Repetitive aeroallergen challenges elucidate maladaptive epithelial and inflammatory traits that underpin allergic airway diseases - 04/08/21
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Aeroallergen challenge chamber, house dust mites, allergic rhinoconjunctivitis, evoked phenotypes, maladaptation
Abbreviations used : AA, ACC, ARC, AUC, Epiintegrity, GOF, HDM, HDM-PARC, HRV, ILC, LOF, MAIT, NK, NKT, sIgE, TSS
Plan
| This study was supported by the Veterans Affairs (VA) Research Center for AIDS and HIV Infection and VA Center for Personalized Medicine (grant no. IP1 CX000875), National Institutes of Health (NIH) (MERIT grant no. R37AI046326), Doris Duke Distinguished Clinical Scientist Award, and Burroughs Wellcome Clinical Scientist Award in Translational Research to S.K.A.; the 59th Medical Wing Intramural Award (grant no. FA8650-17-2-6816 to J.F.O.); the NIH Clinical and Translational Science Award (grant no. UL1-TR002645 to R.A.C.); the NIH (grant nos. K23 AI102970 and R01 HL125816 to L.N.S.); and the NIH COSTAR institutional research training grant (grant no. T32DE014318 to A.M.S.). The views expressed are those of the authors and do not reflect the official views or policy of the Department of Defense or its components. |
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| Disclosure of potential conflict of interest: R. L. Jacobs is the owner of the Biogenics Research Chamber. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 148 - N° 2
P. 533-549 - août 2021 Retour au numéro
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