ASSOCIATION OF Fcγ RECEPTOR IIa (CD32) POLYMORPHISM WITH SEVERE MALARIA IN WEST AFRICA

Cooke, Graham; Aucan, Christophe; Walley, Andrew J.; Segal, Shelley; Greenwood, Brian; Kwiatkowski, Dominic; Hill, Adrian V. S.

doi:10.4269/ajtmh.2003.69.565

Cited by 90 publications

(73 citation statements)

References 21 publications

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“…Some studies, but not others, have found an increased risk of invasive pneumococcal or meningococcal disease with the RR genotype (31,32,41,42). In contrast, RR patients may be protected from severe malaria (33). Thus, in diseases associated with pathogenic or infectious immune complexes, the less efficiently phagocytic RR genotype is disadvantageous.…”

Section: Discussionmentioning

confidence: 98%

FcγRIIa Genotype Predicts Progression of HIV Infection

Forthal

Landucci

Bream

et al. 2007

The Journal of Immunology

119

129

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Polymorphisms in FcγR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcγRIIa RR genotype progressed to a CD4+ cell count of <200/mm3 at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4+ cell count <200/mm3 or development of an AIDS-defining illness) was less impacted by FcγRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcγRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi’s sarcoma. These results demonstrate the importance of FcγRs in AIDS pathogenesis and point toward a critical role for interactions between FcγRs and immune complexes in disease progression.

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Section: Discussionmentioning

confidence: 98%

FcγRIIa Genotype Predicts Progression of HIV Infection

Forthal

Landucci

Bream

et al. 2007

The Journal of Immunology

119

129

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“…Like opsonic phagocytosis, monocyte-mediated antibody-dependent inhibition of the in vitro growth of parasites (3,24,32,36,48,56) positively correlates with in vivo protection (3). The central importance of Fc receptor biology in malaria is indicated by the observation that polymorphisms in Fc receptors modify the outcome of infection (8,10,40,47,65).We tested the hypothesis that sequence diversity in MSP2 renders parasites bearing heterologous MSP2 alleles differentially susceptible to Fc-dependent functions of allele-specific MSP2 antibodies. Antibodies from clinically immune adults living in regions where malaria is endemic were isolated using long synthetic peptides of the family-specific MSP2 sequences devoid of the adjoining conserved domain.…”

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confidence: 99%

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Stubbs¹,

Olugbile

Balam

et al. 2011

Infect Immun

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It is widely accepted that antibody responses against the human parasitic pathogen Plasmodium falciparum protect the host from the rigors of severe malaria and death. However, there is a continuing need for the development of in vitro correlate assays of immune protection. To this end, the capacity of human monoclonal and polyclonal antibodies in eliciting phagocytosis and parasite growth inhibition via Fc␥ receptor-dependent mechanisms was explored. In examining the extent to which sequence diversity in merozoite surface protein 2 (MSP2) results in the evasion of antibody responses, an unexpectedly high level of heterologous function was measured for allele-specific human antibodies. The dependence on Fc␥ receptors for opsonic phagocytosis and monocyte-mediated antibody-dependent parasite inhibition was demonstrated by the mutation of the Fc domain of monoclonal antibodies against both MSP2 and a novel vaccine candidate, peptide 27 from the gene PFF0165c. The described flow cytometry-based functional assays are expected to be useful for assessing immunity in naturally infected and vaccinated individuals and for prioritizing among blood-stage antigens for inclusion in blood-stage vaccines.Merozoite surface protein 2 (MSP2) is a leading Plasmodium falciparum vaccine candidate. Antibody responses to MSP2 have been associated with protection from malaria in humans (1,11,37,43,50,53) and afford protection in mouse models (35,46). However, extreme sequence diversity in MSP2 is considered an obstacle for vaccine design. Hundreds of alleles encoding MSP2 are classified into two main allelic families represented by the 3D7 and FC27/D10 MSP2 sequences (15,28,49,57). The coexistence of parasites bearing the dimorphic alleles at similar frequencies in globally disparate locations indicates their maintenance by selective pressures (9). Given that MSP2 is a blood-stage antigen, it is considered likely that sequence diversification may be driven by the host immune response by allele-specific antibodies. Consistent with this hypothesis, vaccine recipients in the Combination B phase IIb vaccine trial, whose humoral responses against the MSP2-3D7 allele were boosted, were rendered more susceptible than the placebo controls to parasitization with heterologous FC27-type parasites (16,19). Early studies showed that mouse monoclonal antibodies (MAbs) that discriminated between heterologous parasites affected homologous in vitro growth inhibition (7, 13). Curiously, there is scant evidence of the inability of allele-specific MAbs to inhibit heterologous parasites in vitro (45).Like other P. falciparum antigens, MSP2 antibody responses are skewed to cytophilic (IgG1 and IgG3) isotypes (37,43,50,53,54), which have been positively associated with protection from malaria (4,11,21,37,44,50,54). These isotypes bind via their Fc domain to Fc␥ receptors, thereby eliciting cellular immune responses of the innate immune system. Antibody opsonization of P. falciparum-infected erythrocytes and merozoites enhances their phagocytosis (6,12,22,30,3...

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“…The gene that encodes FcgRIIa, FCGR2A (1q23), is predominantly expressed on neutrophils and carries a functional SNP that substitutes an arginine (R) to histidine (H) at position 131. Compared with wildtype 131R homozygotes, 131 homozygotes have high binding affinity for IgG2 and have been associated with a number of infectious [46][47][48] and autoimmune diseases. 49,50 Given that MM is characterized, in part, by an accumulation of IgG-producing monoclonal plasma cells, it is possible that variants in FCGR2A may contribute either directly or indirectly to the genetic susceptibility profile associated with the etiology of this B-cell malignancy.…”

Section: Discussionmentioning

confidence: 99%

Common variants in genes that mediate immunity and risk of multiple myeloma

Brown

Lan

Zheng

et al. 2007

Intl Journal of Cancer

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Multiple myeloma (MM) is a B‐cell malignancy characterized by aberrant immune function. Using genomic DNA extracted from 127 MM cases aged 21–84 years and 545 population‐based controls, we examined the risk of MM associated with 82 common variants in 45 genes that mediate immunity among women of European American descent. Genotyping was determined using validated and optimized TaqMan assays. We estimated haplotype frequencies from unphased genotype data for 20 of these genes using the expectation‐maximization progressive insertion algorithm. Compared with controls, MM risk was positively associated with homozygotes of single loci, IL4R (−28120T, rs2107356) and FCGR2A (−120G, rs1801274) (OR = 1.91, 95% CI 1.08–3.38 and 1.95, 95% CI 1.06–3.60, respectively). For genes in which linkage disequilibrium was observed between multiple loci, MM risk was positively associated with the haplotype block covering part of the LTA*TNF complex (LTA −82C/−90G *TNF −1036C/−487G/−417G, OR = 1.63, 95% CI 1.02–2.16) compared with the most frequently occurring haplotype observed among controls (LTA −82A/−90A *TNF −1036C/−487G/−417G). Our findings provide preliminary evidence that common genetic variants in specific immune‐mediated pathways could influence the risk of MM. © 2007 Wiley‐Liss, Inc.

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ASSOCIATION OF Fcγ RECEPTOR IIa (CD32) POLYMORPHISM WITH SEVERE MALARIA IN WEST AFRICA

Cited by 90 publications

References 21 publications

FcγRIIa Genotype Predicts Progression of HIV Infection

FcγRIIa Genotype Predicts Progression of HIV Infection

Strain-Transcending Fc-Dependent Killing ofPlasmodium falciparumby Merozoite Surface Protein 2 Allele-Specific Human Antibodies

Common variants in genes that mediate immunity and risk of multiple myeloma

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