Modulation of the cellular immune response during Plasmodium falciparum infections in sickle cell trait individuals

Abstract

SUMMARY Plasma and peripheral blood mononuclear cells (PBMC) were obtained from P. falciparum‐infecled individuals with and without the sickle cell trait at diagnosis and 7 days after treatment. I lbAA and HbAS patients were compared for levels of plasma soluble IL‐2 receptors (IL‐2R) and the in vitro cellular reactivity to affinity‐purified soluble P. falciparum antigens (SPAg). PPD and phytohae‐magglutinin (PHA). At diagnosis. HbAS patients with clinical disease had lower plasma‐soluble IL‐2R levels and parasite counts than the corresponding HbAA patients, whereas HbAS and HbAA patients with asymptomatic infections had comparable soluble IL‐2R levels and parasite counts. PBMC from HbAS patients had higher proliferation and IFN‐γ production in response to SPAg than PBMC from HbAA patients. The difference in the lymphoproliferativc responses to SPAg between the two groups was evident in patients with asymptomatic infections. In all patients, the clinical severity, the soluble IL‐2R levels and the parasite counts were directly related. The former two were inversely related to the proliferative responses to SPAg. After treatment, all the studied parameters were comparable in the two groups. The study indicates that during P. falciparum infection, HbAS compared with HbAA patients had lower in vivo cellular activation and higher in vitro cellular reactivity in response to soluble malaria antigens.

Increased plasma levels of soluble IL-2R are associated with severe Plasmodium falciparum malaria

“…and increased serum levels of this receptor during malaria infections have been described in murine models [22]. Estimation of plasma levels of sIL-2R may refiect in vivo lymphocyte activation [23,24]. The results of this study confirm previous reports of elevated sIL-2R levels in the blood of malaria patients [25][26][27] and demonstrate a significant association with disease severity independent of parasitaemia.…”

World Distribution, Population Genetics, and Health Burden of the Hemoglobinopathies

“…The protective effect of HbAS in naturally exposed populations increases with age (Cornille-Brogger et Guggenmoos-Holzmann et al 1981;Le Hesran et al 1999;Williams et al 2005a), indicating that the mechanism might not be entirely innate but might also include an acquired, immunological component. This hypothesis is supported by a number of studies that have reported enhanced malaria-specific immune responses in HbAS individuals (Edozien et al 1960;Marsh et al 1989;Bayoumi et al 1990;Abu-Zeid et al 1992;Odegbemi and Williams 1995;Cabrera et al 2005;Verra et al 2007a), and potentially by recent studies using a mouse model that suggest an immuno-modulatory mechanism mediated through hemoxygenase-1 (Ferreira et al 2011). However, the mouse model of the sickling disorders is metabolically very different to the human sickle-cell traits.…”

“…Recently, this relationship has been quantified statistically, an analysis that found strong geographical support for the malaria hypothesis in Africa but not in either the Americas or in Asia (Piel et al 2010). Hemoglobin S is absent from indigenous populations in the Americas, probably because malaria did not reach the continent until relatively recently, whereas in Asia it follows a rather Friedman 1978;Pasvol et al 1978;Friedman et al 1979 Enhanced removal of parasite-infected HbAS red blood cells Luzzatto et al 1970;Friedman 1978;Roth et al 1978;Shear et al 1993;Ayi et al 2004 Reduced pathogenicity of P. falciparum infected red blood cells because of reduced expression of PfEMP1 Cholera et al 2008;Cyrklaff et al 2011 Improved acquisition of malaria-specific immunity Edozien et al 1960;Cornille-Brogger et al 1979;Guggenmoos-Holzmann et al 1981;Marsh et al 1989;Bayoumi et al 1990;Abu-Zeid et al 1992 a thalassemia Specific protection against malaria-induced anaemia Allen et al 1997;Williams et al 2005d;Wambua et al 2006;May et al 2007;Fowkes et al 2008;Veenemans et al 2008 Reduced pathogenicity through reduced cytoadherence or rosetting Udomsangpetch et al 1993;Carlson et al 1994;Cockburn et al 2004 Immuological priming through crossspecies immunity between P. vivax and P. falciparum Williams et al 1996;Veenemans et al 2011 b thalassemia Enhanced removal of parasite-infected red blood cells Ayi et al 2004 Reduced invasion and growth of P. falciparum parasites Kaminsky et al 1986;Senok et al 1997 Reduced pathogenicity through reduced cytoadherence or rosetting restricted distribution, being confined to a small number of tribal populations in India …”

Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait

“…These data are consistent with previous studies consistently finding lower parasite densities during symptomatic disease in HbAS children compared with HbAA children. 4,6,9,10,[18][19][20] In addition, for the first time to our knowledge, we showed that parasitemia is less likely to progress to symptomatic malaria in HbAS children. This may in part be explained by either the lower number of distinct parasites acquired and/or concurrently present in the blood of HbAS children when parasitemic.…”

“…Multiple studies showed lower parasite densities during symptomatic malaria in HbAS versus HbAA individuals, suggesting that HbAS may enhance control of infection once parasitemia is established. 4,6,9,10,[17][18][19][20] However, to our knowledge, no studies have investigated the effect of HbAS on the progression from patent parasitemia to symptomatic malaria.Both innate and acquired mechanisms have been hypothesized to mediate protection conferred by HbAS. Early studies found that the biochemical and physical properties of HbAS erythrocytes led to decreased intraerythrocytic growth, 21 decreased erythrocyte invasion, 22 and increased sickling of infected erythrocytes.…”