Reduced Immune Complex Binding Capacity and Increased Complement Susceptibility of Red Cells from Children with Severe Malaria-Associated Anemia

Abstract

Plasmodium falciparum malaria causes 1-2 million deaths per year. Most deaths occur as a result of complications such as severe anemia and cerebral malaria (CM) (coma). Red cells of children with severe malaria-associated anemia (SMA) have acquired deficiencies in the complement regulatory proteins complement receptor 1 (CR1, CD35) and decay accelerating factor (DAF, CD55). We investigated whether these deficiencies affect the ability of erythrocytes to bind immune complexes (ICs) and regulate complement activation. We recruited 75 children with SMA (Hb ≤ 6 g/dL) from the holoendemic malaria region of the Lake Victoria basin, western Kenya, and 74 age-and gender-matched uncomplicated malaria controls. In addition, we recruited 32 children with CM and 52 age-and gender-matched controls. Deficiencies in red cell CR1 and CD55 in children with SMA were accompanied by a marked decline in IC binding capacity and increased C3b deposition in vivo and ex vivo. Importantly, these changes were specific because they were not seen in red cells of children with CM or their controls. These data suggest that the declines in red cell CR1 and CD55 seen in children with SMA are of physiologic significance and may predispose erythrocytes to complement-mediated damage and phagocytosis in vivo. Online address: http://www.molmed.org doi: 10.2119/2007-00093. Owuor result of IC formation and complement activation that occur during malaria infection (12)(13)(14)(15).We have shown that red cells of children with SMA have decreased levels of CR1 and CD55 (14,16,17). We hypothesized that these changes could translate into a decreased functional capacity to bind ICs and prevent complement deposition, which could result in their increased rate of destruction. To test our hypothesis we carried out a case-control study in children with SMA and age and gender-matched symptomatic uncomplicated malaria controls and determined their levels of erythrocyte CR1 and CD55, their erythrocyte IC binding capacity, and the susceptibility of their red cells to complement deposition in vivo and ex vivo. As an additional comparison group, we recruited children with cerebral malaria (CM) and age-and gender-matched symptomatic uncomplicated malaria controls. MATERIALS AND METHODS Study Design and PopulationsParticipants were recruited under a human use protocol approved by the Human Use Research Committee, the Walter Reed Army Institute of Research, and the National Ethics Review Committee of the Kenya Medical Research Institute. Informed consent was obtained from all parents or guardians. The study had a matched case-control design. SMA cases, defined as children with asexual P. falciparum parasitemia by Giemsastained thick and thin blood smear and Hb ≤ 6 g/dL, were recruited from the pediatric ward of the Nyanza Provincial General Hospital (NPGH), Kisumu, Kenya, where malaria is holoendemic. Because CM is uncommon in this area, CM cases were recruited from the pediatric ward of the Kisii District Hospital (KDH), as well as from the NPGH. KDH is located in t...

CR1 levels and gene polymorphisms exhibit differential association with falciparum malaria in regions of varying disease endemicity

“…4). Indeed, higher C3b deposition on cells with low CR1 and subsequently enhanced complement-mediated damage and phagocytosis in spleen has recently been demonstrated for RBCs from children with severe malarial anemia [40]. On the other hand, high RBC CR1 levels could cause greater risk of cerebral malaria as a result of increased CR1-mediated rosetting causing obstruction of blood flow in brain capillaries (Fig.…”

Malaria Inhibits Surface Expression of Complement Receptor 1 in Monocytes/Macrophages, Causing Decreased Immune Complex Internalization

“…In malaria, decreased levels of CR1 expression on erythrocytes are considered an important factor in the accumulation of IC during disease (39, 40), because of the contribution of erythrocyte CR1 in IC clearance. Erythrocytes transfer IC to macrophages for degradation, probably by transferring the IC from erythrocyte CR1 to macrophage CR1 (41).…”

Distinct pattern of class and subclass antibodies in immune complexes of children with cerebral malaria and severe malarial anaemia

“…Seventy‐five SMA and 32 CM cases were enrolled and matched to 74 and 52 symptomatic uncomplicated malaria controls, respectively. The demographics and clinical characteristics of the study participants were recently reported (10). The mean age (SD) for SMA cases was 16·9 (13·7) months and that of their controls was 16·8 (13·3) months.…”

“…The study had a matched case‐control design. In comparison to our previous studies, we modified the case definition for SMA cases from Hb ≤ 5 g/dL to Hb ≤ 6 g/dL to increase the probability of finding red cells with complement (C3) deposition in support of other studies (10). Thus, SMA cases, defined as children with asexual P. falciparum parasitemia by Giemsa‐stained thick and thin blood smear and Hb ≤ 6 g/dL, were recruited from the paediatric ward of the Nyanza Provincial General Hospital (NPGH), Kisumu, Kenya, where malaria is holoendemic.…”