循环寄生虫血症成正比，而是与器官中的总寄生虫量(隔离)成正比。因此，清除器官中寄生虫的免疫反应可能会引发导致贫血的变化。在这里，我们使用了一种异种大鼠模型，在这种模型中，增加脾内寄生虫的清除会升级未感染的红细胞的清除。脾寄生虫的清除与激活的CD8+T细胞有关，CD8+T细胞的免疫耗竭阻止了寄生虫的清除。CD8+T细胞的补充和伴随的寄生虫载量的降低与未感染的红细胞的血红蛋白丢失加剧(40%至60%)和特性改变相关。综上所述，这些数据表明，依赖CD8+T细胞的寄生虫清除导致了脾中红细胞的清除，从而导致贫血。在感染人类疟疾寄生虫恶性疟原虫的儿童中，寄生虫生物量的增加(而不是循环寄生虫的数量)使SMA的优势比增加了3.5倍(95%的可信区间[CI95%]，1.8至7.5倍)。CD8+T细胞的扩增/激活独立增加了2.4倍的优势比(CI95%，1.0到5.7倍)。两者的相伴增加使SMA的风险增加了7倍(CI95%，1.9至27.4倍)。总之，这些数据表明，依赖CD8+的寄生虫清除可能使个体更容易发生未感染的红细胞丢失和SMA，从而为严重疾病诊断和疫苗开发策略提供信息。疟疾是一个主要的全球健康问题。重症疟疾贫血(SMA)是一种与部分免疫相关的复杂疾病。通常可以观察到血红蛋白迅速减少20%到50%，必须通过输血才能挽救(这可能会带来感染艾滋病毒的风险)。SMA的原因和风险因素仍然知之甚少。最近的研究表明，SMA与隔离在器官中的寄生虫生物量有关。这促使我们研究清除器官中寄生虫的免疫机制是否会引发贫血。在大鼠中，红细胞生成在很大程度上局限于骨髓，预计在贫血中重要的脾的关键部位与人类相似。因此，利用大鼠模型，我们证明了严重贫血是通过清除依赖CD8+T细胞的寄生虫和清除脾中的红细胞而引起的。CD8激活也可能是非洲儿童SMA的一个新的危险因素。
Severe malarial anemia (SMA) in semi-immune individuals eliminates both infected and uninfected erythrocytes and is a frequent fatal complication. It is proportional not to circulating parasitemia but total parasite mass (sequestered) in the organs. Thus, immune responses that clear parasites in organs may trigger changes leading to anemia. Here, we use an outbred-rat model where increasing parasite removal in the spleen escalated uninfected-erythrocyte removal. Splenic parasite clearance was associated with activated CD8+ T cells, immunodepletion of which prevented parasite clearance. CD8+ T cell repletion and concomitant reduction of the parasite load was associated with exacerbated (40 to 60%) hemoglobin loss and changes in properties of uninfected erythrocytes. Together, these data suggest that CD8+ T cell-dependent parasite clearance causes erythrocyte removal in the spleen and thus anemia. In children infected with the human malaria parasite Plasmodium falciparum, elevation of parasite biomass (not the number of circulating parasites) increased the odds ratio for SMA by 3.5-fold (95% confidence intervals [CI95%], 1.8- to 7.5-fold). CD8+ T cell expansion/activation independently increased the odds ratio by 2.4-fold (CI95%, 1.0- to 5.7-fold). Concomitant increases in both conferred a 7-fold (CI95%, 1.9- to 27.4-fold)-greater risk for SMA. Together, these data suggest that CD8+-dependent parasite clearance may predispose individuals to uninfected-erythrocyte loss and SMA, thus informing severe disease diagnosis and strategies for vaccine development. Malaria is a major global health problem. Severe malaria anemia (SMA) is a complex disease associated with partial immunity. Rapid hemoglobin reductions of 20 to 50% are commonly observed and must be rescued by transfusion (which can carry a risk of HIV acquisition). The causes and risk factors of SMA remain poorly understood. Recent studies suggest that SMA is linked to parasite biomass sequestered in organs. This led us to investigate whether immune mechanisms that clear parasites in organs trigger anemia. In rats, erythropoiesis is largely restricted to the bone marrow, and critical aspects of the spleen expected to be important in anemia are similar to those in humans. Therefore, using a rat model, we show that severe anemia is caused through CD8+ T cell-dependent parasite clearance and erythrocyte removal in the spleen. CD8 activation may also be a new risk factor for SMA in African children.
DOI：
10.1084/jem.158.3.752
发表时间：
1983-09-01
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Fujimoto J;Levy S;Levy R
通讯作者：
Levy R