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(Chest. 2003;123:377S-384S.)
© 2003 American College of Chest Physicians

Developing the Epithelial, Viral, and Allergic Paradigm for Asthma*

Giles F. Filley Lecture

Michael J. Holtzman, MD, FCCP; Eugene Agapov, PhD; Edy Kim, AB; Joo-in Kim, MD and Jeffrey D. Morton, BSc

* From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO.

Correspondence to: Michael J. Holtzman, MD, FCCP, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Ave, St. Louis, MO 63110; e-mail: holtzmanm{at}msnotes.wustl.edu


   Introduction
TOP
 Introduction
An Alternative Model for...
 Incorporating Chronicity and...
 Summary
 References
 
The concept that inflammation leads to hyperreactive and hypersecretory airway diseases (especially asthma and bronchitis) has led to a widening search for the types of inflammatory cells and mediators that are responsible for the cascade of events linking the initial stimulus to the final abnormality in airway function. Cell types implicated in the development of airway inflammation include immune cells as well as parenchymal cells. Cell-cell interactions are attributed to classes of mediators that include lipids, proteases, peptides, and cytokines. It is not yet possible to integrate all of this information into a single model for the development of airway inflammation, but a useful framework is based on the classification of the adaptive immune system, and especially the T-cell responses to allergic and nonallergic stimuli that enter the airway. This scheme was developed in murine models of the immune response in which CD4+ T-cell-dependent responses may be classified into T helper (Th) type 1 or Th2, in which Th1 cells characteristically mediate delayed-type hypersensitivity reactions and Th2 cells promote B-cell-dependent humoral immunity. In turn, the traditional scheme for asthma pathogenesis is based on a relative decrease in Th1 cellular responses in combination with an increase in Th2 responses (Fig 1 ).



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  		Figure 1. Scheme for the role of the airway immune response in the development of asthmatic airway inflammation. Left: illustrates how decreases in virus-driven production of Th1 cytokines (eg, IFN-{gamma} and IL-12) and increases in allergen-dependent production of Th2 cytokines (eg, IL-4, IL-5, IL-9, and IL-13) are characteristic of asthma (designated as an A). This Th2-skewed setting thereby provides for flares of the disease driven either by viral infection (with a functional blockade in the normal Th1 response and a concomitant shift to an increase in the Th2 response) or by allergen (with an increase in the Th2 response). Right: illustrates a modified scheme based on increased activity of both Th1 and Th2 responses. In this case, pathogen-activated Th1 cells in the airway tissue generate factors (eg, tumor necrosis factor [TNF-{alpha}]) that mediate the subsequent recruitment of Th2 cells (eg, via vascular cell adhesion molecule [VCAM]-1), which provide a setting for enhanced allergen responsiveness. Modified from Holtzman et al.21

 
The consequent alteration in cytokine milieu is predicted to drive the asthma phenotype. Evidence for such a shift in the Th1/Th2 balance derives from studies of asthma in cellular and murine models, in which Th cell polarization and the allergen dependence of Th2 responses are most clearly defined, and from human studies that profile cytokine production and immune cell infiltrate. Thus, in the murine system, interleukin (IL)-4, IL-5, IL-9, and IL-13 promote Th2 cell differentiation and B-cell-dependent IgE production, tissue eosinophilia, airway hyperreactivity, and goblet cell hyperplasia.1 Furthermore, these responses are down-regulated by Th1 cytokines such as interferon (IFN)-{gamma} and IL-12 and inversely correlated with the general level of Th1 cell responses.2 3 4 5 In humans, asthma is tied to this paradigm by association with atopy and concomitant increases in the production of IgE and Th2 cell cytokines.6 Recent studies also provide evidence of genetic linkage to polymorphisms in the genes for IL-4, IL-4 receptor, and IL-13.7 Similarly, eosinophils and mast cells are characteristic of asthmatic airway inflammation and may act as critical effector cells, at least under some circumstances.8 9 10

However, several lines of evidence in model systems and in humans raise questions for the Th2 hypothesis as a complete explanation for asthma. For example, Th1 as well as antigen-specific Th2 cells may be necessary for initiating the allergic response even in mouse models of asthma.11 12 Furthermore, end points of the allergic response, such as airway hyperrreactivity and mucus production, may develop without IgE production and eosinophil influx.13 14 15 In some cases, airway reactivity may be dissociated from eosinophilic inflammation based on genetic background.16 17 In fact, in human subjects, the development of allergy and asthma often are dissociated as well,18 and the linkage between asthma and candidate genes for atopy has not been found in large population studies.19 Moreover, treatment aimed at the selective blockade of Th2 pathways has not yet proven to be efficacious in asthma.9 Nonetheless, these discrepancies are generally ascribed to the complexity of the allergic response, so that other features of the response may still lead to the asthma phenotype.20 Even given this diversity, however, the Th2 hypothesis does not take into account the following newly described yet invariant feature of asthma: an intrinsic abnormality in cellular programming of the airway epithelium toward an antiviral Th1 response.21 Thus, as developed below, airway epithelial cells appear to be specially programmed with antiviral networks, and the behavior of these cells in asthma patients resembles a persistent antiviral response.22 26 It is also not certain how the Th2 hypothesis reconciles its insights into the allergic response, an acute response, with the development of a life-long disease.


   An Alternative Model for Asthma Pathogenesis
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 Introduction
 An Alternative Model for...
Incorporating Chronicity and...
 Summary
 References
 
To resolve these outstanding issues for asthma pathogenesis, we have focused on related but distinct aspects of airway immunity that are particularly relevant to the host response against microbial pathogens (especially respiratory viruses). Our initial reasoning was related to the concept that the adaptive immune system (manifested by the diverse repertoire of T and B cells) requires signals about the origin of the antigen and the type of response to be induced. Furthermore, these signals must be provided by the innate immune system. In this general context, and in the particular context of the response to inhaled agents, we proposed (in 1981) that the epithelial cells lining the airway surface represent an ideal candidate to act as a primary sentinel in innate immunity. In particular, our observations in models of airway inflammation and in human subjects with inflammatory airway disease indicated that the immune cell response to inhaled agents was topographically directed toward and then through the airway epithelium. In turn, this finding suggested that the epithelium was charged with directing immune cell traffic to the lumen, so that initial studies were directed toward defining the underlying mechanism for this process.

The initial studies that were aimed at defining the cell biology of the epithelial cell-immune cell interaction were performed in vitro. Specific care was taken to preserve the native properties of cells. Immune cells (eg, T cells) were isolated with minimal purification and no labeling. Epithelial cells were studied in primary culture, since cell lines invariably showed different characteristics and did not provide fidelity to behavior in vivo. In addition, the cell monolayer was modified from the usual ones that are appropriate for studying immune cell traffic out of the circulation (where cells must be slowed and activated, and often move from a luminal to abluminal compartment). In the case of the airway epithelium, immune cells are directed from an abluminal to a luminal surface and the initial immune cell slowing (ie, rolling) is not necessarily a feature of this system. Accordingly, it now appears that airway epithelial cells use a special program for directing immune cell traffic that depends on a two-step area code for, first, cell adhesion and, second, chemotaxis.25 27 28 In the case of T-cell movement, these steps are typified by the distinct expression of intercellular adhesion molecule (ICAM)-1 and secretion of chemokine regulated and normal T cell expressed and secreted (RANTES [later designated CCL5]). For ICAM-1, distribution on both the apical and basolateral cell surfaces mediates efficient cell adhesion at the basal cell surface (to aid in transmigration) and at the apical cell surface (for retention and movement along the airway). For RANTES, a pattern of polarized apical secretion provides for a soluble chemical gradient for T-cell movement from the subepithelium (where levels are low) to the mucosal surface (where levels are higher) and retention at that luminal site. These patterns fit well with the available data for ICAM-1 and RANTES expression in the airway epithelium in vivo (see below), but we emphasize that this pattern of cell adhesion molecule expression and chemokine secretion is distinct for the airway. We have presented a scheme for how these two pathways for controlling cell adhesion and chemotaxis may be coordinated to explain epithelial cell-dependent transmigration of T cells in a basal-to-apical direction.29

Analogous to complementary biological function, we subsequently recognized that epithelial cell-immune cell interaction depends on the expression of a subset of epithelial immune-response genes under synergistic transcriptional and posttranscriptional controls. At the transcriptional level, this epithelial gene network (typified by the gene for ICAM-1) is regulated by IFN-{gamma} signal transduction featuring the Stat1 transcription factor as a critical regulator of gene expression.23 30 31 32 33 At the posttranscriptional level, the gene network (typified by the gene for RANTES) is regulated directly by viral replication (thereby bypassing the need for immune cell contributions) and is controlled by the stabilization of the corresponding messenger RNA for RANTES.22 In studies of a third system,26 34 we found that the epithelial IL-12 p40 gene is also induced in response to viral infection and is capable of forming an IL-12 p80 homodimer with proinflammatory chemotactic activity. In studies of mice with paramyxoviral bronchiolitis, we learned that alterations in epithelial IL-12 p40 production lead to consequences for the antiviral response. In more recent work,21 we also discovered that disruption of other parts of the epithelial network (in the form of genetically null mice for Stat1, ICAM-1, or RANTES) caused even more profound alterations in the host response to viral infection. The precise molecular mechanisms for these epithelial contributions still needs to be fully defined, but the initial results already indicate the critical role of the epithelial immune-response network for optimal defense against respiratory viruses, especially the paramyxoviruses that are linked to the development of asthma in childhood.

In that regard, we next studied the behavior of this epithelial antiviral network in adult subjects with asthma vs control subjects. Remarkably, this entire antiviral network, which is ordinarily reserved for activation during viral infection, is also activated in otherwise healthy subjects with asthma. In the case of stable subjects (who generally receive glucocorticoid treatment), we found constitutive activation of Stat1 in the absence of any change in the airway tissue levels of upstream cytokine (ie, IFN-{gamma}) production.24 This finding implies a specific abnormality in signaling (in this case, epithelial Jak/Stat signaling) vs the usual problem in cytokine production by immune cells. This finding suggests that specific abnormalities in cytokine signaling may be a heretofore unrecognized cause for selectively driving distinct patterns of chronic inflammatory disease. In particular, the abnormality in Stat1 behavior is not found in chronic bronchitis, although the two diseases do share other features (as developed below). In a related study of human subjects,26 we found that the expression of epithelial IL-12 p80 is also increased in asthma. Similar to the case for the Stat1-dependent gene network, the induction of the IL-12 p40 gene is unresponsive to glucocorticoid treatment, unrelated to allergy, and is present in a pattern that is identical to the one found in paramyxoviral infections.

In addition to our studies of stable asthmatic subjects (who are generally receiving treatment with glucocorticoids), we studied asthmatic subjects who experienced a flare of their disease (after the cessation of glucocorticoid treatment). While flares could be driven by increased allergen exposure or heightened signaling responses to viral infection, we reasoned that the distinct cell and molecular biology of the RANTES system also might be a candidate for mediating flares and so be more responsive to glucocorticoid treatment. Indeed, we found that the expression of the epithelial RANTES gene is inducible by treatment withdrawal and that this change occurs in conjunction with airway T-cell infiltration, obstruction, and hyperreactivity25 (M. Castro, MD; M.J. Holtzman, MD; unpublished observations; June 2002). The precise mechanism for increased RANTES gene expression in vivo still needs to be determined, but the absence of notable and relevant transcription factor (especially NF-{kappa}B) activation in this setting suggests that expression may depend on the same messenger RNA stabilization that is characteristic of the response to paramyxoviral replication. In any case, it now appears that, in each of three separate epithelial gene networks, activation is characteristic of the normal response to viral infection and is a signature of the presumably abnormal response in asthma. Taken together, these findings bolstered the role of the epithelial antiviral network in asthma and led us to propose an alternative paradigm for the disease that includes epithelial, viral, and allergic (epi-vir-all) components (Fig 2 ).21



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  		Figure 2. Revised model for the role of the airway immune response in the development of airway inflammation and remodeling. Left: illustrates how increases in epithelial antiviral signals (eg, Stat1 activation and IL-12 p40 expression) and allergen-driven production of Th2 cytokines (eg, IL-4, IL-5, IL-9, and IL-13) are characteristic of subjects with asthma (designated as an A) studied under stable conditions during treatment with glucocorticoids. Right: illustrates how further increases in epithelial signaling (driven by viral infection) or Th2 cytokine production (driven by further allergen exposure) may develop in subjects with asthma studied during a flare without glucocorticoid treatment. In addition, the abnormal phenotype may depend on respiratory viral infection and a subsequent host response that reflect the specific genetic characteristics of each organism. The combination of epi-vir-all components led to the designation of this pathogenesis model as an epi-vir-all paradigm. Modified from Holtzman et al.21

 

   Incorporating Chronicity and Susceptibility Into the Model
TOP
 Introduction
 An Alternative Model for...
 Incorporating Chronicity and...
Summary
 References
 
Our scheme for asthma pathogenesis provided a useful framework for new observations on epithelial cell behavior and antiviral Th1-like pathways, but the experimental models focused largely on the acute response to viral infection. Because asthma is a chronic, likely lifelong, disease and is strongly influenced by genetic background, we next questioned whether our experimental approach could be developed to address the critical issues of chronicity and susceptibility. In particular, could we address whether asthma is not only characterized by an antiviral response, but whether it could also be caused by it? In that regard, could the antiviral response persist, and if so, how? And, if a chronic response does occur, what determines the susceptibility to developing it? Are specific viral and human genetic elements required, and how can they be identified? These questions are especially relevant to the human condition. A relationship between viral infection and the development of chronic inflammatory disease has been proposed for diverse clinical syndromes. Relevant to asthma, paramyxoviral infections are the leading cause of lower respiratory tract illness in infants and young children,35 and children with clinically significant viral bronchiolitis appear to be marked for the subsequent development of a chronic wheezing illness that is independent of allergy.36 With rare exceptions (eg, persistent hepatitis C virus), the mechanistic basis for the relationship between riboviral infection and the development of chronic disease is still uncertain.

To better define viral and host factors in the development of the asthma phenotype, we refined our mouse model of paramyxoviral bronchiolitis to assure that the acute histopathology and physiology were similar to those in the human condition.26 34 Mice are relatively resistant to infection with the most common paramyxoviral pathogen in humans (ie, respiratory syncytial virus), so a high-threshold inoculum of virus must be given, and the resulting all-or-none pattern of illness often includes severe alveolitis.37 We therefore used a mouse parainfluenza virus (ie, Sendai virus [SeV]) that exhibits genetic similarity to human paramyxoviruses. In addition, in mice, SeV causes a top-down infection such that intermediate inoculum limits infection to the airway mucosa and inflammation largely restricted to peribronchial and bronchiolar tissues in a pattern that resembles the pathology of the human condition.26 The mouse strain (C57BL/6J) was determined by experiments indicating that this pattern of illness was not found in other genetic backgrounds, and the consideration that this strain was commonly used as a background for genetically modified mice.

In that regard, we further reasoned that the inhibition of the acute inflammatory response could be achieved by the targeted disruption of airway epithelial immune-response genes. Among candidate genes that might mediate immune cell traffic, ICAM-1 is the predominant determinant for the adhesion of immune cells (especially T cells) to epithelial cells in vitro.25 27 28 Indeed, in these next experiments conducted in vivo,38 we found that ICAM-1 expression is induced primarily on host airway epithelial cells by viral infection and is necessary for the full development of acute inflammation and concomitant postviral airway hyperreactivity. Unexpectedly, however, we also found that a single, primary viral infection causes a persistent asthma phenotype (ie, airway hyperreactivity, goblet cell hyperplasia, and mucin production) despite ICAM-1 deficiency, and that this response is maintained for at least 1 year after the complete clearance of virus (Fig 3 ). A similar phenotype is also inducible by allergen challenge, but in this case, the phenotype resolves spontaneously with time (in the absence of treatment or additional challenges). In addition, the allergic response is sensitive to the levels of IFN-{gamma}, whereas neither the acute nor the chronic response to paramyxoviral infection is altered in IFN-{gamma}-null mice. This finding is consistent with our previous results (noted above), indicating that airway mucosal tissue in asthmatic subjects exhibits no difference from the normally low levels of IFN-{gamma} or IFN-{gamma}-producing cells found in healthy subjects. In the context of previous data, the findings establish the capacity of a single paramyxoviral infection to cause both acute and chronic manifestations of the phenotype for hypersecretory airway disease, and they define the relevance of specific host defense genes in moderating the acute phenotype, but not necessarily the chronic phenotype. These findings therefore raise the possibility that asthma not only resembles a persistent antiviral response24 26 but may also be caused by such a response, and so provide the experimental link between paramyxoviral infection in infancy with subsequent asthma in childhood and perhaps adulthood.



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  		Figure 3. Model for quantitative events in the development of the asthma phenotype induced by experimental viral infection. Based on analysis of the response to respiratory paramyxoviral infection in genetically defined mice, it appears that viral replication peaks on postinoculation days 3 to 5 and is subsequently cleared from the lung. This infection is followed by epithelial immune-response gene expression that peaks on day 5, which is followed by immune cell infiltration that peaks on day 8. Each of these events is linked to acute airway hyperreactivity (which depends on ICAM-1 gene expression and peaks on approximately day 21). After this, there is chronic remodeling (eg, goblet cell hyperplasia) and hyperreactivity that persist for at least 1 year after infection. Within a single susceptible genotype, these chronic phenotypes also can be segregated by their differential development over time. Modified from Holtzman et al.21

 
The new findings indicate that the epi-vir-all paradigm must recognize the interaction between paramyxoviruses and their hosts as a critical driver of the asthma phenotype (Fig 2) . In particular, the revised model must include (and eventually resolve) the following issues: (1) how specific viral genes confer the phenotype, (2) how host genetics determine susceptibility to it, and (3) how memory for the response is preserved. In the case of the first question (ie, concerning the influence of viral genes), it appears that the organism must be equipped with specific components to confer a long-term asthma phenotype. At the least, this will require viral genes encoding for products that target infection to the airways. The SeV F (fusion) gene product is a candidate for mediating this process, since proteolytic cleavage by a specific airway protease is required for infection. At a more complex level, it is now evident that paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes, but the latter is based on a hit-and-run strategy since viral effects persist after clearance. Thus, the results provide the initial evidence of the capacity for nononcogenic riboviruses (ie, Paramyxovirus) to irreversibly reprogram host cell behavior in a manner previously restricted to oncogenic DNA viruses.39 40 Further proof and understanding of this part of the process will depend on identifying the specific viral gene products that are responsible for altering host gene expression and consequent phenotype.

For the second question related to host susceptibility for the chronic response to viral infection, our results already indicate that this response develops only in a specific host genetic background. In that regard, we note that the capacity to develop two postviral chronic phenotypes (ie, goblet cell hyperplasia and airway reactivity) can be separated within a single host genetic background. Thus, at 21 days after viral infection, the epithelial phenotype is fully manifest, whereas the chronic hyperreactivity is not yet fully developed.38 At this time point, the reactivity is still largely subject to influence by ICAM-1 gene expression and presumably acute, ICAM-1-dependent inflammation. By contrast, the recurrence of maximal hyperreactivity at later time points in the ICAM-1-null mouse suggests that this phenotype is regulated by distinct genetic controls independent of this acute response and segregated at least in time from the chronic remodeling response. The findings therefore support a scheme in which a replicating virus causes direct induction of epithelial immune-response gene expression, and this leads to inflammation and inflammation-dependent hyperreactivity in the first few weeks after infection. However, additional genetic analysis will be needed to determine how these chronic phenotypes (ie, airway hyperreactivity and goblet cell hyperplasia) segregate in mice and in humans, and to define the relevant genes for susceptibility at each time point.

The third and final question relates to how memory for the asthma-like phenotype is preserved in the setting of viral infection. Perhaps a clue to the mechanism for this persistence comes from our recent observations as well. Thus, the allergic response appears to be more sensitive than the viral response to regulation by Th cytokines, notably IFN-{gamma}.4 38 41 However, in both allergen challenge and viral infection, the remodeling/hyperreactivity phenotype is at least partially prevented by treatment with glucocorticoids, whether initiated after significant viral clearance but before remodeling or during allergen challenge and remodeling.38 42 As noted above, the results suggest a hit-and-run hypothesis for the viral effect, but even so, there must be some element of memory in the host tissue so that the phenotype can be preserved. Several possibilities exist for this type of memory, but in the setting of viral infection, a conspicuous candidate is the persistence of virus-specific T cells in the lungs.43 44 Subsets of this population (eg, CD8+ T cells) have been variously incriminated as down-regulating and up-regulating the Th2 features of the acute antiviral response.45 46 47 The role of these cells in the chronic response to viral infection still needs to be determined, but the sensitivity of T cells to glucocorticoid action reinforces their candidacy for involvement.48 As noted above, however, these T-cell studies have focused on the acute response to virus, and the relevance of this mechanism for chronic persistent changes must still be defined.


   Summary
TOP
 Introduction
 An Alternative Model for...
 Incorporating Chronicity and...
 Summary
References
 
Abnormal immune cell (especially T-cell) accumulation in the airways is characteristic of patients with asthma. We submit that this immune cell behavior (a manifestation of adaptive immunity) is regulated in turn by the primary response of airway epithelial cells (a critical component of innate immunity), and this cell-cell interaction is especially relevant in the host response to respiratory viral infection. We have presented evidence that a subset of epithelial immune-response genes may be critical for antiviral immunity and may contribute to aberrant immune cell activation in asthma. Thus, paramyxoviral infection and asthma may share a propensity to activate a network of epithelial immune-response genes that are part of the innate immune response.24 25 26 However, these studies did not directly address the issues of the underlying mechanisms for chronicity and susceptibility to the asthma phenotype. Our most recent results extend this concept by analyzing whether a persistent antiviral response can drive the asthma phenotype, at least experimentally. In that regard, we have established the capacity of a single, transient paramyxoviral infection to permanently change epithelial behavior and airway reactivity in a pattern that is remarkably similar to one in asthma and that overlaps with other hypersecretory diseases. Furthermore, this chronic phenotype can be genetically segregated from the acute antiviral response in mice. The teleology of this chronic response is uncertain, but perhaps it represents an evolving but maladaptive attempt to improve antiviral host defense. Similarly, we speculate that these phenotypes (ie, airway hyperreactivity and goblet cell hyperplasia) may ordinarily be beneficial in host defense. In the setting of allergen exposure, several gene products appear to regulate goblet cell hyperplasia, fitting a paradigm in which Th2 products (eg, IL-4, IL-5, IL-9, and IL-13) may up-regulate the response, while Th1 products (eg, IFN-{gamma} and IL-12) down-regulate the response. Further studies will be required to precisely identify the genes that are responsible for epithelial remodeling and chronic hyperreactivity in response to paramyxoviral infection, but the lack of IFN-{gamma}-dependent regulation in this setting implies already that the viral pathway is distinct from the ones driven by allergen. Indeed, the results raise the possibility that primary paramyxoviral infection in the proper genetic background may lead to the chronic dysfunction of host cell behavior that overlaps with but does not depend on allergy.21


   Acknowledgements
 
The authors gratefully acknowledge their colleagues for valuable assistance and advice.


   Footnotes
 
Abbreviations: epi-vir-all = epithelial, viral, and allergic; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; RANTES = regulated and normal T cell expressed and secreted; SeV = Sendai virus; Th = T helper

This research was supported by grants from the National Institutes of Health (Heart, Lung, and Blood Institute), the Martin Schaeffer Fund, and the Alan A. and Edith L. Wolff Charitable Trust.


   References
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 Introduction
 An Alternative Model for...
 Incorporating Chronicity and...
 Summary
 References
 

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