Background: Allergic rhinitis (AR) is strongly associated with a type 2 response, characterized by the cytokines IL-5, IL-4 and IL-13. Several studies have implicated ILC2 and TH2A (CD161+ TH2) but it is not yet entirely clear which subsets are driving the common allergic reactions underlying AR. The objective of this study aims to identify critical pathogenic cell populations associated with AR and to determine their phenotype and functional contribution to disease progression. Methods: We identified integral allergic-specific cell types by transcriptomic sequencing. Whole blood, PBMCs and plasma from a cross-sectional cohort of 216 individuals were analysed by 9-colour flow cytometry and ultra-sensitive cytokine bead arrays using unsupervised clustering algorithms. Clinically active AR cases were further analysed by functional mass cytometry to define phenotype and cytokine secretion (IL-2, IL-3, IL-4, IL-5, IL-9, IL13, IL-17A and IL-22) as well as the expression of the hematopoietic prostaglandin D synthetase (HPGDS). Results: The unbiased analysis revealed that atopy and AR manifestation corelated only with eosinophils, plasma IL-5 and CD161+ TH2 cells. In-depth characterization further revealed that the CD45RB lo CD161+ TH2 subset were most closely associated with severity. This subset is able to concomitantly secrete multiple cytokines including IL-5, IL-13 and IL-4 and has been previously reported to be associated with other eosinophilic allergies. Conclusion: CD45RB lo CD161+ TH2 have key roles in driving the allergic response in AR. Neutralizing the CD45RB lo CD161+ TH2 subset should disrupt the allergic response pathway, thus providing a target for lasting therapeutic interventions.

Disrupted epithelial barrier in nasal polyps characterizes aspirin exacerbated respiratory disease Anand Kumar Andiappan1*, Mohammad Asad2, Celine Chua3, Esha Sehanobish2 , Zhen Ren4, Xue Ying Chan1, Josephine Lum1, Nicholas Ang1, Duan Kaibo1, Adam Gersten2, Waleed M. Abuzeid5, Nadeem Akbar2, Marc Gibber2, Shanshan Howland1, Bernett Lee1, Olaf Rotzschke1, Steven A. Porcelli2, Elina Jerschow2*1 Singapore Immunology Network, Agency for Science, Technology and Research2 Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA3 Department of Biological Science, National University of Singapore4 Division of Allergy and Immunology, Department of Medicine, Washington University Schoolf of Medicine, St Louis, MO, USA5Rhinology and Endoscopic Skull Base Surgery, Department of Otolaryngology – Head and Neck Surgery, University of Washington, Seattle, WA, USA*Correspondence: [email protected]; [email protected]