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Mosquito-transmitted Plasmodium falciparum infection can cause human cerebral malaria (HCM) with high mortality rates. The abundance of infected red blood cells that accumulate in the cerebral vasculature of patients has led to the belief that these brain-sequestered cells solely cause pathogenesis. However, animal models suggest that [CD8.sup.+] T cells migrate to and accumulate in the brain, directly contributing to experimental cerebral malaria (ECM) mortality. In this issue of the JCI, Riggle et al. explored the brain vasculature from 34 children who died from HCM or other causes and frequently found [CD3.sup.+] [CD8.sup.+] T cells in contact with endothelial cells. Further, the authors show that coinfection with HIV enhanced such [CD3.sup.+] [CD8.sup.+] T cell luminal distribution. These findings suggest that the mouse model for cerebral malaria may accurately reflect human disease pathology. This study sheds new light on the mechanisms behind blood-brain barrier breakdown in this complicated neurological disease and opens up alternative approaches for treatment., Sequestration, sequestration, sequestration Human cerebral malaria (HCM), the most severe pathology induced by Plasmodium falciparum infection, encompasses a wide range of neurological complications, including seizures and impaired consciousness (1). Due [...]

Cerebral malaria (CM), a fatal complication of Plasmodium infection that affects children, especially under the age of five, in sub-Saharan Africa and adults in South-East Asia, results from incompletely understood pathogenetic mechanisms. Increased release of circulating miRNA, proteins, lipids and extracellular vesicles has been found in CM patients and experimental mouse models. We compared lipid profiles derived from the plasma of CBA mice infected with Plasmodium berghei ANKA (PbA), which causes CM, to those from Plasmodium yoelii (Py), which does not. We previously showed that platelet-free plasma (18k fractions enriched from plasma) contains a high number of extracellular vesicles (EVs). Here, we found that this fraction produced at the time of CM differed dramatically from those of non-CM mice, despite identical levels of parasitaemia. Using high-resolution liquid chromatography–mass spectrometry (LCMS), we identified over 300 lipid species within 12 lipid classes. We identified 45 and 75 lipid species, mostly including glycerolipids and phospholipids, with significantly altered concentrations in PbA-infected mice compared to Py-infected and uninfected mice, respectively. Total lysophosphatidylethanolamine (LPE) levels were significantly lower in PbA infection compared to Py infection and controls. These results suggest that experimental CM could be characterised by specific changes in the lipid composition of the 18k fraction containing circulating EVs and can be considered an appropriate model to study the role of lipids in the pathophysiology of CM. [ABSTRACT FROM AUTHOR]

Objectives: The role of innate lymphoid cells (ILC), particularly helper ILC, in the pathogenesis of multiple sclerosis (MS) is not well understood. Here, we present a comprehensive analysis of peripheral ILC subsets in MS patients prior and after alemtuzumab administration using mass cytometry. Methods: Circulating ILC were analysed by mass cytometry in MS patients before and after alemtuzumab. These were compared with non‐MS controls. MS‐related shifts among ILC immunophenotypes were further elucidated by fast interpolation‐based t‐SNE (Flt‐SNE) dimensionality reduction. Results: Neither natural killer (NK) cells nor helper ILC (ILC1, ILC2 and ILC3) levels were altered following alemtuzumab treatment. However, CD56bright NK cell expansions were observed in relapsing patients. MS patients prior to alemtuzumab further displayed proportional shifts from ILC1 to ILC2, with MS‐associated decreases in CCR6+ helper ILC proportions. Conclusion: CD56bright NK cells during relapse indicate an immediate response to disease reactivation, while CCR6‐related shifts among helper ILC suggest altered ILC migration to the CNS during MS. [ABSTRACT FROM AUTHOR]

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-[alpha], but not IL-1[beta] or lymphotoxin-[alpha] (LT-[alpha]), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-[alpha] injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies., Introduction Cerebral malaria (CM) is a major cause of death in tropical and subtropical regions, killing over 3 million individuals worldwide per year (1). Platelet sequestration in the cerebral microvasculature [...]