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The Airway Epithelium as Immune Modulator

The LARC Ascending

TVW Telethon Institute for Child Health Research; Centre for Child Health Research, University of Western Australia; School of Paediatrics and Child Health, University of Western Australia; and Princess Margaret Hospital for Children, Perth, Western Australia

Address correspondence to: Stephen Stick, M.D., Ph.D., Department of Respiratory Medicine, Princess Margaret Hospital for Children, Box D184, Perth, Western Australia, 6001. E-mail: stephen.stick{at}health.wa.gov.au

Abbreviations: airway epithelial cell, AEC • dendritic cell, DC • diesel exhaust particle, DEP • granulocyte–macrophage colony-stimulating factor, GM-CSF • human bronchial epithelial cells, HBEC • interleukin, IL • particulate matter, PM

The epithelium constitutes the interface between the internal milieu and the external environment, and as such, it is the first point of contact for inhaled substances, in particular, respiratory viruses, airborne allergens, and environmental pollutants, as well as being a primary target for inhaled respiratory drugs (1, 2). The major function of the respiratory epithelium was once thought to be primarily that of a physical barrier. However, for a number of reasons, there can be little doubt regarding the importance of the airway epithelial cells (AEC) in regulating many of the inflammatory responses seen in respiratory diseases in general and asthma in particular.

The airway response to injury highlights the complex nature of AEC interactions with a range of cells and processes (3). In recent years the participation of AEC has come under close scrutiny, and it is clear that inflammatory cytokines and growth factors produced by AEC contribute significantly to the abnormal repair processes and remodeling observed in asthma and airway fibrosis, and to regulation of a variety of immune responses (4). Additionally, it has been recognized for some time that individuals with asthma appear to be more sensitive to the proinflammatory effects of certain environmental pollutants such as nitrogen dioxide (5) and particulate matter (6). Moreover, there appear to be distinct patterns of cytokine release from AEC from individuals with asthma, compared with AEC from healthy control subjects. Devalia and coworkers investigated constitutive and diesel exhaust particle (DEP)-induced release of several proinflammatory mediators from cultured bronchial epithelial cells (HBEC) (7). They observed that HBEC of patients with asthma constitutively released significantly greater amounts of interleukin (IL)-8, granulocyte macrophage–colony-stimulating factor (GM-CSF), and sICAM-1 than HBEC of subjects without asthma. Moreover, RANTES was only released by HBEC of patients with asthma. They argued that the increased sensitivity of the airways of individuals with asthma to air pollutants such as DEP might be partly explained by greater constitutive and pollutant-induced release of specific proinflammatory mediators from AEC. In a recently reported study, Lordan and colleagues (8) observed enhanced release of IL-8, GM-CSF, and transforming growth factor-ß from HBEC obtained from individuals with asthma in response to combinations of inflammatory cytokines (IL-4, IL-13) and the major dust mite allergen Derp1, suggesting that stimulated AEC from individuals with asthma are likely to augment immunoinflammatory responses within the lung. Although these data provide insight into the phenotypic differences between AEC from individuals with asthma and those from healthy individuals, there is still much to be learned regarding the interactions between AEC and the cells that are critical to the initiation of inflammatory cascades and immune responses within the lung.

The article by Reibman and colleagues in this issue of the AJRCMB (9) suggests a number of potentially important interactions between AEC and airway dendritic cells (DC), including: (i) a mechanism by which airway DC might be implicated in immunoinflammatory responses to particulate pollution; (ii) how exposure to particulate pollution might influence sensitization to specific allergens in sensitized individuals; and (iii) how interactions between AEC and airway DC might play a role in determining the qualitative characteristics of adaptive immune system maturation.

There is now clear evidence that local (airway) and systemic immune responses to inhaled antigen are coordinated such that DC in the airwary epithelium can be provoked to take up, process, and present antigens in situ, or alternatively, to differentiate and migrate to draining lymph nodes to present antigen to systemic T cells (10). AEC are likely to contribute to the regulation of these processes via the cytokines that they produce.

Our understanding of the factors that are responsible for DC influx into the airway is increasing, and a number of studies have indicated that chemokines are crucial for the multistage process that involves recruitment of immature DC into the airway mucosa, and the ensuing maturation and migration of these DC to regional lymph nodes. A current view holds that the whole migration process occurs in distinct steps, each driven by a particular chemokine–chemokine receptor pair (11). There is no doubt that the cellular milieu within the airway mucosa must contribute to the dynamics of these processes in the lung.

The central role of DC in regulating immunologic homeostasis in the lung has recently been reviewed (12). Briefly, the principal function of airway DC is surveillance for inhaled antigens deposited on the airway surfaces. Resident airway DC perform this function avidly but are relatively inefficient at presenting these antigens to T cells, due principally to poor surface expression of co-stimulator molecules (such as CD80/CD86) that are obligatory second signals for T cell activation. Maturation of DC from antigen acquirers into antigen presenters normally does not occur until the cells emigrate from the airway into the T cell zones of regional lymph nodes. During or immediately after this migration, DC mature under the influence of a variety of different cytokines, the most important of which appears to be GM-CSF (13), but also includes IL-1, tumor necrosis factor-, and IL-4. An increasing body of indirect evidence suggests that precocious maturation of the APC functions of DC before their migration to draining lymph nodes may be an important factor in the pathogenesis of immunoinflammatory respiratory diseases such as atopic asthma. This disease is presumed to result from local T cell activation and release of toxic cytokines in the airway wall, and findings of increased GM-CSF (14), activated T cells (15), and activated DC in the airway mucosa of subjects with asthma (16) are consistent with such a pathogenic mechanism.

The DC response following aeroallergen exposure in asthma has both quantitative and qualitative aspects. Although the number of activated DC in the airway mucosa is clearly an important factor in determining the overall intensity of inflammation, the qualitative nature of DC responses to inhaled stimuli is also likely to play an important role in asthma exacerbations in established disease. These DC responses are also likely to play an important role in initial sensitization to aeroallergens during early life. In the early postnatal period, the DC airway network is poorly developed and matures rapidly both quantitatively and qualitatively in response to exposure to antigens and irritants (17). Allergic sensitization is dependent on the development of stable Th2-polarized immunologic memory, whereas protection against such Th2 polarization requires signaling to the T cell system in a format that selectively promotes allergen-specific Th1 immunity and/or immunologic tolerance. Given, first, that the portal of entry of the relevant allergens is via the respiratory tract, and second, that the only antigen-presenting cells present to acquire and transmit these allergenic signals to the T cell system are respiratory tract DC, it is accordingly highly likely that the kinetics of postnatal maturation of the airway DC network is a rate-limiting factor in the development of quantitative and qualitative aspects of T cell immunity to these allergens. In this context, cytokines and chemokines released from epithelial cells that can influence influx, dwell time, maturation, and migration of DC to regional lymph nodes, are potentially key players in controlling this immunologic programming process.

Although the role of the epithelium in this context is incompletely understood, the article by Reibman and colleagues presents an example of how environmental stimuli acting upon AEC can potentially influence this process via effects upon the local cellular milieu. The observations are intriguing because they suggest how environmental exposures might influence functional maturation of airway mucosal DC, and they also indicate a mechanism by which AEC might directly affect the dynamics of adjacent DC. The study examined the ability of primary culture HBEC to synthesize and secrete MIP-3/CCL20 (LARC, exodus-1). This CC chemokine is the unique ligand for CCR6 that is expressed on some immature DC, but not on CD14+ DC precursors or mature DC. HBEC were stimulated with proinflammatory cytokines and small size-fractions of ambient particulate matter (PM). Each of these stimuli induced MIP-3/CCL20 gene and protein expression, suggesting a mechanism by which AEC may facilitate recruitment of DC subsets to the airway. The ultimate effects of such facilitated recruitment of DC in response to environmental pollutants are likely to depend upon (i) whether an individual is sensitized to aeroallergens, and (ii) maturational stage of the adaptive immune system.

In previously sensitized individuals with atopic asthma, it is conceivable that exposure to PM together with allergen would result in enhanced influx of DC into the airway mucosa in response to MIP3/CCL20. Given that the airway epithelium is a rich source of GM-CSF in these individuals (14), a likely consequence of enhanced DC recruitment would accordingly be facilitated recall of allergen-specific T cell memory. The expression of CD80/86 co-stimulatory molecules on resident airway mucosal DC appears to be transient after allergen exposure, and there is thus a window of opportunity for local T cell activation which lasts only a few hours, before the migration of allergen-bearing cells to draining lymph nodes (18). Therefore, concomitant release of AEC-derived MIP3/CCL20 during this critical window period has the potential to markedly amplify localTh2-polarized immunoinflammatory responses, including the influx of eosinophils that is characteristic of asthma.

Exposure to airborne agents such as PM may also play a significant role in initial sensitization to aeroallergens, which is now recognized to commonly occur during infancy and early childhood (19). In this context, one observation that has received much attention in recent times is the apparent exaggeratedTh2 skewing of the immune system during early postnatal development in individuals who subsequently express atopy, resulting from delayed postnatal development of Th1 functions (20). As alluded to previously, the development of Th2-antagonistic Th1-polarized memory requires specific signaling to the T cell system. In particular, recent evidence has suggested that exposure to bacterial products (such as lipopolysacharride) promotes production of Th1-trophic cytokines, including IL-12 and tumor necrosis factor-, which play key roles in regulating the GM-CSF–driven differentiation of DC. These observations are at the heart of the so-called "hygiene hypothesis" that suggests that a paucity of Th1-provoking signals from the environment can result in preferential development of Th2-polarized immunologic memory to inhalant allergens. In this context, the article by Reibmann and coworkers is thought-provoking. For example, is it possible that exposure to PM early in life might influence the maturation of these adaptive immune responses in a way that favors the Th2 phenotype? Recent evidence from studies in the rat suggests that there are relatively few DC in the airways before weaning (17), and further that responsiveness to inhaled microbial signals is attenuated during this life phase (21). In humans there is also evidence that the airway mucosal DC network is normally relatively sparse in the airway mucosa in early life and matures slowly postnatally (22). The stimulus to AEC to produce MIP3/CCL20 by PM at this age has the potential to increase the flux of DC into the airway mucosa. Once located in the pattern of DC maturation will then depend upon the relative balance of Th1- and Th2-provoking signals that includes cytokines and growth factors released from AEC. The data from Devalia and colleagues is one example of differential expression of cytokines (GM-CSF) between asthmatic and healthy AEC. However, most of the studies that have examined the cytokine and chemokine expression by AEC in asthma have focused on cells obtained from adults, and there is a paucity of data from studies on the ontogeny of epithelial responses. This deficiency is largely due to the difficulty in obtaining representative lung tissue from healthy children and from children with asthma at young ages. Clearly, the interactions between AEC and dendritic cells before the establishment of stable T cell memory is an area that warrants further study. Another area of study that has been hampered through the lack of appropriate tissue involves production by AEC of cytokines and chemokines (e.g., IL-10 [23], TGF-ß1 [24], VEGF [25]) that can result in DC quiescence. There are virtually no data from children, yet clearly, understanding the ontogeny of these responses and differences between children with and without asthma is likely to be important for understanding the early immunologic factors involved in asthma genesis. Additionally, a recent study from Culley and coworkers (26) has demonstrated that the sequelae of respiratory viral infections in early life are critically dependent upon maturational factors which influence the Th1/Th2 balance in host antiviral defense. Given the key role of airway intraepithelial DC in surveillance for inhaled viral antigens (27), PM-mediated effects on the cytokine/chemokine milieu of the airway epithelium may be important cofactors in the pathogenesis of these infections, and by inference in viral-induced asthma exacerbations in later life. In theory, the latter may be equally applicable to both atopic and intrinsic asthma.

View larger version (32K): [in this window] [in a new window]   Figure 1. Interaction between AEC and dendritic cells in response to particulates demonstrating possible roles of AEC in potentiation of DC recruitment, maturation, and Th2-mediated late phase response in the airway.

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