Increased concentrations of interleukin-6 and interleukin-1 receptor antagonist and decreased concentrations of beta-2-glycoprotein I in Gambian children with cerebral malaria

Abstract

To investigate the pathogenic versus the protective role of cytokines and toxin-binding factors in Plasmodium falciparum infections, we measured the concentrations of tumor necrosis factor alpha, interleukin-la (IL-la), IL-1,, IL-1 receptor antagonist, and IL-6, as well as soluble receptors of tumor necrosis factor and IL-6 (sIL-6R) in serum of Gambian children with cerebral malaria, mild or asymptomatic malaria, or other illnesses unrelated to malaria. Because cytokine secretion may be triggered by toxic structures containing phosphatidylinositol (PI), we also measured concentrations of anti-PI antibodies and the PI-binding serum protein beta-2-glycoprotein I. We found increased concentrations of IL-6, sIL-6R, IL-lra, and some immunoglobulin M antibodies against PI in children with cerebral malaria, but those who died had decreased concentrations of beta-2-glycoprotein I. We conclude that increased concentrations of cytokines and soluble cytokine receptors represent a normal host response to P. fakciparum infections but that excessive secretion of cytokines like IL-6 may predispose to cerebral malaria and a fatal outcome while beta-2-glycoprotein I may protect against a fatal outcome of cerebral malaria.

Soluble products of inflammatory reactions are not induced in children with asymptomatic Plasmodium falciparum infections

“…Several cell types produce IL-10 and IL-1Ra, but monocytes are likely to be one of the main sources. Increased concentrations of IL-10 have previously been detected in children with malaria [11], in particular in children with severe malaria, and we have found that the concentrations of IL-1Ra were associated with disease severity in Gambian children with malaria [7].…”

“…The serum protein 2 -GPI binds to negatively charged phospholipids and may therefore bind to the malaria parasite toxin. Although binding of 2 -GPI to this toxin has not been reported, we have previously shown that concentrations of 2 -GPI are significantly decreased in children dying of cerebral malaria [7]. In this study, we found that children with asymptomatic P. falciparum infections had higher concentrations of 2 -GPI compared with children with malaria.…”

“…The concentrations of TNFor IL-6 in the study samples were not determined, since we measured only low or undetectable concentrations of these cytokines in sera from children with mild or asymptomatic P. falciparum infections on a previous occasion [7].…”

“…IL-1Ra and sIL-4R levels were measured by ELISA as previously described [7,8]. Assay sensitivities were 30 pg/ml.…”

“…Levels of anti-phosphatidylinositol (PI) IgG and IgM antibodies were measured by an indirect ELISA as described previously [7,10]. Two different procedures were used-procedures A and B. Fetal calf serum (FCS) was used in procedure A.…”