脑型疟发病机制研究进展

脑型疟是恶性疟中最严重的致死性并发症.以T淋巴细胞参与为主的细胞免疫及肿瘤坏死因子(TNF)在鼠脑型疟发病机制中起重要作用。感染恶性疟原虫的宿主红细胞表面结节与脑血管内皮细胞粘附导致的脑微血管床阻塞则是人脑型疟的主要病理特征。已阐明了与结节有关的三种蛋白质,鉴定出三种与细胞粘附直接有关的宿主毛细血管内皮细胞表面受体。研制针对这些细胞粘附相关的蛋白质分子的单克隆抗体,可望开拓出特效的脑型疟防治新方法。     

人体脑型疟的细胞因子理论

在论及脑型疟中感染的红细胞粘附于内皮细胞的机制时许多文献都得出这样的结论:疟原虫阻滞使脑血管机械阻塞导致大脑缺氧是脑型疟的根本原因。已有的证据表明,栓塞不是疟疾脑部症状开始出现的必要条件。脑型疟有一个不能解释的现象,就是幸存者中有很高比率的人没有神经系统的后遗症,尽管曾经历很长的昏迷期。在131例患脑型疟儿童中,90％的幸存者在经历平均31h深度昏迷后神经系统功能仍能完全恢复。成     

感染猴疟原虫(P.coatneyi)的红细胞的可变性减退与脑型疟的关系

脑型疟的病变主要是脑血管栓塞、周围循环衰竭和脑水肿。作者曾用流变学方法证明,受诺氏猴疟原虫感染的红细胞因变形力的减退而不能穿过直径小于红细胞的毛细血管引起栓塞的情况。本文报告用与恶性疟原虫更相类似的P.coatneyi作进一步研究的结果。     

脑型疟免疫病理学机制的研究进展

了解脑型疟发病机制最新进展,可为防治脑型疟、降低死亡率提供依据。研究发现鼠脑型疟是一种多因素参与的致命性的免疫病理性疾病,中枢神经系统血脑屏障渗透性增加、星形胶质细胞变性导致其支持功能的丧失、小胶质细胞与淋巴细胞分泌的各种细胞因子和单核/巨噬细胞相结合共同促使中枢神经系统功能紊乱,诱发脑型疟。在探讨人类脑型疟致病机制时应考虑中枢神经系统内胶质细胞和细胞因子的作用。     

脆弱疟原虫:蒿乙醚(α/β)对脑型疟模型的药效

脑型疟是恶性疟原虫感染的严重合并症。与脑型疟相关的病理表现有:深部血管内裂体增殖,裂殖体在脑微血管积聚造成毛细血管阻塞,血流受阻,缺氧和继发器官衰竭。近年来研究表明,这种积聚是由于宿主的各种粘附分子(如CD_(36),TSP等)作用的结果。脆弱疟原虫和柯氏猴疟原虫感染的猕猴都表现出典型的裂殖体感染的红细胞粘附于脑毛细血管的内皮细胞上,这类似于人体脑型疟。由于脆弱疟原虫和恶性疟原虫感染所致的脑合并症相同,曾有报道采用哺乳动物做脆弱疟原虫人体脑型疟动物模型。本文采用这一动物模型,评价蒿乙醚对血液内裂殖体的杀灭效能。     

赞比亚非洲成年人的脑型疟

本文报道脑型疟患者临床、实验室和病理学的表现。1975～1978年赞比亚SolweziGencral医院共收治疟疾患者458例,其中脑型疟34例(7.4%),诊断标准为所有患者血中2次以上分离出恶性疟原虫、部分死亡病例脑血管中有恶性疟原虫、排除拟似脑型疟的全身性感染以及患者对于化学治疗的反应。男性24例、女性10例,平均年龄为32.6岁(17～48岁)。临床表现主要有寒战、发热(38.9～39.4C)、意识障碍、精神错乱、嗜睡、     

脑型疟免疫病理学机制的研究进展

了解脑型疟发病机制最新进展，可为防治脑型疟、降低死亡率提供依据。研究发现鼠脑型疟是一种多因素参与的致命性的免疫病理性疾病，中枢神经系统血脑屏障渗透性增加、星形胶质细胞变性导致其支持功能的丧失、小胶质细胞与淋巴细胞分泌的各种细胞因子和单核／巨噬细胞相结合共同促使中枢神经系统功能紊乱，诱发脑型疟。在探讨人类脑型疟致病机制时应考虑中枢神经系统内胶质细胞和细胞因子的作用。     

脑型疟和无并发症疟疾患儿对恶性疟原虫抗原的体液反应及其与寄生虫基因型之间的关系

在疟疾流行区,大多数人感染疟原虫后无症状,只有少数人特别是儿童可出现症状,而发生严重病症如贫血和脑型疟者更少,其确切原因尚不清楚,寄生虫与宿主的遗传性状可能起一定的作用。本文的研究目的:1)确定不同的疟原虫抗原的体液反应是否为患脑型疟和温和型疟疾的重要决定因素;2)研究疟原虫基因型与体液反应之间的关系。     

约氏疟原虫感染对小鼠红细胞膜蛋白组分及其与内皮细胞黏附力的影响

目的分析约氏疟原虫感染后小鼠红细胞膜蛋白及受染红细胞与内皮细胞黏附能力的变化,为进一步探索脑型疟的发生机制提供线索。方法提取约氏疟原虫感染的BALB/c小鼠红细胞膜蛋白,进行SDS-PAGE电泳,检测红细胞膜蛋白的变化。用内皮细胞株与小鼠红细胞共同培养,观察受染红细胞与内皮细胞黏附能力的改变。结果 SDS-PAGE显示约氏疟原虫感染后的小鼠红细胞膜蛋白中含有分子质量约137ku组分,53/54ku固有膜蛋白减少。与未感染对照组比较,受染红细胞对内皮细胞的黏附能力增强约3倍,差异有统计学意义(P<0.05)。结论疟原虫感染可改变宿主红细胞膜蛋白组成,增强受染红细胞与内皮细胞的黏附力。这些变化可能与脑型疟的发生有关。     

TNF在疟疾感染中的免疫保护及免疫病理机制

本文综述了TNF在疟疾感染中杀伤及抑制疟原虫发育的免疫保护机制和引起宿主病理损伤,尤其是在脑型疟形成过程中的作用机制。     

TNF-α和ICAM-1在脑型疟发病中的作用

[目的 ]研究粘附分子 TNF- α、ICAM- 1与脑型疟 (cerebral malaria,CM)的关系 ,并通过体内注射外源性 TNF- α来观察 ICAM- 1的表达情况及其对 CM发生的影响。 [方法 ]通过建立 CM小鼠模型 ,酶联免疫吸附实验 (EL ISA)检测感染小鼠血清 TNF-α浓度。免疫组织化学 SP法检测感染小鼠脑微血管的 ICAM- 1表达 ,结果用真彩色图象分析仪半定量分析。 [结果 ]发生 CM小鼠的血清 TNF- α明显高于其它小鼠 ,只有发生 CM的小鼠脑微血管有 ICAM- 1表达 ,体内注射 r TNF-α能促进 CM的发生 ,并显著增加脑微血管的 ICAM- 1的表达。 [结论 ]大量的 TNF- α在 CM的发病中可能有直接致病作用 ,但主要可能通过调节脑微血管的 ICAM- 1表达发挥作用     

Cytokines associated with pathology in the brain tissue of fatal malaria

Cytoadherence of Plasmodium falciparum-infected erythrocytes to the brain microvascular endothelial cells is believed to be an important cause of circulatory blockage in cerebral malaria. Cytokines released during acute infection may activate brain endothelial cells leading to increased binding of infected erythrocytes in the brain and reduced cerebral blood flow. This effect may be direct and more potent with the tissue-localized cytokines in the brain. In order to establish this relationship, brain tissues of cerebral and noncerebral malaria were compared. The most prominent histopathologic changes in the brain included edema, neuronal degeneration, ring hemorrhage, and percentage of parasitized erythrocytes sequestration were observed in cerebral malaria. Immunohistochemical staining of the brain sections demonstrated that tissue-localized TNF-alpha, IFN-gamma, IL-I1B, and IL-10 were associated with the histopathology. However, IL-4 was the only cytokine presented at moderate level in the brain tissue of noncerebral malaria which histopathology was the least. No tissue-localized cytokine was observed in the brain of P. vivax infection or of the car accident control cases.     

Cerebral metabolic reduction in severe malaria: fluorodeoxyglucose-positron emission tomography imaging in a primate model of severe human malaria with cerebral involvement

Cerebral metabolic changes in Japanese macaques (Macaca fuscata) infected with Plasmodium coatneyi, a primate model of severe human malaria with cerebral involvement, were directly evaluated by fluorodeoxyglucose-positron emission tomography (FDG-PET). We observed diffuse and heterogeneous reduction of metabolism in the cerebral cortex in the acute phase of malaria infection. Neuropathologic examination showed preferential sequestration of parasitized red blood cells in the cerebral microvasculature. However, hemorrhagic change or necrosis was not observed in hematoxylin and eosin-stained and Nissl-stained brain tissues. This suggests that reduction of cerebral metabolism occurs before parenchymal changes appear in the brain. This may be one reason why more than half of the patients with cerebral malaria have no neurologic sequelae after recovery.     

Recombinant human erythropoietin prevents the death of mice during cerebral malaria

Cerebral involvement during malaria is a complication that leads to seizure, coma, and death. The effect of new neuroprotective therapies has not yet been investigated, although cerebral malaria shares some features with neurological stroke. Erythropoietin (EPO) is one of the more promising drugs in this area. We measured the effect of EPO on the survival of mice infected with Plasmodium berghei ANKA and demonstrated that inoculations of recombinant human EPO at the beginning of the clinical manifestations of cerebral malaria protect >90% of mice from death. This drug has no effect on the course of parasitemia. The effect of EPO was not related to either the inhibition of apoptosis in the brain or the regulation of the increase and decrease of nitric oxide production in the brain and blood, respectively. Tumor necrosis factor-alpha and interferon-gamma mRNA overexpression was inhibited by EPO, and treated mice had fewer brain hemorrhages. EPO has been used in patients with chronic diseases for years, and more recently it has been used to treat acute ischemic stroke. The data presented here provide the first evidence indicating that this cytokine could be useful for the symptomatic prevention of mortality during the acute stage of cerebral malaria.     

Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria

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.     

Cerebral malaria protection in mice by species-specific Plasmodium coinfection is associated with reduced CC chemokine levels in the brain

Cerebral malaria is a major pathological complication of Plasmodium falciparum infection in humans. Epidemiological observations have suggested that the clinical evolution of P. falciparum infections may be influenced by the concurrent presence of another Plasmodium species. Infection of susceptible mouse strains with P. berghei ANKA (PbA) provides an experimental model of cerebral malaria which has been extensively used to identify different components of the immune system involved in cerebral malaria. This model has also been employed to investigate the influence of experimental mixed-Plasmodium-species infections on the expression of cerebral malaria; PbA-induced cerebral malaria is completely inhibited by the simultaneous presence of P. yoelii yoelii 17 X clone 1.1 parasites, and accumulation of CD8(+) T cells in the brain vasculature is abolished. We investigated whether brain levels of CD8(+) -T-cell-chemoattractant chemokines CCL3, CCL4 and CCL5 are reduced in these protected coinfected mice compared with PbA-infected mice. Coinfected mice were found to exhibit significantly reduced levels of all three chemokines on day 6 post-infection. This finding may contribute to the abolition of the accumulation of CD8(+) T cells in the brain vasculature and the prevention of the development of cerebral malaria in coinfected mice.     

An ultrastructural study of the brain in fatal Plasmodium falciparum malaria

Cerebral malaria (CM) is a major cause of death in severe Plasmodium falciparum malaria. We present quantitative electron microscopic findings of the neuropathologic features in a prospective clinicopathologic study of 65 patients who died of severe malaria in Thailand and Vietnam. Sequestration of parasitized red blood cells (PRBCs) in cerebral microvessels was significantly higher in the brains of patients with CM compared with those with non-cerebral malaria (NCM) in all parts of the brain (cerebrum, cerebellum, and medulla oblongata). There was a hierarchy of sequestration with more in the cerebrum and cerebellum than the brain stem. When cerebral sequestration was compared with the peripheral parasitemia pre mortem, there were 26.6 times more PRBCs in the brain microvasculature than in the peripheral blood. The sequestration index was significantly higher in CM patients (median = 50.7) than in NCM patients (median = 6.9) (P = 0.042). The degree of sequestration of P. falciparum-infected erythrocytes in cerebral microvessels is quantitatively associated with pre-mortem coma.     

Imaging analysis of the brain in a primate model of cerebral malaria

This paper reviews our studies concerning imaging analysis of the brain in a primate model of cerebral malaria. To elucidate the clinical features of cerebral malaria, we performed positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) scanning and magnetic resonance imaging (MRI) of the brain in Japanese macaques (Macaca fuscata) infected with Plasmodium coatneyi, a primate model of severe human malaria with cerebral involvement. On FDG-PET scanning, we observed diffuse and heterogeneous reduction of metabolism in the cerebral cortex in the acute phase of malaria infection. Although the monkey exhibited severe clinical signs, MR imaging did not reveal any significant changes during the course of infection. Histopathologic examination frequently revealed preferential sequestration of PRBCs in the cerebral and cerebellum capillaries, but neither parenchymal injury nor neuronal necrosis was found in the tissues. These results suggest that heterogeneous metabolic reduction and lack of abnormalities on MRI in the acute phase of CM may be due to any avoidance mechanisms from ischemia caused by sequestration. This may be one reason why more than half of CM patients have no neurological sequelae following recovery.     

Sequestration and microvascular congestion are associated with coma in human cerebral malaria

The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.     

Cyclooxygenase-2 in the pathogenesis of murine cerebral malaria

Cerebral malaria (CM) is a severe complication of malaria, in which cytokine production can produce immunopathological consequences. Cytokines can up-regulate prostaglandin synthesis via an increase in cyclooxygenase (COX) enzyme activity. We investigated the expression of COX enzymes, COX-1 and COX-2, in the brain by use of murine models of CM and of malaria without cerebral involvement. Although COX-1 mRNA was induced in the brain in both models of malaria, COX-2 mRNA was induced specifically in CM. Inhibition of COX-2 with celecoxib resulted in an earlier onset of CM. Treatment with celecoxib did not alter the outcome of malaria infection without cerebral involvement. These data suggest that induction of COX-2 expression and prostaglandin synthesis may have a protective effect in CM.