Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels

Munde, Elly O.; Okeyo, Winnie A.; Anyona, Samuel B.; Raballah, Evans; Konah, Stephen; Okumu, Wilson; Ogonda, Lilian; Vulule, John; Ouma, Collins

doi:10.1128/iai.00945-12

Cited by 14 publications

(9 citation statements)

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“…Our study revealed no association between the FcγRIIIA-176F/V polymorphism and susceptibility to SMA in this pediatric population. This may imply that this particular variant is not independently associated with susceptibility to SMA which is consistent with our previous study involving the combined effect of toll-like receptor 9 and FcγRIIIA polymorphisms [ 39 ]. The FcγRIIIB is a C-terminus linked glycosylphosphatidylinositol (GPI) moiety anchored receptor, exclusively expressed on neutrophils with three characterized allotypes i.e.…”

Section: Discussionsupporting

confidence: 90%

Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya

et al. 2017

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12879-017-2390-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 90%

Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya

et al. 2017

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“…Phagocytosis of parasitic products, such as P. falciparum -derived haemozoin ( Pf Hz), alters inflammatory mediator production and promotes suppression of erythropoiesis [11,12]. Our previous genetic investigations in Kenyan children demonstrate that polymorphic variability in host immune response genes can impart functional changes in inflammatory mediator production that influence susceptibility to SMA [[13], [14], [15], [16], [17], [18]]. We recently used an unbiased approach to further identify genes and gene pathways involved in the pathogenesis of SMA by performing high-throughput genotyping and whole transcriptome in a subset of Kenyan children with discrete mild and severe malaria phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling

et al. 2019

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Background Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to a myriad of inflammatory diseases. Our recent investigations of severe malarial anaemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants which were associated with decreased LAIR1 transcripts enhanced the longitudinal risk of SMA and all-cause mortality. Methods To characterize the molecular mechanism(s) responsible for altered LAIR1 signalling in severe malaria, we determined LAIR1 transcripts and protein, sLAIR1, sLAIR2, and complement component 1q (C1q) in children with malarial anaemia, followed by a series of in vitro experiments investigating the LAIR1 signalling cascade. Findings Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P < .0001). The LAIR1 antagonist, sLAIR2, was also elevated in the circulation of children with SMA (1.59 fold-change, P < .0001). There was a positive correlation between sLAIR1 and sLAIR2 (ρ = 0.741, P < .0001). Conversely, circulating levels of complement component 1q (C1q), a LAIR1 natural ligand, were lower in SMA (−1.21-fold P = .048). These in vivo findings suggest that reduced membrane-bound LAIR1 expression in SMA is associated with elevated production of sLAIR1, sLAIR2 (antagonist), and limited C1q (agonist) availability. Since reduced LAIR1 transcripts in SMA were associated with increased acquisition of haemozoin ( Pf Hz) by monocytes ( P = .028), we explored the relationship between acquisition of intraleukocytic Pf Hz, LAIR1 expression, and subsequent impacts on leukocyte signalling in cultured PBMCs from malaria-naïve donors stimulated with physiological concentrations of Pf Hz (10 μg/mL). Phagocytosis of Pf Hz reduced LAIR1 transcript and protein expression in a time-dependent manner ( P < .050), and inhibited LAIR1 signalling through decreased phosphorylation of LAIR1 ( P < .0001) and SH2-domain containing phosphatase-1 (SHP-1) ( P < .001). This process was associated with NF-κB activation ( P < .0001) and enhanced production of IL-6, IL-1β, and TNF-α (all P < .0001). Interpretation Collectively, these findings demonstrate that SMA is characterized by reduced LAIR1 transmembrane expression, reduced C1q, and enhanced production of sLAIR1 and s...

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“…Hemophagocytic macrophages that appeared in response to infection, had markers of anti-inflammatory M2 phenotype [ 114 ]. Genetic mutations may predispose patients to the development of hemophagocytes in response to infections [ 107 , 115 ].…”

Section: Nutritional Immunity and Infection-induced Anemiamentioning

confidence: 99%

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

et al. 2018

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Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection.

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Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels

Abstract: An understanding of the immunogenetic basis of naturally acquired immunity to

Cited by 14 publications

References 65 publications

Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya

Association between Fcγ receptor IIA, IIIA and IIIB genetic polymorphisms and susceptibility to severe malaria anemia in children in western Kenya

Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling

Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

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