A Functional Single‐Nucleotide Polymorphism in the<i>CR1</i>Promoter Region Contributes to Protection against Cerebral Malaria

Teeranaipong, Phairote; Ohashi, Jun; Patarapotikul, Jintana; Kimura, Ryosuke; Nuchnoi, Pornlada; Hananantachai, Hathairad; Naka, Izumi; Putaporntip, Chaturong; Jongwutiwes, Somchai; Tokunaga, Katsushi

doi:10.1086/593338

Cited by 39 publications

(34 citation statements)

References 32 publications

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“…To this end, we used a total of 18 SNPs, which were previously genotyped [31]–[36], or additionally genotyped in this study as candidate SNPs for susceptibility to cerebral malaria. Those 18 SNPs were divided into 11 neutral and 7 non-neutral SNPs, as evaluated by heterozygosity, F ST and iHS statistics using the Human Evolution Database (supplementary table S3 and supplementary table S4) [37].…”

Section: Resultsmentioning

confidence: 99%

Significant Association of KIR2DL3-HLA-C1 Combination with Cerebral Malaria and Implications for Co-evolution of KIR and HLA

et al. 2012

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Cerebral malaria is a major, life-threatening complication of Plasmodium falciparum malaria, and has very high mortality rate. In murine malaria models, natural killer (NK) cell responses have been shown to play a crucial role in the pathogenesis of cerebral malaria. To investigate the role of NK cells in the developmental process of human cerebral malaria, we conducted a case-control study examining genotypes for killer immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands in 477 malaria patients. We found that the combination of KIR2DL3 and its cognate HLA-C1 ligand was significantly associated with the development of cerebral malaria when compared with non-cerebral malaria (odds ratio 3.14, 95% confidence interval 1.52–6.48, P = 0.00079, corrected P = 0.02). In contrast, no other KIR-HLA pairs showed a significant association with cerebral malaria, suggesting that the NK cell repertoire shaped by the KIR2DL3-HLA-C1 interaction shows certain functional responses that facilitate development of cerebral malaria. Furthermore, the frequency of the KIR2DL3-HLA-C1 combination was found to be significantly lower in malaria high-endemic populations. These results suggest that natural selection has reduced the frequency of the KIR2DL3-HLA-C1 combination in malaria high-endemic populations because of the propensity of interaction between KIR2DL3 and C1 to favor development of cerebral malaria. Our findings provide one possible explanation for KIR-HLA co-evolution driven by a microbial pathogen, and its effect on the global distribution of malaria, KIR and HLA.

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Section: Resultsmentioning

confidence: 99%

Significant Association of KIR2DL3-HLA-C1 Combination with Cerebral Malaria and Implications for Co-evolution of KIR and HLA

et al. 2012

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“…Paradoxically, two studies performed in Thailand showed that patients with severe malaria have a higher frequency of the L/L genotype and express lower RBC CR1 levels than patients with uncomplicated malaria, suggesting that high CR1 expression protects against severe disease (438). Circulating immune complexes could contribute to the pathogenesis of cerebral malaria, and high CR1 expression could facilitate clearance of these complexes and protect against severe disease.…”

Section: Complement Receptorsmentioning

confidence: 99%

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

2010

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SUMMARY The complement system comprises several fluid-phase and membrane-associated proteins. Under physiological conditions, activation of the fluid-phase components of complement is maintained under tight control and complement activation occurs primarily on surfaces recognized as “nonself” in an attempt to minimize damage to bystander host cells. Membrane complement components act to limit complement activation on host cells or to facilitate uptake of antigens or microbes “tagged” with complement fragments. While this review focuses on the role of complement in infectious diseases, work over the past couple of decades has defined several important functions of complement distinct from that of combating infections. Activation of complement in the fluid phase can occur through the classical, lectin, or alternative pathway. Deficiencies of components of the classical pathway lead to the development of autoimmune disorders and predispose individuals to recurrent respiratory infections and infections caused by encapsulated organisms, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. While no individual with complete mannan-binding lectin (MBL) deficiency has been identified, low MBL levels have been linked to predisposition to, or severity of, several diseases. It appears that MBL may play an important role in children, who have a relatively immature adaptive immune response. C3 is the point at which all complement pathways converge, and complete deficiency of C3 invariably leads to severe infections, including those caused by meningococci and pneumococci. Deficiencies of the alternative and terminal complement pathways result in an almost exclusive predisposition to invasive meningococcal disease. The spleen plays an important role in antigen processing and the production of antibodies. Splenic macrophages are critical in clearing opsonized encapsulated bacteria (such as pneumococci, meningococci, and Escherichia coli) and intraerythrocytic parasites such as those causing malaria and babesiosis, which explains the fulminant nature of these infections in persons with anatomic or functional asplenia. Paramount to the management of patients with complement deficiencies and asplenia is educating patients about their predisposition to infection and the importance of preventive immunizations and seeking prompt medical attention.

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“…Intriguingly, only the HL genotype associated with protection whereas homozygotes for LL exhibiting only a non-significant trend towards protection. In disagreement with this finding, in Thailand two reports showed that low CR1 densities (homozygotes for LL) are not associated with protection from severe disease forms (Nagayasu et al, 2001;Teeranaipong et al, 2008). Several other studies further contribute to this discrepancy between reports (Fowkes et al, 2008;Kosoy et al, 2011;Lin et al, 2010;Panda et al, 2012;Rout et al, 2011;Sinha et al, 2009).…”

Section: Cr1 Expression Polymorphismmentioning

confidence: 94%

More than just immune evasion: Hijacking complement by Plasmodium falciparum

Schmidt

Kennedy

Tham

2015

Molecular Immunology

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A Functional Single‐Nucleotide Polymorphism in theCR1Promoter Region Contributes to Protection against Cerebral Malaria

Cited by 39 publications

References 32 publications

Significant Association of KIR2DL3-HLA-C1 Combination with Cerebral Malaria and Implications for Co-evolution of KIR and HLA

Significant Association of KIR2DL3-HLA-C1 Combination with Cerebral Malaria and Implications for Co-evolution of KIR and HLA

Infections of People with Complement Deficiencies and Patients Who Have Undergone Splenectomy

More than just immune evasion: Hijacking complement by Plasmodium falciparum

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