Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma

Arima, Kazuhiko; Suyama, Ritsuko; Sakata, Yasuhisa; Akaiwa, Mina; Mao, Xiao-Quan; Enomoto, Tadao; Dake, Yoshio; Shimazu, Shin-ichiro; Yamashita, Tetsuji; Sugawara, Naoto; Brodeur, Scott R.; Geha, Raif S.; Puri, Raj K.; Sayegh, Mohamad H.; Adra, Chaker N.; Hamasaki, Naotaka; Hopkin, Julian M.; Shirakawa, Taro; Izuhara, Kenji

doi:10.1067/mai.2002.124656

Cited by 128 publications

(113 citation statements)

References 44 publications

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“…13 Moreover, molecular modeling suggests that the Arg130Gln amino-acid substitution is functionally important because it affects the binding site of IL-13 with its receptor. 6,45 Thus, the relatively high frequency of the Gln130 amino acid in non-Africans and the low frequency of this variant in Africans could have implications for differential susceptibility to disease in populations originating from these regions. The common À1111T allele in the promoter region has also been associated with asthma, high levels of serum IL-13 and IgE, as well as asthma-proximal phenotypes (bronchial hyper-responsiveness and skin-test responsiveness) in case-control studies with European populations.…”

Section: Patterns Of Genetic Diversity At Il13mentioning

confidence: 99%

“…45 Having a strong Th2 immune response could be selectively advantageous or disadvantageous, depending on environmental conditions; a hyperactive Th2 immune response could be advantageous for ridding the body of parasites, but could be disadvantageous by increasing susceptibility to autoimmune disorders, or generating tissue damage in the host. 13 In order to distinguish a genetic signature of natural selection and to identify SNPs which are of potential functional significance, we have applied several statistical tests to infer if the pattern of genetic diversity at IL13 is consistent with a neutral model.…”

Section: Evolutionary Inferences and Tests Of Selectionmentioning

confidence: 99%

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Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

Tarazona‐Santos

Tishkoff

2004

Genes Immun

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Interleukin-13 (IL-13) is a cytokine involved in Th2 immune response, which plays a role in susceptibility to infection by extracellular parasites as well as complex diseases of the immune system such as asthma and allergies. To determine the pattern of genetic diversity at the IL13 gene, we sequenced 3950 bp encompassing the IL13 gene and its promoter in 264 chromosomes from individuals originating from East and West Africa, Europe, China and South America. Thirty-one singlenucleotide polymorphisms (SNPs) arranged in 88 haplotypes were indentified, including the nonsynonymous substitution Arg130Gln in exon 4, which differs in frequency across ethnic groups. We show that genetic diversity and linkage disequilibrium (LD) are not evenly distributed across the gene and that sites in the 5 0 and 3 0 regions of the gene show strong differentiation among continental groups. We observe a divergent pattern of haplotype variation and LD across geographic regions and we identify a set of htSNPs that will be useful for functional genetic association studies of complex disease. We use several statistical tests to distinguish the effects of natural selection and demographic history on patterns of genetic diversity at the IL13 locus.

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Section: Patterns Of Genetic Diversity At Il13mentioning

confidence: 99%

Section: Evolutionary Inferences and Tests Of Selectionmentioning

confidence: 99%

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

Tarazona‐Santos

Tishkoff

2004

Genes Immun

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“…Arima et al (29) showed that IL-13Ra2-bearing cells can deplete extracellular IL-13, detectable as a reduction in IL-13 bioactivity. However, because mice also have a soluble form of IL-13Ra2, the influence of cell surface IL-13Ra2 on IL-13 internalization may be difficult to discern.…”

Section: Discussionmentioning

confidence: 99%

“…IL-13Ra2 efficiently mediates internalization of bound cytokine (28), and it was suggested that IL-13Ra2 mediates clearance of local IL-13 (29), although this has not been clearly demonstrated in vivo. With inducible expression on several cell types that make up the bulk of tissue, cell surface IL-13Ra2 could be a critical modulator of IL-13 exposure.…”

mentioning

confidence: 99%

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

Kasaian

Raible²,

Marquette

et al. 2011

The Journal of Immunology

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Human studies using Abs to two different, nonoverlapping epitopes of IL-13 suggested that epitope specificity can have a clinically significant impact on clearance of IL-13. We propose that Ab modulation of IL-13 interaction with IL-13Rα2 underlies this effect. Two Abs were administered to healthy subjects and mild asthmatics in separate dose-ranging studies and allergen-challenge studies. IMA-638 allows IL-13 interaction with IL-13Rα1 or IL-13Rα2 but blocks recruitment of IL-4Rα to the IL-13/IL-13Rα1 complex, whereas IMA-026 competes with IL-13 interaction with IL-13Rα1 and IL-13Rα2. We found ∼10-fold higher circulating titer of captured IL-13 in subjects treated with IMA-026 compared with those administered IMA-638. To understand how this difference could be related to epitope, we asked whether either Ab affects IL-13 internalization through cell surface IL-13Rα2. Humans inducibly express cell surface IL-13Rα2 but lack the soluble form that regulates IL-13 responses in mice. Cells with high IL-13Rα2 expression rapidly and efficiently depleted extracellular IL-13, and this activity persisted in the presence of IMA-638 but not IMA-026. The potency and efficiency of this clearance pathway suggest that cell surface IL-13Rα2 acts as a scavenger for IL-13. These findings could have important implications for the design and characterization of IL-13 antagonists.

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“…This SNP causes exchange of arginine at the 110 (130) amino acid for glutamine. Several functional differences between the arginine type and the glutamine type have been demonstrated (30)(31)(32): (1) The glutamine type has lower affinity with the IL-13R 2 chain, a decoy receptor for IL-13, than the arginine type. (2) The glutamine type has enhanced stability over the arginine type (3).…”

Section: Il-13 Genementioning

confidence: 99%

The Roles of Th2-Type Cytokines in the Pathogenesis of Atopic Dermatitis

Izuhara¹,

Shiraishi²,

Arima³

et al. 2012

Atopic Dermatitis - Disease Etiology and Clinical Management

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Upregulation of IL-13 concentration in vivo by the IL13 variant associated with bronchial asthma

Cited by 128 publications

References 44 publications

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

Divergent patterns of linkage disequilibrium and haplotype structure across global populations at the interleukin-13 (IL13) locus

IL-13 Antibodies Influence IL-13 Clearance in Humans by Modulating Scavenger Activity of IL-13Rα2

The Roles of Th2-Type Cytokines in the Pathogenesis of Atopic Dermatitis

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