@article{25ecd8501efd43d39c2319ee6d6a4fe1,
title = "The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice",
abstract = "Background: Atopic dermatitis (AD) is characterized by TH2-dominated skin inflammation and systemic response to cutaneously encountered antigens. The TH2 cytokines IL-4 and IL-13 play a critical role in the pathogenesis of AD. The Q576->R576 polymorphism in the IL-4 receptor alpha (IL-4Rα) chain common to IL-4 and IL-13 receptors alters IL-4 signaling and is associated with asthma severity. Objective: We sought to investigate whether the IL-4Rα R576 polymorphism is associated with AD severity and exaggerates allergic skin inflammation in mice. Methods: Nighttime itching interfering with sleep, Rajka-Langeland, and Eczema Area and Severity Index scores were used to assess AD severity. Allergic skin inflammation following epicutaneous sensitization of mice 1 or 2 IL-4Rα R576 alleles (QR and RR) and IL-4Rα Q576 (QQ) controls was assessed by flow cytometric analysis of cells and quantitative RT-PCR analysis of cytokines in skin. Results: The frequency of nighttime itching in 190 asthmatic inner-city children with AD, as well as Rajka-Langeland and Eczema Area and Severity Index scores in 1116 White patients with AD enrolled in the Atopic Dermatitis Research Network, was higher in subjects with the IL-4Rα R576 polymorphism compared with those without, with statistical significance for the Rajka-Langeland score. Following epicutaneous sensitization of mice with ovalbumin or house dust mite, skin infiltration by CD4+ cells and eosinophils, cutaneous expression of Il4 and Il13, transepidermal water loss, antigen-specific IgE antibody levels, and IL-13 secretion by antigen-stimulated splenocytes were significantly higher in RR and QR mice compared with QQ controls. Bone marrow radiation chimeras demonstrated that both hematopoietic cells and stromal cells contribute to the mutants{\textquoteright} exaggerated allergic skin inflammation. Conclusions: The IL-4Rα R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice.",
keywords = "Atopic dermatitis, IL-4Rα R576 polymorphism, allergic skin inflammation",
author = "Barbara Yang and Hazel Wilkie and Mrinmoy Das and Maheshwor Timilshina and Wayne Bainter and Brian Woods and Michelle Daya and Boorgula, {Meher P.} and Mathias, {Rasika A.} and Peggy Lai and Petty, {Carter R.} and Edie Weller and Hani Harb and Chatila, {Talal A.} and Leung, {Donald Y.M.} and Beck, {Lisa A.} and Simpson, {Eric L.} and Hata, {Tissa R.} and Barnes, {Kathleen C.} and Wanda Phipatanakul and Leyva-Castillo, {Juan Manuel} and Geha, {Raif S.}",
note = "Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health ( NIH ) Atopic Dermatitis Research Network (ADRN) (grant no. 1UM1AI151958). B.Y. was supported by NIAID T-32 training grant (grant no. T32 AI007306). J.M.L.C. was supported by NIAID T32 training grant (grant no. 5T32AI007512-32), Boston Children{\textquoteright}s Hospital Office of Faculty Development (OFD)/Basic/Translational Research Executive Committee (BTREC) and the Clinical and Translational Research Executive Committee (CTREC) Faculty Career Development Fellowship, and Harvard Catalyst , The Harvard Clinical and Translational Science Center , National Center for Research Resources and the National Center for Advancing Translational Sciences , NIH (award no. UL1 TR002541), and financial contributions from Harvard University and its affiliated academic health care centers. Funding Information: We thank Dana-Farber/Harvard Cancer Center in Boston, Mass, for the service provided by the Rodent Histopathology Core. Dana-Farber/Harvard Cancer Center is supported in part by a National Cancer Institute Cancer Center Support grant (grant no. NIH 5 P30 CA06516). Funding Information: This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) Atopic Dermatitis Research Network (ADRN) (grant no. 1UM1AI151958). B.Y. was supported by NIAID T-32 training grant (grant no. T32 AI007306). J.M.L.C. was supported by NIAID T32 training grant (grant no. 5T32AI007512-32), Boston Children's Hospital Office of Faculty Development (OFD)/Basic/Translational Research Executive Committee (BTREC) and the Clinical and Translational Research Executive Committee (CTREC) Faculty Career Development Fellowship, and Harvard Catalyst, The Harvard Clinical and Translational Science Center, National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH (award no. UL1 TR002541), and financial contributions from Harvard University and its affiliated academic health care centers. Publisher Copyright: {\textcopyright} 2023 American Academy of Allergy, Asthma & Immunology",
year = "2023",
month = may,
doi = "10.1016/j.jaci.2023.01.011",
language = "English (US)",
volume = "151",
pages = "1296--1306.e7",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "5",
}