The IL-4Ra Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice

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-4Ra) 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-4Ra 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-4Ra R576 alleles (QR and RR) and IL-4Ra 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-4Ra 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 CD41 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' exaggerated allergic skin inflammation.Conclusions: The IL-4Ra R576 polymorphism predisposes to more severe AD and increases allergic skin inflammation in mice. (J Allergy Clin Immunol 2023;151:1296-306.)