Prognostic value of anti-Plasmodium falciparum-specific immunoglobulin G3, cytokines, and their soluble receptors in West African patients with severe malaria

Abstract

Forty-one African patients suffering from clinically defined severe malaria were studied in the intensive medical care unit of the main hospital in Dakar, Senegal, West Africa. All of these individuals lived in Greater Dakar, an area of low and seasonal Plasmodium falciparum endemicity. Twenty-seven patients (mean age ؎ 1 standard deviation, 19.2 ؎ 12.7 years) survived this life-threatening episode, but 14 (30.8 ؎ 16.2 years old) died despite initiation of adequate treatment. On the day of admission (day 0) and 3 days later, one to two blood samples (i.e., approximately 10 to 15 ml) were obtained from each subject, and different biological parameters were evaluated in the two groups. Plasma samples were tested for their content in tumor necrosis factor alpha (TNF-␣), soluble receptors I and II for TNF-␣ (TNF-␣ sRI and TNF-␣ sRII), interleukin-6 (IL-6), IL-6 sR, IL-10, and IL-2 sR. The concentrations of all these cytokines and/or their receptors was significantly elevated in patient plasma samples on day 0, and it rapidly decreased in the group of individuals who survived. By comparison, the mean concentration of the same parameters decreased slowly in the group of patients who died (except for IL-10, which dramatically fell in all patient plasma samples soon after initiation of antimalarial treatment). The TNF-␣ sRI level remained significantly elevated among the patients who died, and the highest levels of soluble TNF-␣ sRI receptor were found among the older patients. Parasite-specific immunoglobulin M (IgM), total IgG, IgG1, IgG2, IgG3, and IgG4 were evaluated by enzyme-linked immunosorbent assay using a crude extract of a local P. falciparum isolate as antigen and human class-and subclass-specific monoclonal antibodies. Parasite-specific IgM, total IgG, and IgG1 were detectable in the plasma samples of most of these African patients, whereas IgG2 and IgG4 mean values were low. The mean level of parasite-specific IgG3 was different (P ‫؍‬ 0.024) at day 0, i.e., before initiation of intensive medical care, between the group of the 27 surviving subjects and the group of 14 patients dying of severe malaria. As a consequence, most of the African patients who died had only trace amounts or almost no detectable level of parasite-specific IgG3 at the time of admission. In contrast, the presence of even limited IgG3 activity at day 0 was found to be associated with a significantly increased probability of recovering from severe malaria. Therefore, in our study, both an elevated level of TNF-␣ sRI and absence of IgG3 activity were of bleak prognostic significance, whereas a favorable outcome was usually observed when parasite-specific IgG3 activity was detectable. This finding was strongly suggestive of a prime role for these parasite-specific immunoglobulins in the capacity to help recovery from severe malaria.

Inflammatory cytokine and humoral responses to Plasmodium falciparum glycosylphosphatidylinositols correlates with malaria immunity and pathogenesis

“…These results suggest that TNF-a and IL-6 are associated with the pathogenesis of human SM. These results are in line with several other observations, reporting high circulating levels of proinflammatory cytokines, such as TNF-a [7,29,31] and IL-6 [6,7,29,32,33] during the acute phase of SM in human, as well as in experimental models [31].…”

Analysis of antibody responses to selected Plasmodium falciparum merozoite surface antigens in mild and cerebral malaria and associations with clinical outcomes

“…Secondly, IgG3 and IgM responses did not differ between MM and CM in this study as opposed to higher levels associated with MM in other studies [36,45]. There was a trend towards lower levels of IgG3 against ME in surviving CM compared to fatal outcome, contrary to previously reported observations in the same setting [47], a study involving a lower number of individuals (n = 31) where IgG3 levels in fatal CM were markedly lower than in surviving patients.…”

Naturally acquired immunoglobulin (Ig)G subclass antibodies to crude asexual Plasmodium falciparum lysates: evidence for association with protection for IgG1 and disease for IgG2

“…Consistent with this idea, protective immunity to malaria has been reported to be associated in varying degrees with IgG1 and IgG3 activity specific to ring-infected erythrocyte surface antigen (7) and exo-antigens (8); IgG1 specific to crude asexual blood stage antigen (4), MSP1 (9) and exo-antigens (10); and IgG3 specific to MSP2 (11) and crude asexual blood stage antigen (12,13). Here, we tested whether IgG1 and IgG3 antibody levels present before the beginning of a transmission season (preseason) against crude asexual blood stage antigen, protected children who were living in malaria endemic areas from developing severe malaria.…”