Abstract
BackgroundNaturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection. Fc gamma receptors (FcγRs) bind to immunoglobulin G (IgG) antibodies and mediate phagocytosis of opsonized microbes, thereby, linking humoral and cellular immunity. FcγR polymorphisms influence binding affinity to IgGs and consequently, can influence clinical malaria outcomes. Specifically, variations in FcγRIIA -131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 modulate immune responses through altered binding preferences to IgGs and immune complexes. Differential binding, in turn, changes ability of immune cells to respond to infection through production of inflammatory mediators during P. falciparum infection.MethodsWe determined the association between haplotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 variants and severe malarial anemia (SMA; hemoglobin < 6.0 g/dL, any density parasitemia) in children (n = 274; aged 6–36 months) presenting for their first hospital visit with P. falciparum malaria in a holoendemic transmission region of western Kenya. FcγRIIA-131Arg/His and FcγRIIIA-176F/V genotypes were determined using TaqMan® SNP genotyping, while FcγRIIIBNA1/NA2 genotypes were determined using restriction fragment length polymorphism. Hematological and parasitological indices were measured in all study participants.ResultsCarriage of FcγRIIA-131Arg/FcγRIIIA-176F/FcγRIIIBNA2 haplotype was associated with susceptibility to SMA (OR = 1.70; 95% CI; 1.02–2.93; P = 0.036), while the FcγRIIA-131His/ FcγRIIIA-176F/ FcγRIIIB NA1 haplotype was marginally associated with enhanced susceptibility to SMA (OR: 1.80, 95% CI; 0.98–3.30, P = 0.057) and higher levels of parasitemia (P = 0.009). Individual genotypes of FcγRIIA-131Arg/His, FcγRIIIA-176F/V and FcγRIIIB-NA1/NA2 were not associated with susceptibility to SMA.ConclusionThe study revealed that haplotypes of FcγRs are important in conditioning susceptibility to SMA in immune-naive children from P. falciparum holoendemic region of western Kenya.
Highlights
Naturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection
Demographic clinical and laboratory characteristics of study participants We conducted a cross-sectional analysis of children (n = 274, aged 6–36 months) presenting with acute P. falciparum malaria (See Additional file 1)
The study participants were classified into two categories based on a previous study in an age- and geographically-defined reference population from western Kenya [25], i.e., severe malaria anemia (SMA; Hb < 6.0 g/dL; n = 114) and nonSMA (Hb ≥ 6.0 g/dL, n = 160)
Summary
Naturally-acquired immunity to Plasmodium falciparum malaria develops after several episodes of infection. Fc gamma receptors (FcγRs) bind to immunoglobulin G (IgG) antibodies and mediate phagocytosis of opsonized microbes, thereby, linking humoral and cellular immunity. Even though not fully understood, severe clinical malaria is a multi-factorial process involving sequestration of infected red blood cells (iRBCs) in particular organs such as spleen [2], bone marrow suppression leading to dyserythropoiesis [3], and limited, malaria-specific antibody immunity and dysregulation in inflammatory responses [4]. The binding of immunoglobulin domains to Fc receptors on target cells is important to initiate immunological defense against pathogens including antigen presentation, phagocytosis, cytotoxicity, induction of inflammatory processes and modulation of immune responses [6]. Fc gamma receptors (FcγRs) are important in providing a significant link between the humoral and cellular immunity by bridging the interaction between specific antibodies and effector cells [7]. Previous studies demonstrate that polymorphic variability in these receptors is an important determinant of susceptibility to infections [8, 9]
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