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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 FREE TO VIEW

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.

Figures in this Article

It has long been recognized that risk for asthma in childhood tracks with intensity of expression of the atopic phenotype,1 and this association is strongest during the teen years.1,2 These findings have been replicated in multiple birth cohort studies, some extending to early adulthood (reviewed in Holt and Sly3). It is also established that sensitization is an independent asthma risk factor in early childhood4,5 and that the earlier sensitization occurs the greater the risk of subsequent asthma development.6-9 This is thought to reflect the differential sensitivity of rapidly growing lung tissues during early life to the persistent inflammation accompanying sensitization to perennial aeroallergens, which has potential to perturb normal patterns of lung differentiation.3 However, it has been unclear how atopy-associated inflammation in young children can attain sufficient intensity to severely damage airway tissues.

Early sensitization to aeroallergens in this context implies failure to generate protective immunologic tolerance, which is the normal default response of the healthy immune system to de novo allergen exposures (reviewed in Strickland and Holt10). Data from birth cohorts exemplified by our findings11 have pinpointed the first few years of life as the time when sensitization to ubiquitous aeroallergens is most frequently initiated in atopics, implying that immunoregulatory mechanisms underlying tolerogenesis may be developmentally compromised during this period.

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.4-6,12,13 Notably, recurrent symptomatic lower respiratory viral infections (LRIs) have been identified as the strongest independent risk factor for asthma inception and for its persistence through later childhood. Until comparatively recently, the focus of interest was predominantly upon respiratory syncytial virus, particularly in infants,14 but additional evidence has also demonstrated a major role for rhinovirus,15 particularly beyond preschool age.

It is pertinent to note that upper respiratory infections, in contrast, are not associated with increased asthma risk,9 indicating that initial failure of innate immune defenses to contain primary infections at the upper respiratory infection site is a necessary first step toward unmasking the asthmatogenic potential of these pathogens. This may be due in part to an intrinsic defect in the interferon (IFN)-producing capacity of epithelial cells in susceptible subjects.16,17 However, it is additionally noteworthy that LRIs per se are not associated with increased asthma risk,9 only those events evoking severe symptoms of wheeze and/or fever,9,12 suggesting that underlying failure to control the intensity/duration of adaptive immune antiviral responses may also be a key predisposing factor. This hints at deficiencies in T-regulatory cell (Treg) functions, which have been identified as a potential risk factor in asthma pathogenesis,10,18,19 including in infants and school children.20,21

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 is associated with either of these factors alone,4,5,9,15 suggesting synergistic interaction between underlying asthmatogenic inflammatory pathways.

There is a wide body of complementary evidence in the literature for similar interactions at later stages of the disease, including (1) increased susceptibility of atopic children with asthma to intensification and spread of viral infections from the upper to lower respiratory tract with attendant loss of asthma control,22 (2) amplification of rhinovirus cold symptoms in atopic adults,23 (3) rhinovirus-induced triggering of T helper cell (Th) 2-associated immunity in the lower respiratory tract of adult patients with asthma,24 (4) potentiation of Th2-associated airways inflammation in rhinovirus-infected atopic adults by allergen bronchoprovocation,25 and (5) synergism between atopy and recurrent LRI in relation to risk for de novo onset of asthma in adulthood.26 However, the most profound examples relate to hospitalization for severe virus-associated asthma exacerbation: Depending upon study methodologies, up to 90% of affected children beyond preschool age and > 60% of affected adults are sensitized and concomitantly exposed to perennial allergens.3,11,27,28 Moreover, this subgroup of atopics typically comes from the severe end of the sensitization spectrum as defined by IgE titers.27,28

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 increased risk for early-onset asthma.29 Second, the application of highly sensitive metagenomic technology to analysis of samples from the lower airways has identified a previously unrecognized and complex resident microbiome.30 There are significant differences in the density and diversity of bacterial species between children with asthma and control subjects,30 but the presence of a broad range of potential pathogens in microbiome samples from healthy individuals indicates that the presence of bacteria per se in this microenvironment is not necessarily associated with disease risk. This suggests that effective mechanisms must normally operate in airway tissues to protect against transepithelial incursions in situations where local homeostasis is temporarily disrupted, for example, during inflammatory episodes (exemplified by relatively common viral LRI) in which compromised barrier function is a recognized feature.

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 those who develop persistent asthma (Fig 1B31,32). The likely role of specific IgG1 antibody is to accelerate phagocytic clearance of organisms that breach mucosal barriers during cycles of episodic airways inflammation, and a relative deficiency in production of this antibody could plausibly be associated with increased accumulation of infection-associated tissue damage over time. It is additionally pertinent to note that susceptibility to severe virus-associated exacerbations in atopic children with asthma is associated with a comparable relative deficiency in bacterial-specific IgG1.33

Figure Jump LinkFigure 1. Amplification of virus-associated airway epithelial damage via bacterial incursions. IL = interleukin; TNF = tumor necrosis factor. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location

In the schema illustrated in Figure 1A, the first line of cell-mediated immune defense against bacterial invasion in the healthy airway is provided by resident airway mucosal macrophage populations. At baseline, these cells normally display the resting phenotype and are capable of presenting antigen-specific inductive signals to Th-memory cells. However, uptake of bacteria via a combination of IgG1- and Toll-like receptor (TLR)-dependent mechanisms constitutes one of the most potent signals known for macrophage activation, which shuts down their T-cell stimulation functions and triggers secretion of chemokines and inflammatory cytokines exemplified by interleukin-1 (IL-1)/IL-6/tumor necrosis factor (TNF)-α. The resultant danger of bystander tissue damage via this pathway is significant unless bacterial clearance is effected rapidly. As noted previously, the continuous occupancy of lower respiratory epithelial surfaces by bacteria means that low-level breakthrough into underlying tissues is likely to be a relatively frequent occurrence, and hence these dangers are always present. We have described a mechanism that may be central to ongoing homeostatic control of potential bystander damage via this pathway, in the form of Th2-polarized cellular immunity directed at particulate antigens associated with bacterial membranes.34 Notably, Th2 immunity against respiratory mucosal-dwelling bacteria, detectable as bacterial-specific serum IgE, is virtually universal across the population, and the strength of this immunity is inversely associated with risk for asthma (Fig 2A).

Figure Jump LinkFigure 2. Th2-mediated regulation of bacterial-associated inflammation. Th = T-helper cell. See Figure 1 legend for expansion of other abbreviations. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location

It is unlikely that high-affinity IgE receptor (FcεR1)-mediated reactions per se play any significant role in this context as this bacterial-specific IgE is directed against nonsoluble membrane antigens which are only revealed during intracellular processing by antigen-presenting cells; these antigens are unlikely to be bioavailable as they are not released in the soluble form necessary to crosslink receptor-bound IgE.35,36 However, this IgE is also a surrogate marker for underlying populations of bacterial-specific Th2-memory cells secreting the IL-4/IL-13 required for IgE class switching (Fig 2B), and such memory cells have previously been documented.37,38 Relevant to this issue, an additional recognized function of IL-4/IL-13 is downregulation of bacterial-induced TLR-dependent macrophage activation and resultant prevention of secretion of proinflammatory IL-1/IL-6/TNFα (reviewed in Hollams et al34) (Fig 2B). The titers of bacterial-specific IgE antibodies in individual subjects should reflect the relative abundance of their circulating populations of bacterial-specific Th2 memory cells, and this may explain the association seen in Figure 2A. Thus, in situations of low-level bacterial breakthrough (which may be relatively common), presentation of processed bacterial antigen to incoming specific Th2-memory cells by airway tissue macrophages actively engaged in bacterial clearance provides an autocrine-like mechanism for avoidance of excessive activation during this process (Fig 2B); at higher bacterial loads, it is likely that this mechanism would be overwhelmed.

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 studies. These include the demonstration in a murine parainfluenza model of type1 IFN-dependent FcεR1 upregulation on lung DCs,40 and complimentary findings in a murine influenza model in which FcεR1 upregulation in infected lung tissue was accompanied by enhanced susceptibility to Th2 cell-associated airways inflammation.41 FcεR1 upregulation has also been observed on plasmacytoid DCs, and cross-linking of FcεR1 on these cells has been shown to inhibit their type1 IFN responses to viral exposure.42,43

An additional interaction mechanism has been suggested by studies on acute virus-associated asthma exacerbation in children, involving comparative gene expression profiling of circulating cell populations at baseline vs during exacerbation.28 These studies suggest that during the early phase of exacerbations in atopics concomitantly exposed to aeroallergen, initial upregulation of FcεR1 may occur on resident airway mucosal DCs in situ via viral-induced type 1 IFN resulting in stimulation of production of the FcεR1 γ chain, the availability of which limits overall receptor expression.3,28 This is followed by recruitment of fresh FcεR1hi myeloid DCs via cytokine signals that are translocated to precursors in bone marrow,3,28 presumably carried by migrating cells initially activated in the airways as demonstrated in earlier bronchial challenge models.44 Based on observations relating to atopic dermatitis lesions wherein FcεR1hi DCs use IgE to maximize allergen capture/processing/presentation for Th2-memory activation,45 it is plausible that transient FcεR1 hyperexpression on airway DCs of viral-infected atopic asthmatics could recruit allergen-induced Th2 cytokine storms into the inflammatory milieu of the infected airway, contributing directly to tissue damage and also potentially antagonizing Th1-polarized antiviral immunity.28

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 challenge regardless of the class of antigen (viral, bacterial, allergenic) involved, with kinetics equivalent to or exceeding those exhibited by neutrophils.47

Consistent with the phenotype of DCs in other tissues, it is evident that their functions in the airway mucosa include initial recognition and classification of incoming foreign antigens via pattern recognition receptors, and subsequent programming of adaptive immunity to meet the specific challenge. The complex hierarchical process orchestrated by airway mucosal DCs during initial exposures, illustrated in the inset in Figure 3, includes (1) discrimination between pathogen-derived vs non-pathogen-derived inhaled antigens, (2) induction of tolerance to the latter via T-cell deletion or generation of specific Treg populations, (3) discrimination between classes of pathogens, and (4) programming of balanced pathogen-specific responses comprising Th/effector memory and/or cytotoxic T-cell (CTL) memory responses appropriate to the pathogen class, together with parallel cohorts of Tregs required to control the intensity of downstream effector responses.

Figure Jump LinkFigure 3. Immune surveillance functions of airway mucosal dendritic cell (DC) populations. CTL = cytotoxic T cell; Teff =  T-effector cell; Theff =  T-helper/effector cell; Treg = T-regulatory cell. See Figure 2 legend for expansion of other abbreviations. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location

These events occur following the migration of antigen-bearing DCs to regional lymph nodes where they acquire T-cell-activating properties, as the DCs normally remain in quiescent (surveillance only) mode in peripheral tissues. On subsequent reexposure to antigens to which Th-memory has been primed (eg, reinfection with pathogen), local CD40-ligand-dependent interactions with transiting Th memory cells trigger rapid in situ functional maturation of antigen-bearing DCs involving uploading of processed peptide onto surface major histocompatibility complex (MHC) and expression of T-cell-docking and costimulator molecules50; these armed DCs proceed to activate any incoming memory cells they subsequently encounter leading to intense local expression of T-effector responses (Fig 3); cytokine(s) from these cells may also contribute to local CTL activation. In situations where tolerance mechanisms have previously failed and aeroallergen-specific Th-memory has been primed, a similar sequence of events follows reexposure via inhalation, triggering local Th2-associated inflammation.50 However, as illustrated in Figure 3, such responses (as well as Th1/CTL-memory responses directed against pathogens) are subject to an additional level of control in the form of Tregs which modulate the local transition of DCs from antigen surveillance mode into T-cell activation mode; it is important to emphasize that the initial generation of these Tregs is itself DC-dependent (eg, Holt et al47 and Strickland et al51).

The precise relationship between these particular Treg populations and those that normally induce tolerance during initial encounters with inhaled antigens lacking pathogen-associated molecular signatures remains to be established. However, it is pertinent to note that in experimental models the efficiency of DC-dependent sampling of antigen/allergen from airway mucosal surfaces has been directly linked to the efficiency of tolerance induction during initial exposures, and also to the intensity/duration of airway inflammatory responses that follow aeroallergen challenge of presensitized animals. Of note, genetically determined susceptibility to airways inflammation in one such model was circumvented by optimal loading of airway mucosal DCs ex vivo with high-dose aeroallergen to compensate for the diminished in vivo antigen surveillance capacity of the affected animal strain, resulting in restoration of normal levels of Treg function and reversal of their airways hyperresponsiveness.51 Several lines of epidemiologic evidence (reviewed in Strickland et al51) suggest that a comparable human phenotype, defined by an inverse relationship between levels of aeroallergen exposure and susceptibility to development of symptomatic allergic airways inflammation, is relatively common in the population.

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 surveillance phenotype described here, is also a marker of risk for adult-onset nonatopic asthma.26 The most prominent manifestations of the immune surveillance defect described here are seen in the functions of the DC population which is at the epicenter of the complex cellular networks that maintain overall immunologic homeostasis in the lung and airways, effectively bridging the gap between the innate and adaptive arms of the immune system. Nevertheless it is pertinent to reemphasize that deficiencies in surveillance-related functions in susceptible populations are also seen in mesenchymal cells16,17 and in migratory inflammatory cells present within BAL52 and peripheral blood mononuclear cells.53-55

A key question arising from these findings is whether they point toward new and potentially better asthma treatment strategies for the future. Specifically targeting the DC at center stage in airway mucosal immune surveillance appears a tall order at present, particularly given the overlap between these cells and closely related macrophage population(s) within the myeloid lineage. However, a common factor linking the surveillance functions of virtually all the cell types/lineages implicated here is the TLR family of receptors, the functions of which are central to protection against pathogens, and which also appear to extend to allergen surveillance.56,57 There is growing interest in drugs targeting TLR-associated pathways, and the data accumulating are providing increasingly plausible rationales for this approach to asthma control.

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.

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Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev. 2004;202:175-190. [CrossRef] [PubMed]
 
Huh JC, Strickland DH, Jahnsen FL, et al. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med. 2003;198(1):19-30. [CrossRef] [PubMed]
 
Strickland DH, Judd S, Thomas JA, Larcombe AN, Sly PD, Holt PG. Boosting airway T-regulatory cells by gastrointestinal stimulation as a strategy for asthma control. Mucosal Immunol. 2011;4(1):43-52. [CrossRef] [PubMed]
 
Sykes A, Edwards MR, Macintyre J, et al. Rhinovirus 16-induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol. 2012;129(6):1506-1514.e6. [CrossRef] [PubMed]
 
Gehlhar K, Bilitewski C, Reinitz-Rademacher K, Rohde G, Bufe A. Impaired virus-induced interferon-alpha2 release in adult asthmatic patients. Clin Exp Allergy. 2006;36(3):331-337. [CrossRef] [PubMed]
 
Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL. A defective type 1 response to rhinovirus in atopic asthma. Thorax. 2002;57(4):328-332. [CrossRef] [PubMed]
 
Roponen M, Yerkovich ST, Hollams E, Sly PD, Holt PG, Upham JW. Toll-like receptor 7 function is reduced in adolescents with asthma. Eur Respir J. 2010;35(1):64-71. [CrossRef] [PubMed]
 
Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15(4):410-416. [CrossRef] [PubMed]
 
Wills-Karp M. Allergen-specific pattern recognition receptor pathways. Curr Opin Immunol. 2010;22(6):777-782. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Amplification of virus-associated airway epithelial damage via bacterial incursions. IL = interleukin; TNF = tumor necrosis factor. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location
Figure Jump LinkFigure 2. Th2-mediated regulation of bacterial-associated inflammation. Th = T-helper cell. See Figure 1 legend for expansion of other abbreviations. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location
Figure Jump LinkFigure 3. Immune surveillance functions of airway mucosal dendritic cell (DC) populations. CTL = cytotoxic T cell; Teff =  T-effector cell; Theff =  T-helper/effector cell; Treg = T-regulatory cell. See Figure 2 legend for expansion of other abbreviations. (Illustrations by Haderer & Müller Biomedical Art, LLC.)Grahic Jump Location

Tables

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Huh JC, Strickland DH, Jahnsen FL, et al. Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma. J Exp Med. 2003;198(1):19-30. [CrossRef] [PubMed]
 
Strickland DH, Judd S, Thomas JA, Larcombe AN, Sly PD, Holt PG. Boosting airway T-regulatory cells by gastrointestinal stimulation as a strategy for asthma control. Mucosal Immunol. 2011;4(1):43-52. [CrossRef] [PubMed]
 
Sykes A, Edwards MR, Macintyre J, et al. Rhinovirus 16-induced IFN-α and IFN-β are deficient in bronchoalveolar lavage cells in asthmatic patients. J Allergy Clin Immunol. 2012;129(6):1506-1514.e6. [CrossRef] [PubMed]
 
Gehlhar K, Bilitewski C, Reinitz-Rademacher K, Rohde G, Bufe A. Impaired virus-induced interferon-alpha2 release in adult asthmatic patients. Clin Exp Allergy. 2006;36(3):331-337. [CrossRef] [PubMed]
 
Papadopoulos NG, Stanciu LA, Papi A, Holgate ST, Johnston SL. A defective type 1 response to rhinovirus in atopic asthma. Thorax. 2002;57(4):328-332. [CrossRef] [PubMed]
 
Roponen M, Yerkovich ST, Hollams E, Sly PD, Holt PG, Upham JW. Toll-like receptor 7 function is reduced in adolescents with asthma. Eur Respir J. 2010;35(1):64-71. [CrossRef] [PubMed]
 
Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med. 2009;15(4):410-416. [CrossRef] [PubMed]
 
Wills-Karp M. Allergen-specific pattern recognition receptor pathways. Curr Opin Immunol. 2010;22(6):777-782. [CrossRef] [PubMed]
 
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