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Defective Respiratory Tract Immune Surveillance in AsthmaDefective Immune Surveillance of Mucosal Surfaces: A Primary Causal Factor in Disease Onset and Progression

Patrick G. Holt, DSc; Deborah H. Strickland, PhD; Belinda J. Hales, PhD; Peter D. Sly, MD
Author and Funding Information

From the Telethon Institute for Child Health Research and Centre for Child Health Research (Profs Holt, Strickland, Hales, and Sly), The University of Western Australia, Perth, WA; and QCMRI-Queensland Children’s Medical Research Institute and University of Queensland (Profs Holt and Sly), Brisbane, QLD, Australia.

Correspondence to: Patrick G. Holt, DSc, Division of Cell Biology, Telethon Institute for Child Health Research, PO Box 855, W Perth, WA 6872, Australia; e-mail: patrick@ichr.uwa.edu.au


Funding/Support: The authors are supported by the National Health and Medical Research Council of Australia.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(2):370-378. doi:10.1378/chest.13-1341
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The relative importance of respiratory viral infections vs inhalant allergy in asthma pathogenesis is the subject of ongoing debate. Emerging data from long-term prospective birth cohorts are bringing increasing clarity to this issue, in particular through the demonstration that while both of these factors can contribute independently to asthma initiation and progression, their effects are strongest when they act in synergy to drive cycles of episodic airways inflammation. An important question is whether susceptibility to infection and allergic sensitization in children with asthma arises from common or shared defect(s). We argue here that susceptibility to recurrent respiratory viral infections, failure to generate protective immunologic tolerance to aeroallergens, and ultimately the synergistic interactions between inflammatory pathways triggered by concomitant responses to these agents all result primarily from functional deficiencies within the cells responsible for local surveillance for antigens impinging on airway surfaces: the respiratory mucosal dendritic cell (DC) network. The effects of these defects in DCs from children wtih asthma are accentuated by parallel attenuation of innate immune functions in adjacent airway epithelial cells that reduce their resistance to the upper respiratory viral infections, which are the harbingers of subsequent inflammatory events at asthma lesion site(s) in the lower airways. An important common factor underpinning the innate immune functions of these unrelated cell types is use of an overlapping series of pattern recognition receptors (exemplified by the Toll-like receptor family), and variations in the highly polymorphic genes encoding these receptors and related molecules in downstream signaling pathways appear likely contributors to these shared defects. Findings implicating recurrent respiratory infections in adult-onset asthma, much of which is nonatopic, suggest a similar role for deficient immune surveillance in this phenotype of the disease.

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