Journal List > Allergy Asthma Immunol Res > v.5(4) > 1052330

Kim, Kim, Jeon, and Kim: Immunopathogenesis of Allergic Asthma: More Than the Th2 Hypothesis

Abstract

Asthma is a chronic obstructive airway disease that involves inflammation of the respiratory tract. Biological contaminants in indoor air can induce innate and adaptive immune responses and inflammation, resulting in asthma pathology. Epidemiologic surveys indicate that the prevalence of asthma is higher in developed countries than in developing countries. The prevalence of asthma in Korea has increased during the last several decades. This increase may be related to changes in housing styles, which result in increased levels of indoor biological contaminants, such as house dust mite-derived allergens and bacterial products such as endotoxin. Different types of inflammation are observed in those suffering from mild-to-moderate asthma compared to those experiencing severe asthma, involving markedly different patterns of inflammatory cells and mediators. As described in this review, these inflammatory profiles are largely determined by the involvement of different T helper cell subsets, which orchestrate the recruitment and activation of inflammatory cells. It is becoming clear that T helper cells other than Th2 cells are involved in the pathogenesis of asthma; specifically, both Th1 and Th17 cells are crucial for the development of neutrophilic inflammation in the airways, which is related to corticosteroid resistance. Development of therapeutics that suppress these immune and inflammatory cells may provide useful asthma treatments in the future.

INTRODUCTION

Asthma is defined by the Global Initiative for Asthma as "a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role; the chronic inflammation is associated with airway hyperresponsiveness (AHR) that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the morning; these episodes are usually associated with widespread, but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment".1 Asthma was recognized in Ancient Egypt and was treated by drinking an incense mixture known as kyphi.2 Asthma was first named and recognized as a specific respiratory problem by Hippocrates, circa 450 BC. During the 1930-50s, asthma was considered to be a psychosomatic disorder, and its etiology was considered to be psychological, with treatment often based on psychoanalysis.3 In the 1980s, advances in medical research methodologies, such as studies on bronchoscopic biopsy and induced sputum in asthmatic patients, demonstrated that asthma is characterized by chronic inflammatory disease in the airways.4,5
The World Health Organization estimates that 300 million people worldwide currently suffer from asthma. Moreover, asthma is the most common chronic disease among children, leading to approximately 250,000 deaths per year.6-8 Although the prevalence of asthma is 7%-10% worldwide,9 there is great regional disparity in its prevalence globally, with higher asthma rates tending to exist in more developed and westernized countries than developing countries,10 with as much as 20- to 60-fold differences. Asthma is a heterogeneous inflammatory disease involving many cell types.11 Asthma is clinically classified according to the frequency of symptoms, forced expiratory volume in 1 second, and peak expiratory flow rate.12 Although asthma can be classified based on the severity of symptoms, there is no advanced classification method that allows differentiation of asthma subgroups for asthma pharmacotherapy.13 Therefore, identifying subgroups that respond well to different types of treatment is currently an important goal of asthma research.
Our understanding of the pathogenesis of asthma has changed dramatically. Whereas mast cells and eosinophils were initially believed to play a central role in driving the airway inflammation associated with asthma, new data imply that T helper cells are critical.14 In recent decades, immunologic mechanisms have been studied extensively, and asthma is now regarded as an IgE-mediated sensitization to inhaled allergens with a Th2 cell response and subsequent eosinophilic inflammation and AHR.15 The "Th2 asthma hypothesis" is based on the assumption that IgE and eosinophils play crucial roles in the pathogenesis of asthma; Th2 cytokines are believed to regulate IgE synthesis, and eosinophil numbers and activity are thought to play a major role in driving its pathogenesis.16,17 Additionally, it has been proposed that immune deviation toward a Th1 response can protect against asthma, since Th1 cells antagonize the functions of Th2 cells.18,19 However, much evidence using sputum induction and/or bronchoalveolar lavage (BAL) techniques to measure and characterize airway inflammation in asthma patients indicates that a substantial proportion of asthma cases have an underlying pathology that is clearly different from Th2 eosinophilic asthma.20-23 Specifically, such patients have severe and persistent asthma in the absence of eosinophilic inflammation, and may experience an exacerbation of asthma without an increase in eosinophilic inflammation.20 In addition, persistent asthma may be associated with the presence of significant neutrophilic inflammation,23 predominant neutrophilic inflammation has been linked to corticosteroid resistance in stable asthma patients,24 and neutrophils rather than eosinophils often predominate in patients with difficult-to-control asthma.21 In this review, we discuss recent progress in knowledge of the immunological pathogenesis of allergic asthma induced by inhaled allergens, based mainly on data from animal experiments.

ANIMAL MODELS OF ALLERGIC ASTHMA: GENERAL CONSIDERATIONS

Animal model studies form the basis for much of our current understanding of the pathophysiology of allergic asthma, and are central to the preclinical development of drug therapies. Early animal models of allergic asthma used a variety of species and focused on the AHR phenomenon.25 Rat models have been widely employed, notably the Brown-Norway strain because of its propensity to exhibit a later allergic response following antigen challenge.26 The monkey has attracted attention as a useful model due to its greater human relevance than rodent models.27 Nevertheless, most asthma-related research has been conducted using the mouse, which is currently the species of choice for asthma research involving animals.
In the early 1980s, a greater awareness of the role of inflammation in asthma was driven by an increased understanding of allergic responses and observations that human asthmatics frequently exhibited marked symptoms when challenged with antigens of various kinds. The first inflammatory cell to be linked firmly to asthma pathogenesis was the eosinophil,28,29 followed soon after by the T cell.30 Research focused on allergic inflammation by sensitizing and challenging animals with a variety of foreign proteins with or without adjuvants has led to an increased understanding of the immunological factors that mediate the inflammatory response and its physiological expression in the form of AHR. Allergic asthma mouse models are generated by sensitization to a foreign protein, most commonly ovalbumin (OVA). Sensitization is accomplished by injecting the protein intraperitoneally along with an adjuvant, typically aluminum hydroxide, which elicits an inflammatory reaction in the lungs that is characterized by an influx of eosinophils and AHR. Despite extensive use of this sensitization strategy, this model has two major drawbacks with respect to clinical relevance: the peritoneal sensitization of allergen may differ from an initial immune response to inhaled allergens, and the use of aluminum hydroxide induces eosinophilic airway inflammation, which reflects only a subset of eosinophilic asthma.

ROLES OF HELPER T CELL SUBSETS IN ALLERGIC ASTHMA PATHOGENESIS

Results from animal model studies have implied that allergic asthma involves a complex interplay between the innate and adaptive immune systems. Adaptive immunity begins with naïve T cells that differentiate into T helper cells that potentially regulate the fate, function, and location of a variety of immune and inflammatory cells. Different subsets of T helper cells, such as Th1, Th17, and Th2 cells, have been defined on the basis of the cytokines they secrete. Th1 and Th17 cell production is promoted primarily by IL-12 and IL-6, respectively,31-33 whereas differentiation into Th2 cells occurs in the presence of IL-4 (Fig. 1).34
Allergic asthma is associated with a Th2 type of immune response, as Th2 cytokines are known to cause many of the features of the disease.35 Eosinophilia in the airways has long been linked to allergic asthma, and Th2 cytokines, such as IL-4, IL-5, and IL-13, are responsible for eosinophilic inflammation in the airways (Fig. 1).36,37 Although a number of cytokines are involved in promoting B cells to produce antibodies and generate plasma cells, only IL-4 and IL-13 are known to promote isotype switching to IgE.38-40
Th17 cells, a CD4 subset that has emerged within the last 5 years, require both TGF-β and IL-6 for differentiation although these cytokines are not sufficient for differentiation.41 Th17 cells produce mainly IL-17, some IL-22 and IL-21, small amounts of IFN-γ, and no IL-4.42 IL-17 is clearly detectable in inflamed lungs, and IL-17 may be needed for the initial development of airway inflammation in mice; however, administration of IL-17 decreases eosinophilia.33,43,44 Adoptive transfer of Th17 cells induces neutrophilia and imparts resistance to steroid therapy, suggesting that IL-17 may function to promote neutrophil recruitment and could therefore be particularly important in steroid-resistant neutrophilic asthma (Fig. 1).33,45 In addition, IL-17 has been shown to interfere with epithelial cell production of eotaxin,46 which plays a major role in the recruitment and activation of eosinophils.47 Therefore, IL-17 may regulate the eosinophil-neutrophil balance in the lung.
Increased levels of Th1 cytokine IFN-γ were found in the serum, lung tissues, and induced sputum of asthmatic patients. Moreover, the expression of IFN-γ in induced sputum was enhanced in patients with severe asthma compared to those with mild-to-moderate asthma, and correlated with the numbers of sputum neutrophils.32 Transgenic mouse experiments clearly demonstrated that high levels of IFN-γ in airways induce neutrophilic lung inflammation, emphysema48 and AHR.49 In addition, IFN-γ inhibits allergen-induced eosinophil recruitment into mouse lung tissue.18 TGF-β1 is a key mediator in the development of eosinophilic inflammation and tissue remodeling induced by Th2 cells, such as airway fibrosis.50 We showed that TGF-β1 production and eosinophilic inflammation after an allergen challenge are enhanced in IFN-γ-deficient mice.32 Moreover, Wenzel et al.21 found that the airways of patients with severe eosinophilic asthma had greater subbasement membrane thickening and TGF-β1-producing cell numbers than those with non-eosinophilic asthma. Taken together, these findings suggest that IFN-γ is a key mediator in the development of non-eosinophilic severe asthma (Fig. 1).

ENDOTOXIN EXPOSURE AS A RISK FACTOR FOR ALLERGIC ASTHMA

The endotoxin lipopolysaccharide (LPS) is a cell wall component of Gram-negative bacteria that is ubiquitous in our living environment. Although human exposure to endotoxin is inevitable, the level of airway exposure is highly variable and presumably correlates with the amount of inhalable endotoxin in house dust particles and air pollutants. LPS concentrations in house dust range from 0.59 to 41.04 ng/mg51; Michel et al.52 indicated that the median LPS concentration in house dust is roughly 2.58 ng/mg; at a mean total density of 171.6 mg/m2 in homes, the mean total LPS density is 446 ng/m2. In a subject inhaling a total of 5 m3, the total LPS exposure at the intrabronchial level is approximately 27 ng over 24 hours in a domestic dwelling.52 When airborne materials like LPS are inhaled, a proportion is rapidly cleared from the nose into the throat by mucociliary action, and this portion of the dose is swallowed. Accordingly, it has been estimated that only 30% of the inhaled dose is actually delivered into the lower airways,53 and the intrabronchial level is approximately 30-ng LPS (defined as the amount to which a subject is exposed at a median LPS concentration during 1 day in an indoor environment).
Epidemiology studies in industrialized countries suggest that a reduced infectious burden (with endotoxin as a marker) is inversely correlated with an increased prevalence of allergic diseases in the population, apparently supporting the 'hygiene hypothesis'.54,55 However, accumulating evidence suggests that endotoxin exposure is inversely associated with developing atopy, but positively associated with an increased risk of asthma and asthma severity in both adults and children.56 Similarly, increasing evidence suggests that the infectious burden in early childhood is positively associated with the development of atopic asthma.57,58 Moreover, patients with neutrophilic asthma had a greater prevalence of airway bacterial colonization and a trend of higher levels of endotoxin in their airways.59 Occupational exposure to dust is associated with an increased prevalence of respiratory disease.60 Several studies revealed that the concentrations of LPS in dust, not dust itself, were positively correlated with decreased pulmonary functions.61,62 Collectively, endotoxin exposure in early childhood may be related to asthma development and/or severity, although this exposure is negatively associated with IgE sensitization to common allergens.

MODELING ALLERGIC ASTHMA USING INHALATION OF LPS-CONTAINING ALLERGENS

Airway application of allergen alone was ineffective and inconsistent in eliciting allergic asthmatic responses in mice. The reason was not clear until Eisenbarth et al.63 systematically investigated the effect of contaminating LPS in ovalbumin allergen preparation. In their study, sensitization was carried out by intranasal instillation three times using OVA with no LPS, low-dose LPS (100 ng/mouse), or high-dose LPS (100 µg/mouse). Allergen challenge was performed through intranasal OVA administration alone. LPS-depleted OVA did not induce an inflammatory response in the lung. OVA plus low-dose LPS induced a typical Th2 cell response, including eosinophilic infiltration in the BAL and lung tissue, mucus production, increased serum OVA-specific IgE and IgG1, and draining lymph node (DLN) Th2 cytokine production. On the other hand, high-dose LPS induced a strong Th1 inflammatory response, including neutrophilia, increased IgG2a in the serum, and DLN Th1 cytokine production without mucus. This study provided experimental evidence that the nature of the inflammation depends on the dose of LPS.
We also investigated whether LPS at different doses may lead to different forms of allergen-induced asthma phenotypes, including AHR.32 Our studies demonstrated that OVA with low-dose (100 ng/mouse) LPS induced a Th2 cell response with eosinophilia and allergen-specific IgE production, whereas OVA with high-dose (10 µg/mouse) LPS induced a Th1 cell response with neutrophilia in BAL fluid. More importantly, in both situations after the OVA challenge, AHR to methacholine challenge was significantly enhanced, which is an important component of the allergic asthma phenotype. More recently, we found that OVA with high-dose LPS induced increased expression of Th17 cells and neutrophilic inflammation, which were impaired in IL-17-deficient mice.33 Thus, the neutrophilic inflammation seen in the case of high-dose LPS is actually a mixture of Th1 and Th17 inflammation.

IMMUNOLOGIC MECHANISM OF TH2 CELL POLARIZATION BY INHALATION OF LPS-CONTAINING ALLERGENS

The default immune response to inhaled innocuous proteins (allergens) is the development of immune tolerance.64,65 It is well known that IL-4, via STAT6 signaling, is a key mediator of the development of Th2 cell polarization.66,67 We found that airway application of low-dose LPS (100 ng/mouse) enhanced the production of IL-4 during allergen sensitization and induced an allergen-specific Th2 cell response. In addition, the Th2 cell response induced by allergens containing low-dose LPS was impaired in STAT6-deficient mice.32 These findings indicate that IL-4-induced STAT6 signaling during T cell polarization is critical in the development of Th2 cells (Fig. 2).
In terms of the effect of the LPS-induced innate immune response on the development of Th2 cell polarization, Eisenbarth et al.63 showed that TNF-α co-administration with inhaled allergens elicits a Th2 response rather than T cell tolerance. Our data also indicated that allergen sensitization with low-dose LPS induces the Th2 cell response in association with upregulation of TNF-α production during allergen sensitization. Moreover, we found that allergen-specific low-dose LPS-enhanced Th2 inflammation and AHR were impaired in TNFR1-deficient mice.32 Taken together, these findings suggest that TNF-α induced by low-dose LPS is a key mediator of the development of the Th2 cell response to inhaled allergens, mainly via IL-4 and the STAT6 signaling pathway (Fig. 2).

IMMUNOLOGIC MECHANISM OF TH1 CELL POLARIZATION BY INHALATION OF LPS-CONTAINING ALLERGENS

It has been well documented that IL-12, produced by the innate arm of the immune system, is an important regulator of Th1 cell development.68-70 We found that LPS dose-dependently enhanced IL-12 expression during allergen sensitization.32 A biological effect of IL-12 is to induce Th1 cell polarization via the STAT4 signaling pathway.71 In the allergic asthma mouse model induced by LPS-containing allergens, we found that the AHR and neutrophilic inflammation induced by sensitization with OVA plus high-dose LPS (10 µg/mouse) were inhibited in STAT4-deficient mice. We also found that lung infiltration of Th1 cells was completely impaired in STAT4-deficient mice.32 These findings indicate that Th1 cell polarization is dependent on the IL-12 induced by exposure to high levels of LPS, which results in IFN-γ production via STAT4 signaling (Fig. 3).
IFN-γ, a dimerized soluble cytokine, is the only member of the type II class of interferons and is critical for innate and adaptive immunity. IFN-γ is produced predominantly by natural killer (NK) and NKT cells as part of the innate immune response, and by Th1 and cytotoxic T effector cells after development of antigen-specific immunity. IFN-γ promotes Th1 cell polarization by upregulating the transcriptional factor T-bet, which suppresses Th2 cell polarization.18 To summarize, IFN-γ production induced by high-dose LPS upregulates IL-12 expression in antigen-presenting cells, and then the STAT4 signaling pathway mediates a positive feedback loop between IL-12 and IFN-γ during Th1 recall in response to inhaled allergens (Fig. 3).

IMMUNOLOGIC MECHANISM OF TH17 CELL POLARIZATION BY INHALATION OF LPS-CONTAINING ALLERGENS

The mechanism by which Th17 cells are polarized from naïve T cells has been studied extensively; IL-6, in synergy with TGF-β, induces IL-17 expression in T cells via the STAT3-RORγt pathway.72 In the allergic asthma mouse model induced by LPS-containing allergens, our data indicate that the production of IL-6 is enhanced by high-dose LPS (10 µg/mouse), but not by low-dose LPS (100 ng/mouse). Moreover, the Th17 cell response induced by an allergen containing high-dose LPS is abolished in IL-6-deficient mice.33 These findings suggest that the enhancement of IL-6 by LPS is a key mediator of the development of Th17 cell polarization, and acts via the STAT3 signaling pathway (Fig. 4).
Vascular endothelial growth factor (VEGF) was originally described as a vascular permeability factor based on its ability to generate tissue edema.73 Enhanced levels of VEGF have been detected in tissues and biological samples from patients with asthma.74,75 VEGF is produced during the LPS-induced innate immune response.76 Lung-specific VEGF transgenic experiments revealed that high levels of VEGF in the airways induce lung inflammation and enhance T cell priming to inhalant allergens.77 In the atopic asthma mouse model induced by LPS-containing allergens, we found that airway exposure to high-dose LPS (10 µg/mouse) upregulates the production of VEGF. In addition, recombinant VEGF enhances T cell priming on exposure to allergens alone.33 Moreover, our previous data revealed that T cell priming; e.g., over-expression of costimulatory molecules on dendritic cells (DC) and DC migration into regional DLN, and subsequent proliferation of naïve T cells in DLN, are blocked by treatment with a VEGFR1 inhibitor in the atopic asthma model. However, pharmacological intervention with a VEGFR-2 inhibitor abolished the LPS-induced production of IL-6 (but not IL-12p70), and the subsequent development of an allergen-specific Th17 cell response.78 Together, these findings suggest that LPS-induced VEGF is a key mediator of the development of T cell priming and the Th17 cell response to inhaled LPS-contaminated allergens. In addition, T cell priming to LPS-containing allergens is dependent on VEGFR1-mediated signaling, and the subsequent Th17 polarization is dependent on on VEGFR2 signaling (Fig. 4).

CONCLUSIONS

Biological contaminants in indoor air can induce immune dysfunction and inflammation, resulting in inflammatory pulmonary disorders, such as asthma and chronic obstructive pulmonary disease (COPD).32 A recent nationwide survey indicates that household LPS exposure is a significant risk factor for increased asthma prevalence.79 Asthma prevalence has been increasing over recent decades in developed countries, particularly in urban areas.80 This increase in asthma prevalence may be related to increased indoor activity. Homes insulated from outside exposure, such as apartments in urban areas, contain greater concentrations of biological contaminants. This change in living environment may be related to the increased asthma prevalence due to enhanced exposure of the airway to the biological contaminants such as house dust mite-derived allergens and bacterial products (including LPS) present in indoor dust.
New therapeutic approaches may stem from a greater understanding of immunopathogenesis of asthma. Mild and moderate asthma may be related to eosinophilic inflammation, whereas severe asthma is associated with neutrophilic inflammation.11,82 In terms of immunopathogenesis, eosinophilic asthma represents Th2 cytokine-dependent inflammation, whereas neutrophilic asthma is related to both IFN-γ- and IL-17-dependent inflammation.33,82,83 In view of the different immune and inflammatory patterns of atopic asthma, it is not surprising that responses to anti-inflammatory therapies differ: mild-to-moderate eosinophilic asthma is usually highly responsive to inhaled corticosteroid therapy, whereas patients with neutrophilic (severe) asthma respond poorly. Future therapeutic strategies for neutrophilic asthmatic patients may be aimed at inhibiting corticosteroid resistance. To achieve this aim, suppression of Th1 and Th17 cell responses and inflammation may be a useful approach to asthma therapy.

ACKNOWLEDGMENTS

This study was supported by grants from the National Research Foundation of Korea funded by the Korean Government (No. 2011-0000879).

Notes

There are no financial or other issues that might lead to conflict of interest.

References

1. Agostinis F, Foglia C, Landi M, Cottini M, Lombardi C, Canonica GW, Passalacqua G. The safety of sublingual immunotherapy with one or multiple pollen allergens in children. Allergy. 2008; 63:1637–1639. PMID: 19032238.
crossref
2. Manniche L, Forman W. Sacred luxuries: fragrance, aromatherapy, and cosmetics in Ancient Egypt. New York, NY: Cornell University Press;1999.
3. Opolski M, Wilson I. Asthma and depression: a pragmatic review of the literature and recommendations for future research. Clin Pract Epidemiol Ment Health. 2005; 1:18. PMID: 16185365.
4. Louis R, Lau LC, Bron AO, Roldaan AC, Radermecker M, Djukanović R. The relationship between airways inflammation and asthma severity. Am J Respir Crit Care Med. 2000; 161:9–16. PMID: 10619791.
crossref
5. Vrugt B, Wilson S, Underwood J, Bron A, de Bruyn R, Bradding P, Holgate ST, Djukanovic R, Aalbers R. Mucosal inflammation in severe glucocorticoid-dependent asthma. Eur Respir J. 1999; 13:1245–1252. PMID: 10445597.
crossref
6. Fanta CH. Asthma. N Engl J Med. 2009; 360:1002–1014. PMID: 19264689.
crossref
7. Braman SS. The global burden of asthma. Chest. 2006; 130:4S–12S. PMID: 16840363.
crossref
8. Kroegel C. Global Initiative for Asthma (GINA) guidelines: 15 years of application. Expert Rev Clin Immunol. 2009; 5:239–249. PMID: 20477002.
crossref
9. Lazarus SC. Clinical practice. Emergency treatment of asthma. N Engl J Med. 2010; 363:755–764. PMID: 20818877.
10. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998; 351:1225–1232. PMID: 9643741.
11. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O'Byrne P, Pedersen SE, Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ. Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J. 2008; 31:143–178. PMID: 18166595.
crossref
12. Denlinger LC, Sorkness CA, Chinchilli VM, Lemanske RF Jr. Guideline-defining asthma clinical trials of the National Heart, Lung, and Blood Institute's Asthma Clinical Research Network and Childhood Asthma Research and Education Network. J Allergy Clin Immunol. 2007; 119:3–11. quiz 12-3. PMID: 17141853.
13. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D'Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER. National Heart, Lung, and Blood Institute's Severe Asthma Research Program. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010; 181:315–323. PMID: 19892860.
crossref
14. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: central mediator of allergic asthma. Science. 1998; 282:2258–2261. PMID: 9856949.
crossref
15. Holt PG, Macaubas C, Stumbles PA, Sly PD. The role of allergy in the development of asthma. Nature. 1999; 402:B12–B17. PMID: 10586890.
crossref
16. Savelkoul HF, Seymour BW, Sullivan L, Coffman RL. IL-4 can correct defective IgE production in SJA/9 mice. J Immunol. 1991; 146:1801–1805. PMID: 1826012.
17. Dent LA, Strath M, Mellor AL, Sanderson CJ. Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med. 1990; 172:1425–1431. PMID: 2230651.
crossref
18. Iwamoto I, Nakajima H, Endo H, Yoshida S. Interferon gamma regulates antigen-induced eosinophil recruitment into the mouse airways by inhibiting the infiltration of CD4+ T cells. J Exp Med. 1993; 177:573–576. PMID: 8093895.
crossref
19. Lack G, Bradley KL, Hamelmann E, Renz H, Loader J, Leung DY, Larsen G, Gelfand EW. Nebulized IFN-gamma inhibits the development of secondary allergic responses in mice. J Immunol. 1996; 157:1432–1439. PMID: 8759723.
20. Turner MO, Hussack P, Sears MR, Dolovich J, Hargreave FE. Exacerbations of asthma without sputum eosinophilia. Thorax. 1995; 50:1057–1061. PMID: 7491553.
crossref
21. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999; 160:1001–1008. PMID: 10471631.
crossref
22. Marguet C, Jouen-Boedes F, Dean TP, Warner JO. Bronchoalveolar cell profiles in children with asthma, infantile wheeze, chronic cough, or cystic fibrosis. Am J Respir Crit Care Med. 1999; 159:1533–1540. PMID: 10228122.
crossref
23. Gibson PG, Simpson JL, Saltos N. Heterogeneity of airway inflammation in persistent asthma : evidence of neutrophilic inflammation and increased sputum interleukin-8. Chest. 2001; 119:1329–1336. PMID: 11348936.
24. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002; 57:875–879. PMID: 12324674.
crossref
25. Wanner A, Abraham WM, Douglas JS, Drazen JM, Richerson HB, Ram JS. NHLBI Workshop Summary. Models of airway hyperresponsiveness. Am Rev Respir Dis. 1990; 141:253–257. PMID: 2297181.
26. Turner DJ, Myron P, Powell WS, Martin JG. The role of endogenous corticosterone in the late-phase response to allergen challenge in the brown Norway rat. Am J Respir Crit Care Med. 1996; 153:545–550. PMID: 8564095.
crossref
27. Dybas JM, Andresen CJ, Schelegle ES, McCue RW, Callender NN, Jackson AC. Deep-breath frequency in bronchoconstricted monkeys (Macaca fascicularis). J Appl Physiol. 2006; 100:786–791. PMID: 16467390.
crossref
28. Marsh WR, Irvin CG, Murphy KR, Behrens BL, Larsen GL. Increases in airway reactivity to histamine and inflammatory cells in bronchoalveolar lavage after the late asthmatic response in an animal model. Am Rev Respir Dis. 1985; 131:875–879. PMID: 4003939.
29. Dunn CJ, Elliott GA, Oostveen JA, Richards IM. Development of a prolonged eosinophil-rich inflammatory leukocyte infiltration in the guinea-pig asthmatic response to ovalbumin inhalation. Am Rev Respir Dis. 1988; 137:541–547. PMID: 3345036.
crossref
30. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986; 136:2348–2357. PMID: 2419430.
31. Boehm U, Klamp T, Groot M, Howard JC. Cellular responses to interferon-gamma. Annu Rev Immunol. 1997; 15:749–795. PMID: 9143706.
32. Kim YK, Oh SY, Jeon SG, Park HW, Lee SY, Chun EY, Bang B, Lee HS, Oh MH, Kim YS, Kim JH, Gho YS, Cho SH, Min KU, Kim YY, Zhu Z. Airway exposure levels of lipopolysaccharide determine type 1 versus type 2 experimental asthma. J Immunol. 2007; 178:5375–5382. PMID: 17404323.
crossref
33. Kim YS, Hong SW, Choi JP, Shin TS, Moon HG, Choi EJ, Jeon SG, Oh SY, Gho YS, Zhu Z, Kim YK. Vascular endothelial growth factor is a key mediator in the development of T cell priming and its polarization to type 1 and type 17 T helper cells in the airways. J Immunol. 2009; 183:5113–5120. PMID: 19786548.
crossref
34. Tanaka T, Katada Y, Higa S, Fujiwara H, Wang W, Saeki Y, Ohshima S, Okuda Y, Suemura M, Kishimoto T. Enhancement of T helper2 response in the absence of interleukin (IL-)6; an inhibition of IL-4-mediated T helper2 cell differentiation by IL-6. Cytokine. 2001; 13:193–201. PMID: 11237426.
35. Greenfeder S, Umland SP, Cuss FM, Chapman RW, Egan RW. Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease. Respir Res. 2001; 2:71–79. PMID: 11686868.
36. Pope SM, Brandt EB, Mishra A, Hogan SP, Zimmermann N, Matthaei KI, Foster PS, Rothenberg ME. IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001; 108:594–601. PMID: 11590387.
crossref
37. Lukacs NW, Strieter RM, Chensue SW, Kunkel SL. Interleukin-4-dependent pulmonary eosinophil infiltration in a murine model of asthma. Am J Respir Cell Mol Biol. 1994; 10:526–532. PMID: 8179915.
crossref
38. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, Chu C, Quelle FW, Nosaka T, Vignali DA, Doherty PC, Grosveld G, Paul WE, Ihle JN. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996; 380:630–633. PMID: 8602264.
39. Fish SC, Donaldson DD, Goldman SJ, Williams CM, Kasaian MT. IgE generation and mast cell effector function in mice deficient in IL-4 and IL-13. J Immunol. 2005; 174:7716–7724. PMID: 15944273.
crossref
40. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G, de Waal Malefyt R, de Vries JE. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993; 90:3730–3734. PMID: 8097323.
crossref
41. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006; 441:231–234. PMID: 16648837.
42. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009; 27:485–517. PMID: 19132915.
crossref
43. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Pagé N, Olivenstein R, Elias J, Chakir J. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001; 108:430–438. PMID: 11544464.
crossref
44. Schnyder-Candrian S, Togbe D, Couillin I, Mercier I, Brombacher F, Quesniaux V, Fossiez F, Ryffel B, Schnyder B. Interleukin-17 is a negative regulator of established allergic asthma. J Exp Med. 2006; 203:2715–2725. PMID: 17101734.
crossref
45. McKinley L, Alcorn JF, Peterson A, Dupont RB, Kapadia S, Logar A, Henry A, Irvin CG, Piganelli JD, Ray A, Kolls JK. TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice. J Immunol. 2008; 181:4089–4097. PMID: 18768865.
crossref
46. Kawaguchi M, Kokubu F, Kuga H, Matsukura S, Hoshino H, Ieki K, Imai T, Adachi M, Huang SK. Modulation of bronchial epithelial cells by IL-17. J Allergy Clin Immunol. 2001; 108:804–809. PMID: 11692108.
crossref
47. Mould AW, Ramsay AJ, Matthaei KI, Young IG, Rothenberg ME, Foster PS. The effect of IL-5 and eotaxin expression in the lung on eosinophil trafficking and degranulation and the induction of bronchial hyperreactivity. J Immunol. 2000; 164:2142–2150. PMID: 10657668.
crossref
48. Wang Z, Zheng T, Zhu Z, Homer RJ, Riese RJ, Chapman HA Jr, Shapiro SD, Elias JA. Interferon gamma induction of pulmonary emphysema in the adult murine lung. J Exp Med. 2000; 192:1587–1600. PMID: 11104801.
49. Lee BJ, Moon HG, Shin TS, Jeon SG, Lee EY, Gho YS, Lee CG, Zhu Z, Elias JA, Kim YK. Protective effects of basic fibroblast growth factor in the development of emphysema induced by interferon-gamma. Exp Mol Med. 2011; 43:169–178. PMID: 21297377.
50. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001; 194:809–821. PMID: 11560996.
51. Olenchock SA, May JJ, Pratt DS, Morey PR. Occupational exposures to airborne endotoxins in agriculture. Prog Clin Biol Res. 1987; 231:475–487. PMID: 3588637.
52. Michel O, Ginanni R, Duchateau J, Vertongen F, Le Bon B, Sergysels R. Domestic endotoxin exposure and clinical severity of asthma. Clin Exp Allergy. 1991; 21:441–448. PMID: 1913267.
crossref
53. Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids: lessons for the new millennium. Drug Saf. 2000; 23:11–33. PMID: 10915030.
54. Holt PG. Parasites, atopy, and the hygiene hypothesis: resolution of a paradox? Lancet. 2000; 356:1699–1701. PMID: 11095252.
crossref
55. Voelker R. The hygiene hypothesis. JAMA. 2000; 283:1282.
crossref
56. Looringh van Beeck FA, Hoekstra H, Brunekreef B, Willemse T. Inverse association between endotoxin exposure and canine atopic dermatitis. Vet J. 2011; 190:215–219. PMID: 21130010.
crossref
57. Illi S, von Mutius E, Lau S, Bergmann R, Niggemann B, Sommerfeld C, Wahn U. MAS Group. Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001; 322:390–395. PMID: 11179155.
crossref
58. von Mutius E, Illi S, Hirsch T, Leupold W, Keil U, Weiland SK. Frequency of infections and risk of asthma, atopy and airway hyperresponsiveness in children. Eur Respir J. 1999; 14:4–11. PMID: 10489821.
crossref
59. Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007; 62:211–218. PMID: 16844729.
crossref
60. Hnizdo E. Lung function loss associated with occupational dust exposure in metal smelting. Am J Respir Crit Care Med. 2010; 181:1162–1163. PMID: 20535848.
crossref
61. Park JH, Gold DR, Spiegelman DL, Burge HA, Milton DK. House dust endotoxin and wheeze in the first year of life. Am J Respir Crit Care Med. 2001; 163:322–328. PMID: 11179100.
crossref
62. Dosman JA, Fukushima Y, Senthilselvan A, Kirychuk SP, Lawson JA, Pahwa P, Cormier Y, Hurst T, Barber EM, Rhodes CS. Respiratory response to endotoxin and dust predicts evidence of inflammatory response in volunteers in a swine barn. Am J Ind Med. 2006; 49:761–766. PMID: 16917830.
crossref
63. Eisenbarth SC, Piggott DA, Huleatt JW, Visintin I, Herrick CA, Bottomly K. Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen. J Exp Med. 2002; 196:1645–1651. PMID: 12486107.
crossref
64. Gereda JE, Leung DY, Thatayatikom A, Streib JE, Price MR, Klinnert MD, Liu AH. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet. 2000; 355:1680–1683. PMID: 10905243.
crossref
65. Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH, Berry G, DeKruyff RH, Umetsu DT. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med. 2002; 8:1024–1032. PMID: 12145647.
crossref
66. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996; 4:313–319. PMID: 8624821.
67. Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE. Stat6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. J Immunol. 2001; 166:7276–7281. PMID: 11390477.
crossref
68. Neurath MF, Finotto S, Glimcher LH. The role of Th1/Th2 polarization in mucosal immunity. Nat Med. 2002; 8:567–573. PMID: 12042806.
crossref
69. Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu Rev Immunol. 1999; 17:255–281. PMID: 10358759.
crossref
70. Gavett SH, O'Hearn DJ, Li X, Huang SK, Finkelman FD, Wills-Karp M. Interleukin 12 inhibits antigen-induced airway hyperresponsiveness, inflammation, and Th2 cytokine expression in mice. J Exp Med. 1995; 182:1527–1536. PMID: 7595222.
crossref
71. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol. 2003; 21:713–758. PMID: 12500979.
crossref
72. Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol. 2007; 8:967–974. PMID: 17581537.
crossref
73. Senger DR, Van de Water L, Brown LF, Nagy JA, Yeo KT, Yeo TK, Berse B, Jackman RW, Dvorak AM, Dvorak HF. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev. 1993; 12:303–324. PMID: 8281615.
crossref
74. Lee YC, Lee HK. Vascular endothelial growth factor in patients with acute asthma. J Allergy Clin Immunol. 2001; 107:1106. PMID: 11398093.
crossref
75. Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol. 2001; 107:295–301. PMID: 11174196.
crossref
76. Hahn RG. Endotoxin boosts the vascular endothelial growth factor (VEGF) in rabbits. J Endotoxin Res. 2003; 9:97–100. PMID: 12803882.
crossref
77. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Kim YK, McDonald DM, Elias JA. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med. 2004; 10:1095–1103. PMID: 15378055.
crossref
78. Kim YS, Choi SJ, Tae YM, Lee BJ, Jeon SG, Oh SY, Gho YS, Zhu Z, Kim YK. Distinct roles of vascular endothelial growth factor receptor-1- and receptor-2-mediated signaling in T cell priming and Th17 polarization to lipopolysaccharide-containing allergens in the lung. J Immunol. 2010; 185:5648–5655. PMID: 20921519.
crossref
79. Thorne PS, Kulhánková K, Yin M, Cohn R, Arbes SJ Jr, Zeldin DC. Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing. Am J Respir Crit Care Med. 2005; 172:1371–1377. PMID: 16141442.
80. Cho SH, Park HW, Rosenberg DM. The current status of asthma in Korea. J Korean Med Sci. 2006; 21:181–187. PMID: 16614498.
crossref
81. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001; 344:350–362. PMID: 11172168.
crossref
82. Choi JP, Kim YS, Tae YM, Choi EJ, Hong BS, Jeon SG, Gho YS, Zhu Z, Kim YK. A viral PAMP double-stranded RNA induces allergen-specific Th17 cell response in the airways which is dependent on VEGF and IL-6. Allergy. 2010; 65:1322–1330. PMID: 20415720.
crossref
83. Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F. Th17 cells: new players in asthma pathogenesis. Allergy. 2011; 66:989–998. PMID: 21375540.
crossref
Fig. 1
General scheme of helper T cell priming and polarization. T cell priming requires both signals 1 and 2. Signal 1 is the antigen-specific signal that is mediated by T-cell receptor triggering by MHC class-II-associated peptides processed from antigens. Signal 2 is the costimulatory signal, mediated mainly by triggering of CD28 (by CD80 and CD86 expressed by dendritic cells after ligation of pattern-recognition receptors (PRR), which are specialized to sense pathogens through recognition of pathogen-associated molecular patterns (PAMP). Primed T cells are induced by signal 3 to differentiate into T cells that secrete distinct cytokines. Signal 3 is the polarizing cytokine signal (such as IL-12, IL-6 and IL-4) that promotes the development of Th1, Th17 or Th2 cells, respectively. The nature of signal 3 depends on the activation of a particular PRR by PAMP. Generally, Th1 cells are important for protection against intracellular pathogens, Th17 cells against extracellular pathogens, and Th2 cells against large worms (helminths). Furthermore, T cell responses to innocuous antigens (allergens) are important for the development of chronic inflammation in the airways. The Th2 cell response is related to eosinophilic inflammation, whereas both Th1 and Th17 cells induce non-eosinophilic (or neutrophilic) inflammation.
aair-5-189-g001
Fig. 2
Proposed mechanism of Th2 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At low levels, lipopolysaccharide (LPS) induces TNF-α production by airway structural cells, such as epithelial cells, mast cells, or NKT cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DC, TNF-α, produced in response to low-level LPS, induces DC maturation, expression of costimulatory molecules, and upregulation of DC IL-4 expression. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th2 cells, via IL-4 and the STAT6 signaling pathway.
aair-5-189-g002
Fig. 3
Proposed mechanism of Th1 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At high levels, lipopolysaccharide (LPS) induces IFN-γ production by airway structural cells, such as epithelial cells, macrophages or NK cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DC, IFN-γ, produced in response to high-level LPS, induces DC maturation, expression of costimulatory molecules, and upregulation of DC IL-12 expression. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th1 cells, via IL-12 and the STAT4 signaling pathway.
aair-5-189-g003
Fig. 4
Proposed mechanism of Th17 cell polarization by inhalation of allergen contaminated with endotoxin (lipopolysaccharide). At high levels, lipopolysaccharide (LPS) induces VEGF production by airway structural cells, such as epithelial cells, macrophages or NK cells. Immature dendritic cells (DCs) uptake allergens, and then migrate to draining lymph nodes (DLN). During allergen uptake by DCs, VEGF (produced by high-level LPS) induces DC maturation and expression of costimulatory molecules via the VEGFR1-dependent pathway. IL-6 expression in DCs is also upregulated by VEGF via the VEGFR2-dependent pathway. In DLN, mature DCs induce proliferation of naïve T cells (T cell priming), which subsequently differentiate into Th17 cells, via IL-6 and the STAT3 signaling pathway.
aair-5-189-g004
TOOLS
Similar articles