title: Decoding asthma: translating genetic variation in IL33 and IL1RL1 into disease pathophysiology.
abstract: Asthma is a complex disease that results from the interaction between genetic predisposition and environmental factors. Recently, genome-wide association studies have identified a number of genes that significantly contribute to asthma. Two of these genes, IL33 and IL-1 receptor-like 1 (IL1RL1), act in one signal transduction pathway. IL33 encodes a cytokine released on damage of cells, whereas IL1RL1 encodes part of the IL-33 receptor complex. Recent progress made in functional studies in human subjects and mouse models of allergic airway disease indicate a central role of IL-33 signaling in driving TH2 inflammation, which is central to eosinophilic allergic asthma. Here, IL-33 acts on cells of both the adaptive and innate immune systems. Very recently, a novel population of IL-33-responsive innate immune cells, the type 2 innate lymphoid cells, was found to produce hallmark TH2 cytokines, such as IL-5 and IL-13. The relevance of these cells for asthma is underscored by the identification of retinoic acid-related orphan receptor α(RORA), the gene encoding the transcription factor critical for their differentiation, as another asthma gene in genome-wide association studies. This review describes the mechanisms through which genetic variation at the IL33 and IL1RL1 loci translates into increased susceptibility for asthma. We propose that genetic variation associated with asthma at the IL33 and IL1RL1 loci can be dissected into independent signals with distinct functional consequences for this pathway that is central to asthma pathogenesis.
authors: Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors: Néomi S
authors: NS
authors: Grotenboer
authors: Maria E
authors: ME
authors: Ketelaar
authors: Gerard H
authors: GH
authors: Koppelman
authors: Martijn C
authors: MC
authors: Nawijn
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics* / Q000276:immunology
chemical_list: C508590:IL1R1 protein, human; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D053573:Receptors, Interleukin-1 Type I