Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases

Alisha M. Smith, Nathan Harper, Justin A. Meunier, Anne P. Branum, Fabio Jimenez, Lavanya Pandranki, Andrew Carrillo, Charles S. Dela Cruz, Marcos I. Restrepo, Diego J. Maselli, Cynthia G. Rather, Anna H. Heisser, Daniel A. Ramirez, Weijing He, Robert A. Clark, Charles P. Andrews, Scott E. Evans, Jacqueline A. Pugh, Nu Zhang, Grace C. LeeAlvaro G. Moreira, Leopoldo N. Segal, Robert M. Ramirez, Robert L. Jacobs, Muthu Saravanan Manoharan, Jason F. Okulicz, Sunil K. Ahuja*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Background: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. Objective: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. Methods: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. Results: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. Conclusions: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

Original languageEnglish
Pages (from-to)533-549
Number of pages17
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Aug 2021
Externally publishedYes


  • Aeroallergen challenge chamber
  • allergic rhinoconjunctivitis
  • evoked phenotypes
  • house dust mites
  • maladaptation


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