Polymorphic Variability in the Interleukin (IL)–1β Promoter Conditions Susceptibility to Severe Malarial Anemia and Functional Changes in IL‐1β Production

Ouma, Collins; Davenport, Gregory C.; Awandare, Gordon A.; Keller, Christopher; Were, Tom; Otieno, Michael F.; Vulule, John; Martinson, Jeremy; Ong’echa, John Michael; Ferrell, Robert E.; Perkins, Douglas J

doi:10.1086/592055

Cited by 45 publications

(45 citation statements)

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“…Our previous investigations in the cohort investigated here demonstrated that multi-site haplotypes are highly informative allelic markers that can reveal associations with malaria disease outcomes not identifiable with single polymorphisms (Ouma et al 2008a; Ouma et al 2008b). As such, the role of FcγRIIA-131H/R and FcγRIIIB-NA1/NA2 haplotypes in mediating susceptibility to SMA and functional changes in IFN-γ levels were examined in children with acute malaria (n=528; 3-36 mos.)…”

Section: Introductionmentioning

confidence: 81%

Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children

et al. 2011

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Development of protective immunity against Plasmodium falciparum is partially mediated through binding of malaria-specific IgG to Fc gamma (γ) receptors. Variation in human FcγRIIA-H/R-131 and FcγRIIIB-NA1/NA2 affect differential binding of IgG sub-classes. Since variability in FcγR may play an important role in severe malarial anemia (SMA) pathogenesis by mediating phagocytosis of red blood cells and triggering cytokine production, the relationship between FcγRIIA-H/R131 and FcγRIIIB-NA1/NA2 haplotypes and susceptibility to SMA (Hb<6.0g/dL) was investigated in Kenyan children (n=528) with acute malaria residing in a holoendemic P. falciparum transmission region. In addition, the association between carriage of the haplotypes and repeated episodes of SMA and all-cause mortality were investigated over a three-year follow-up period. Since variability in FcγR can alter interferon (IFN)-γ production, a mediator of innate and adaptive immune responses, functional associations between the haplotypes and IFN-γ were also explored. During acute malaria, children with SMA had elevated peripheral IFN-γ levels (P=0.006). Although multivariate logistic regression analyses (controlling for covariates) revealed no associations between the FcγR haplotypes and susceptibility to SMA during acute infection, the FcγRIIA-131H/FcγRIIIB-NA1 haplotype was associated with decreased peripheral IFN-γ (P=0.046). Longitudinal analyses showed that carriage of the FcγRIIA-131H/FcγRIIIB-NA1 haplotype was associated with reduced risk of SMA (RR; 0.65, 95%CI, 0.46-0.90; P=0.012) and all-cause mortality (P=0.002). In contrast, carriers of the FcγRIIA-131H/FcγRIIIB-NA2 haplotype had increased susceptibility to SMA (RR; 1.47, 95%CI, 1.06-2.04; P=0.020). Results here demonstrate that variation in the FcγR gene alters susceptibility to repeated episodes of SMA and mortality, as well as functional changes in IFN-γ production.

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Section: Introductionmentioning

confidence: 81%

Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children

et al. 2011

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“…with SMA being the single severe disease manifestation in regions of holoendemicity. Utilizing such an approach, focusing specifically on innate immune response genes in parasitized children, we have identified a number of genes that have significant relationships with both the risk of developing SMA and functional changes in their respective gene products (4,37,38). To extend these results, we investigated two functional promoter polymorphisms in IL-18 at positions Ϫ137 and Ϫ607 in children with and without SMA.…”

Section: Discussionmentioning

confidence: 99%

“…Based on historical presence of the disease, malaria has exerted a large impact on the human genome such that potentially harmful variants are preserved, largely because of the advantage offered in heterozygous individuals that are often protected from severe, complicated, and fatal malaria (14,19,21). Studies in our laboratory focused on variations in key cytokine genes have demonstrated associations between polymorphisms and SMA (4,37,38).…”

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confidence: 99%

Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality

et al. 2011

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“…Sustained release of IL-1β, as experienced in malaria, has the potential of inducing several hematologic and immunologic anomalies with anemia as a candidate [47,48]. However, cytokine IL-1β has a protective role in certain haplotypes, which are predisposed to produce higher levels of this cytokine and prevents anemia development [49].…”

Section: Severe Malarial Anemia and The Inflammasomementioning

confidence: 99%

Severe Malarial Anemia (SMA) Pathophysiology and the Use of Phytotherapeutics as Treatment Options

Mavondo¹,

Mzingwane²

2018

Current Topics in Anemia

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Hemolytic anemia results when red blood cells (RBCs) are destroyed prematurely by a number of agents. Obligate intracellular parasites like the Plasmodium species proliferate by infecting RBCs, growing through different stages of their life cycles, expanding their population to unsustainable numbers and eventually rupturing the cell membranes in order to transmit and infect new RBCs. In this manner, more RBCs are infected by the parasites and destroyed together with some nonparasitized cells. Membranes of RBCs are altered and deformed by parasite antigens expressed on the surfaces of both parasitized and nonparasitized cells, which lead to their premature phagocytosis and destruction by the reticuloendothelial system. Parasites and the hemoglobin waste products produced by them are released when the RBCs burst. Activated leukocytes take up the hemoglobin waste (hemozoin which is a polymerized heme), which stimulates the innate immune system leading to the synthesis and secretion of pro-and anti-inflammatory cytokines, chemokines, growth factors and mediators. Together with the destruction of RBCs in malaria, imbalance between pro-and anti-inflammatory events results in the modification of erythroid cell proliferation leading to severe malarial anemia (SMA) and other pathophysiologies of malaria. While current malarial management is targeted at the destruction of the parasite, it is the malaria-related pathophysiology (disease aspect of malaria) like severe malarial anemia that results in the high malaria morbidity and mortality. Antidisease approaches promise to be more effective at malarial management. Triterpenes with antioxidant, pro-oxidant, anti-inflammatory and antiparasitic effect show effects at retarding and abrogating severe malarial anemia. Asiatic acid, amongst other triterpenes like oleanolic acid, masilinic acid administered through oral or transdermal route improves severe malaria anaemia providing promise in the management of malaria pathophysiology.

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Polymorphic Variability in the Interleukin (IL)–1β Promoter Conditions Susceptibility to Severe Malarial Anemia and Functional Changes in IL‐1β Production

Cited by 45 publications

References 46 publications

Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children

Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children

Functional Promoter Haplotypes of Interleukin-18 Condition Susceptibility to Severe Malarial Anemia and Childhood Mortality

Severe Malarial Anemia (SMA) Pathophysiology and the Use of Phytotherapeutics as Treatment Options

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