Defective Respiratory Tract Immune Surveillance in Asthma: A Primary Causal Factor in Disease Onset and Progression

doi:10.1378/chest.13-1341

Chest

Volume 145, Issue 2, February 2014, Pages 370-378

https://doi.org/10.1378/chest.13-1341 Get rights and content

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.

Section snippets

Respiratory Viral Infections

The first years of life are also acknowledged as the period of highest risk for respiratory infections, which, in first-world countries, represent the most frequent cause of hospitalization in this age group. The possible link between early respiratory infections and risk for asthma in children has been recognized since the 1970s, but the full impact of this causal pathway on community disease rates has only become evident through long-term follow-ups from the major prospective birth cohorts.4,

Double Jeopardy

An important issue arising from these epidemiologic findings concerns the potential effects of comorbidity, given that risk for both sensitization to aeroallergens and for respiratory infections are concomitantly maximal during this early life phase. Evidence (reviewed in Holt and Sly³) argues strongly that recurrent symptomatic LRI during the first 2 to 3 years of life occurring against a background of preexisting sensitization to aeroallergens results in much higher risk for asthma onset than

An Additional Role for Bacterial Infections in Asthma Pathogenesis?

The question of the role of bacteria, either as independent inducers of airways inflammation or as secondary agents operating in conjunction with viral infections, has been brought sharply into focus by a series of findings. First, in relation to asthma initiation, studies using conventional bacterial culture methodology suggest that nasopharyngeal colonization during infancy with common respiratory pathogens exemplified by Haemophilus influenzae and Streptococcus pneumoniae is associated with

Host: Respiratory Microbiome Interactions–Multiple Layers of Defense

The characterization of immunologic interactions between the host immune system and the respiratory microbiome is at an early stage, but recent findings underscore the potential significance of this issue in asthma pathogenesis. In particular, our birth cohort data indicate that the postnatal development of IgG1 responses to common microbiome constituents exemplified by Haemophilus is attenuated in children who subsequently develop sensitization to ubiquitous aeroallergens, and particularly in

Antiviral and Atopic Inflammatory Pathways: Potential Interaction Mechanisms

Animal model studies suggest a variety of mechanisms through which these pathways may interact. First, IL-4-/IL-13-dependent alternatively activated macrophages have been identified as possible contributors to postviral lung damage, and IL-13-secreting invariant natural killer T cells have been implicated in their local induction/activation.³⁹ Second, a potentially important role for viral modulation of FcεR1 expression, particularly on myeloid dendritic cells (DCs), is suggested via a range of

Airway Mucosal DCs at Center Stage

Since the discovery of an organized network of DCs within and below the epithelium of the conducting airways,⁴⁶ subsequent investigations from multiple groups (reviewed in Holt et al,⁴⁷ Lambrecht and Hammad,⁴⁸ and Wills-Karp⁴⁹) have elucidated many of the functions of these cells and confirmed predictions that they play a gatekeeper role in local immune surveillance of mucosal surfaces. Of particular note, mobilization of this DC network constitutes the universal default response to inhalation

Conclusions

A variety of evidence is thus accumulating which suggests that underlying susceptibility to asthma initiation and progression is a series of related defects in mechanisms that underpin capacity to sample, classify, and respond appropriately to inhaled antigens, regardless of the class of antigens involved. The emphasis in this review has been upon childhood atopic asthma, but it is noteworthy that recurrent respiratory tract infections, one of the key indices of the deficient immune

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

References (57)

S Illi et al.
Perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study
Lancet
(2006)
JK Peat et al.
Longitudinal changes in atopy during a 4-year period: relation to bronchial hyperresponsiveness and respiratory symptoms in a population sample of Australian schoolchildren
J Allergy Clin Immunol
(1990)
MM Kusel et al.
Early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma
J Allergy Clin Immunol
(2007)
DH Strickland et al.
T regulatory cells in childhood asthma
Trends Immunol
(2011)
PG Holt et al.
Interaction between adaptive and innate immune pathways in the pathogenesis of atopic asthma: operation of a lung/bone marrow axis
Chest
(2011)
DA Stern et al.
Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study
Lancet
(2008)
KM James et al.
Risk of childhood asthma following infant bronchiolitis during the respiratory syncytial virus season
J Allergy Clin Immunol
(2013)
WW Busse et al.
Role of viral respiratory infections in asthma and asthma exacerbations
Lancet
(2010)
CM Lloyd et al.
Regulatory T cells in asthma
Immunity
(2009)
B Schaub et al.
Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells
J Allergy Clin Immunol
(2009)

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Addressing these questions was the first aim of this study. Secondly, there is currently a resurgence of interest in the possible role of pathogen-specific IgE in interference with pathogen clearance mechanisms during infections, driven by the recognition that alternative forms of the high affinity IgE receptor (FcεR1) are expressed in functional form(s) on a range of bone marrow derived cell populations with immunomodulatory activity (reviewed [15]). Against this background, we have gone back to cryobanked serum samples collected here during a series of earlier studies on immune responses among DTwP and DTaP vaccinated children, to re-assess “bystander” effects of vaccination on specific and total IgE production and the degree to which this may be modified via variations in the infant priming schedule.
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Funding/Support: The authors are supported by the National Health and Medical Research Council of Australia.

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Translating Basic Research Into Clinical PracticeDefective Respiratory Tract Immune Surveillance in Asthma: A Primary Causal Factor in Disease Onset and Progression

Section snippets

Respiratory Viral Infections

Double Jeopardy

An Additional Role for Bacterial Infections in Asthma Pathogenesis?

Host: Respiratory Microbiome Interactions–Multiple Layers of Defense

Antiviral and Atopic Inflammatory Pathways: Potential Interaction Mechanisms

Airway Mucosal DCs at Center Stage

Conclusions

Acknowledgments

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J Allergy Clin Immunol

Trends Immunol

Chest

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J Allergy Clin Immunol

Lancet

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J Allergy Clin Immunol

J Allergy Clin Immunol

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J Allergy Clin Immunol

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Mucosal Immunol

J Allergy Clin Immunol

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J Exp Med

Translating Basic Research Into Clinical Practice
Defective Respiratory Tract Immune Surveillance in Asthma: A Primary Causal Factor in Disease Onset and Progression