The IL-4Rα Q576R Polymorphism Promotes systemic Th2 Skewing In Atopic Dermatitis Patients

Abstract

Atopic Dermatitis (AD) is an inflammatory skin disease characterized by barrier disruption and T helper 2 (Th2)-driven inflammation. The Th2 cytokine receptors IL-4 and IL-13 share the common IL-4 receptor alpha (IL-4Rα) chain. The Q576->R576 polymorphism in the IL-4Rα chain, which is common in African Americans and Hispanics (~35%), has been linked with atopy and asthma. Meta-analysis of clinical scoring of 1116 patients reveals the R576 polymorphism is associated with increased AD severity. Epicutaneous sensitization of mice carrying the R576 mutation with ovalbumin reveals that the polymorphism behaves in a dominant fashion causing increased type 2 allergic skin inflammation and an increased systemic Th2 response. Patients with active AD were recruited to determine the effect of the R576 polymorphism on the Th2 response in patients with AD. The results revealed that the R576 polymorphism promotes the generation of skin homing T cells and systemic Th2 skewing in AD patients as evidenced by increased percentages of circulating CD4+CLA+ skin homing T cells, CD4+IL-13+ Th2 cells, and elevated serum levels of the Th2 driven chemokine TARC. Unsupervised transcriptome analysis of of lesional skin and circulating peripheral blood mononuclear cells segregated patients that carry the R576 polymorphism from those who do not. Additionally, the R576 polymorphism is associated with increased S. aureus colonization on non-lesional skin. Our findings suggest that the IL-4R R576 polymorphism exaggerates the systemic Th2 response in AD and has important implications for therapy of AD patients who carry the IL-4R R576 variant.