IL-13 R130Q, a common variant associated with allergy and asthma, enhances effector mechanisms essential for human allergic inflammation.
Frank D. Vladich,Susan M. Brazille,Debra A. Stern,Michael L. Peck,Raffaella Ghittoni,Raffaella Ghittoni,Donata Vercelli +6 more
TLDR
The data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy, and suggests that increased allergic inflammation in carriers ofIL13+2044A depends on enhanced IL-13-mediated Th2 effector functions rather than increased Th2 differentiation.Abstract:
Genetic factors are known to strongly influence susceptibility to allergic inflammation. The Th2 cytokine IL-13 is a central mediator of allergy and asthma, and common single-nucleotide polymorphisms in IL13 are associated with allergic phenotypes in several ethnically diverse populations. In particular, IL13+2044G→A is expected to result in the nonconservative replacement of arginine 130 (R130) with glutamine (Q). We examined the impact of IL13+2044G→A on the functional properties of IL-13 by directly comparing the activity of WT IL-13 and IL-13 R130Q on primary human cells involved in the effector mechanisms of allergic inflammation. Our results show that IL-13 R130Q was significantly more active than WT IL-13 in inducing STAT6 phosphorylation and CD23 expression in monocytes and hydrocortisone-dependent IgE switching in B cells. Notably, IL-13 R130Q was neutralized less effectively than WT IL-13 by an IL-13Rα2 decoy. Decreased neutralization of the minor variant could contribute to its enhanced in vivo activity. Neither IL-13 variant was able to engage T cells, which suggests that increased allergic inflammation in carriers of IL13+2044A depends on enhanced IL-13–mediated Th2 effector functions rather than increased Th2 differentiation. Collectively, our data indicate that natural variation in the coding region of IL13 may be an important genetic determinant of susceptibility to allergy.read more
Citations
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Asthma genetics 2006: the long and winding road to gene discovery.
Carole Ober,Sabine Hoffjan +1 more
TL;DR: The methods that have been used to identify susceptibility genes for common diseases and the status of asthma genetic research are discussed and current challenges and future directions are discussed.
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Discovering susceptibility genes for asthma and allergy
TL;DR: Despite the achievements made in asthma genetics formidable challenges remain, the development of novel, powerful tools for gene discovery, and a closer integration of genetics and biology should help to overcome these challenges.
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Importance of cytokines in murine allergic airway disease and human asthma.
Fred D. Finkelman,Simon P. Hogan,Gurjit K. Khurana Hershey,Marc E. Rothenberg,Marsha Wills-Karp +4 more
TL;DR: Studies of murine allergic airway disease (MAAD) and human asthma that evaluate the importance of Th2 cytokines, Th2 response-promoting cytokine, IL-17, and proinflammatory and anti-inflammatory cytokines in MAAD and people with asthma are reviewed.
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Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma.
TL;DR: Current studies of compounds targeting the interleukin-4/interleuk in-13 pathway are summarised to provide a rationale for the development of such compounds for this use and provide a new therapeutic modality for patients with uncontrolled severe asthma.
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FcγRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling
Hajime Kono,Chieko Kyogoku,Takeshi Suzuki,Naoyuki Tsuchiya,Hiroaki Honda,Kazuhiko Yamamoto,Katsushi Tokunaga,Zen-ichiro Honda +7 more
TL;DR: The present findings indicate that the Ile232Thr substitution affects the localization and function of FcgammaRIIB and that the molecular mechanism may link the polymorphism and susceptibility to SLE.
References
More filters
Journal ArticleDOI
Interleukin-13: Central Mediator of Allergic Asthma
Marsha Wills-Karp,Jackie Luyimbazi,Xueying Xu,Brian Schofield,Tamlyn Neben,Christopher L. Karp,Debra D. Donaldson +6 more
TL;DR: In this paper, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Journal Article
Interleukin-13: Central mediator of allergic asthma
Marsha Wills-Karp,Jackie Luyimbazi,Xueying Xu,Brian Schofield,Tamlyn Neben,Christopher L. Karp,Debra D. Donaldson +6 more
TL;DR: In this article, the type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma.
Journal ArticleDOI
Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease.
Kirk E. Lohmueller,Celeste Leigh Pearce,Malcolm C. Pike,Eric S. Lander,Joel N. Hirschhorn,Joel N. Hirschhorn +5 more
TL;DR: It is concluded that there are probably many common variants in the human genome with modest but real effects on common disease risk, and that studies using large samples will convincingly identify such variants.
Journal ArticleDOI
Requirement for IL-13 Independently of IL-4 in Experimental Asthma
Gabriele Grünig,Martha L. Warnock,Adil E. Wakil,Rajeev Venkayya,Frank Brombacher,Donna M. Rennick,Dean Sheppard,Markus Mohrs,Debra D. Donaldson,Richard M. Locksley,David B. Corry +10 more
TL;DR: This article showed that IL-4 receptor α chain-dependent pathway may underlie the genetic associations of asthma with both the human 5q31 locus and the IL4 receptor and showed that selective neutralization of IL-13, a cytokine related to interleukin-4 that also binds to the α chain of the IL 4 receptor, ameliorated asthma phenotype.
Journal ArticleDOI
High-resolution haplotype structure in the human genome.
Mark J. Daly,John D. Rioux,Stephen F. Schaffner,Thomas J. Hudson,Thomas J. Hudson,Eric S. Lander +5 more
TL;DR: A high-resolution analysis of the haplotype structure across 500 kilobases on chromosome 5q31 using 103 single-nucleotide polymorphisms (SNPs) in a European-derived population offers a coherent framework for creating a haplotype map of the human genome.
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