title: Neutralization of malaria glycosylphosphatidylinositol in vitro by serum IgG from malaria-exposed individuals.
abstract: Parasite-derived glycosylphosphatidylinositol (GPI) is believed to be a major inducer of the pathways leading to pathology and morbidity during Plasmodium falciparum infection and has been termed a malaria "toxin." The generation of neutralizing anti-GPI ("antitoxic") antibodies has therefore been hypothesized to be an important step in the acquisition of antidisease immunity to malaria; however, to date the GPI-neutralizing capacity of antibodies induced during natural Plasmodium falciparum infection has not been evaluated. Here we describe the development of an in vitro macrophage-based assay to assess the neutralizing capacity of malarial GPI-specific IgG. We demonstrate that IgG from Plasmodium falciparum-exposed individuals can significantly inhibit the GPI-induced activation of macrophages in vitro, as shown by reduced levels of tumor necrosis factor production and attenuation of CD40 expression. The GPI-neutralizing capacity of individual IgG samples was directly correlated with the anti-GPI antibody titer. IgG from malaria-exposed individuals also neutralized the macrophage-activating effects of P. falciparum schizont extract (PfSE), but there was only a poor correlation between PfSE-neutralizing activity and the anti-GPI antibody titer, suggesting that PfSE contains other macrophage-activating moieties, in addition to GPI. In conclusion, we have established an in vitro assay to test the toxin-neutralizing activities of antimalarial antibodies and have shown that anti-GPI antibodies from malaria-immune individuals are able to neutralize GPI-induced macrophage activation; however, the clinical relevance of anti-GPI antibodies remains to be proven, given that malarial schizonts contain other proinflammatory moieties, in addition to GPI.
authors.affiliation: Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, United Kingdom. Brian.deSouza@lshtm.ac.uk
authors.forename: J Brian
authors.initials: JB
authors.lastname: de Souza
authors.forename: Manohursingh
authors.initials: M
authors.lastname: Runglall
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Corran
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Okell
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Kumar
authors.forename: D Channe
authors.initials: DC
authors.lastname: Gowda
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
mesh_terms: D000328:Adult; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D019013:CD40 Antigens / Q000032:analysis; D017261:Glycosylphosphatidylinositols / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008262:Macrophage Activation; D016778:Malaria, Falciparum / Q000276:immunology*; D009500:Neutralization Tests; D010963:Plasmodium falciparum / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D019013:CD40 Antigens; D017261:Glycosylphosphatidylinositols; D007074:Immunoglobulin G