Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi

Active fungal proteinases are powerful allergens that induce experimental allergic lung disease strongly resembling atopic asthma, but the precise relationship between proteinases and asthma remains unknown. Here, we analyzed dust collected from the homes of asthmatic children for the presence and sources of active proteinases to further explore the relationship between active proteinases, atopy, and asthma. Active proteinases were present in all houses and many were derived from fungi, especially Aspergillus niger. Proteinase-active dust extracts were alone insufficient to initiate asthma-like disease in mice, but conidia of A. niger readily established a contained airway mucosal infection, allergic lung disease, and atopy to an innocuous bystander antigen. Proteinase produced by A. niger enhanced fungal clearance from lung and was required for robust allergic disease. Interleukin 13 (IL-13) and IL-5 were required for optimal clearance of lung fungal infection and eosinophils showed potent anti-fungal activity in vitro. Thus, asthma and atopy may both represent a protective response against contained airway infection due to ubiquitous proteinase-producing fungi.     

IL‐5‐induced airway eosinophilia – the key to asthma?

Summary: Bronchial asthma is a chronic inflammatory airway disease defined by reversible airway obstruction and non-specific airway hyper-responsiveness (AHR). Although profound insights have been made into the pathophysiology of asthma, the exact mechanisms inducing and regulating the disease are still not fully understood. Yet, it is generally accepted that the pathological changes in asthma are induced by a chronic inflammatory process which is characterized by infiltration of the bronchial mucosa with lymphocytes and eosinophils, increased mucus production and submucosal edema. There is increasing evidence that an imbalance in the T-helper (Th) cell response of genetically predisposed individuals to common environmental antigens plays a pivotal role in the pathogenesis of allergic bronchial asthma and other atopic disorders. Following allergic sensitization, T cells from atopic patients tend to produce elevated levels of Th2-type cytokines, especially interleukin (IL)-4, IL-13, IL-5 and IL-6, which induce and regulate IgE production and eosinophil airway infiltration. In this review, the role of Th2-type cytokines, IgE and airway eosinophils in the induction of airway inflammation and AHR is discussed, and animal studies of asthma and AHR, mainly in rodents will be considered. A better understanding of the underlying mechanisms leading to asthma pathology may yield more specific immunological strategies for the treatment of this disease which is increasing worldwide.
I thank the many colleagues in the laboratory of Dr. E. W. Gelfand, National Jewish Research Center, Denver CO, USA, for continuous support and encouragement. E.H. is a fellow of the Deutsche Forschungsgemeinschaft (DFG Ha 2162/1-1 and 2-1).     

The sentinel role of the airway epithelium in asthma pathogenesis

The adoption of the concept that asthma is primarily a disease most frequently associated with elaboration of T-helper 2 (Th2)-type inflammation has led to the widely held concept that its origins, exacerbation, and persistence are allergen driven. Taking aside the asthma that is expressed in non-allergic individuals leaves the great proportion of asthma that is associated with allergy (or atopy) and that often has its onset in early childhood. Evidence is presented that asthma is primarily an epithelial disorder and that its origin as well as its clinical manifestations have more to do with altered epithelial physical and functional barrier properties than being purely linked to allergic pathways. In genetically susceptible individuals, impaired epithelial barrier function renders the airways vulnerable to early life virus infection, and this in turn provides the stimulus to prime immature dendritic cells toward directing a Th2 response and local allergen sensitization. Continued epithelial susceptibility to environmental insults such as viral, allergen, and pollutant exposure and impaired repair responses leads to asthma persistence and provides the mediator and growth factor microenvironment for persistence of inflammation and airway wall remodeling. Increased deposition of matrix in the epithelial lamina reticularis provides evidence for ongoing epithelial barrier dysfunction, while physical distortion of the epithelium consequent upon repeated bronchoconstriction provides additional stimuli for remodeling. This latter response initially serves a protective function but, if exaggerated, may lead to fixed airflow obstruction associated with more severe and chronic disease. Dual pathways in the origins, persistence, and progression of asthma help explain why anti-inflammatory treatments fail to influence the natural history of asthma in childhood and only partially does so in chronic severe disease. Positioning the airway epithelium as fundamental to the origins and persistence of asthma provides a rationale for pursuit of therapeutics that increase the resistance of the airways to environmental insults rather than concentrating all effort on suppressing inflammation.     

Where Asthma and Hypersensitivity Pneumonitis Meet and Differ : Noneosinophilic Severe Asthma

Asthma is a type-I allergic airway disease characterized by Th₂ cells and IgE. Episodes of bronchial inflammation, eosinophilic in nature and promoting bronchoconstriction, may become chronic and lead to persistent respiratory symptoms and irreversible structural airway changes. Representative mostly of mild to moderate asthma, this clinical definition fails to account for the atypical and often more severe phenotype found in a considerable proportion of asthmatics who have increased neutrophil cell counts in the airways as a distinguishing trait. Neutrophilic inflammation is a hallmark of another type of allergic airway pathology, hypersensitivity pneumonitis. Considered as an immune counterpart of asthma, hypersensitivity pneumonitis is a prototypical type-III allergic inflammatory reaction involving the alveoli and lung interstitium, steered by Th₁ cells and IgG and, in its chronic form, accompanied by fibrosis. Although pathologically very different and commonly approached as separate disorders, as discussed in this review, clinical studies as well as data from animal models reveal undeniable parallels between both airway diseases. Danger signaling elicited by the allergenic agent or by accompanying microbial patterns emerges as critical in enabling immune sensitization and in determining the type of sensitization and ensuing allergic disease. On this basis, we propose that asthma allergens cause severe noneosinophilic asthma because of sensitization in the presence of hypersensitivity pneumonitis-promoting danger signaling.     

The influence of obesity on inflammation and clinical symptoms in asthma

Obesity and asthma are both important public health issues. Increasing number of studies suggest the association between obesity and asthma which may be causal or accidental. The studies on animal models show innate enhancement of airway hyper-responsiveness which suggest that chronic airway hyper-responsiveness may be related to chronic low-grade systemic inflammation occurring in obesity. These results are confirmed by studies on asthmatic patients which show that levels of inflammation markers were higher in obese asthma patients and are related to the parameters of obesity. However, adipokines secreted by adipose tissue have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma, especially in obese female patients. The studies on the association between adiposity and atopy have conflicting results and the issue needs to be investigated in the future. Obesity also decreases lung volume and increases airway resistance inducing symptoms that could mimic asthma. Clinical studies suggest that asthma in obese subjects may differ from the classical phenotype of the disease. Obese patients referred for asthma exacerbation present a reduced response to standard asthma medications.The review indicates that mechanical and inflammatory effects of obesity may explain the influence on asthma. Further studies on the association between adiposity and atopy on airway inflammation may confirm the active role of fat tissue, not only simple mechanical impairment of the thorax movement. Longitudinal studies are needed to understand the association between asthma, and obesity, which may open new therapeutic options for asthma treatment in obese patients.     

Past, Present, and Future of Allergy in Korea

Korean allergology has made great progress in keeping pace with global scientific advances in spite of a short history. Outstanding academic and scientific researches have been performed in a variety of allergy fields in Korea. Epidemiologic studies revealed increasing prevalence of asthma and allergic diseases and considerable morbidity and mortality in Korea. Novel inhalant allergens such as citrus red mite and two-spotted spider mite as causes of asthma and allergic rhinitis have been discovered and reported in Korea. Bidirectional translational researches have been performed and are underway to elucidate the pathogenesis of asthma and allergy, mechanisms of airway inflammation and remodeling, and new therapeutic modalities for asthma and allergic diseases. Experimental asthma models of different phenotypes according to exposed levels of lipopolysaccharide or double-stranded RNA suggested the crucial role of the innate immunity in the development of allergic airway inflammation and a new insight for asthma pathogenesis, in which both Th1 and Th2 inflammation are involved. In the field of genetic researches, numerous genetic associations with asthma and asthma-related phenotypes, such as atopy, IgE production, and airway hyperresponsiveness, have been demonstrated in Korean population. The Easy Asthma Management (EAM) program, a computer-assisted asthma management program, is anticipated to facilitate the achievement of more successful clinical outcomes by filling the gaps between guidelines and actual practices. The Integration of these multi-disciplinary allergy research resources and translation of scientific achievements to the bedside and society will lead to better allergy and asthma control in Korea.     

Tumor necrosis factor-related apoptosis-inducing ligand mediates the resolution of allergic airway inflammation induced by chronic allergen inhalation

Allergic asthma can vanish over time either spontaneously or induced by allergen-specific immunotherapy. In mice with established airway allergic inflammation, chronic intranasal (IN) allergen challenges decreases progressively airway allergic inflammation. Here we compared the contribution of different regulatory pathways that could be associated with this phenomenon, known as local inhalational tolerance. We found that inhalational tolerance was not associated with increased number of regulatory T cells or suppressive cytokines. Instead, it was associated with increased apoptosis of airway inflammatory leukocytes revealed by annexin-V staining and the expression of apical caspase 8 and effector caspase 3. Also, the transition from acute to chronic phase was associated with a shift in the expression of pro-allergic to pro-apoptotic molecules. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was found to be a key molecule in mediating resolution of allergic inflammation because anti-TRAIL treatment blocked apoptosis and increased the infiltration of T helper type 2 (Th2) cells and eosinophils. Notably, repeated IN treatment with recombinant TRAIL in established airway allergic inflammation augmented leukocyte apoptosis and decreased the frequency of interleukin-5-producing Th2 cells and eosinophils to airways. Our data indicate that TRAIL signaling is sufficient for downmodulation of allergic airway disease, suggesting a potential therapeutic use of TRAIL for asthma treatment.     

Novel T‐cell epitopes on Schistosoma japonicum SjP40 protein and their preventive effect on allergic asthma in mice

Allergic asthma is a chronic inflammatory disease mediated by Th2 cell immune responses. Currently, immunotherapies based on immune deviation are attractive, preventive, and therapeutic strategies for asthma. Many studies have shown that intracellular bacterial infections such as mycobacteria and their components can suppress asthmatic reactions by enhancing Th1 responses, while helminth infections and their proteins can inhibit allergic asthma via immune regulation. However, some helminth proteins such as SmP40, the major egg antigen of Schistosoma mansoni, are found as Th1 type antigens. Using a panel of overlapping peptides, we identified T‐cell epitopes on SjP40 protein of Schistosoma japonicum, which can induce Th1 cytokine and inhibit the production of Th2 cytokines and airway inflammation in a mouse model of allergic asthma. These results reveal a novel form of immune protective mechanism, which may play an important role in the modulating effect of helminth infection on allergic asthmatic reactions.     

Cross-roads in the lung: immune cells and tissue interactions as determinants of allergic asthma

Allergic asthma is a chronic disease of the lung characterized by underlying Th2- and IgE-mediated inflammation, structural alterations of the bronchial wall, and airway hyperresponsiveness. Initial allergic sensitization and later development of chronic disease are determined by close interactions between lung structural cells and the resident and migratory immune cells in the lung. Epithelial cells play a crucial role in allergic sensitization by directly influencing dendritic cells induction of tolerant or effector T cells and production of type 2 cytokines by innate immune cells. During chronic disease, the bronchial epithelium, stroma, and smooth muscle become structurally and functionally altered, contributing to the perpetuation of tissue remodeling. Thus, targeting tissue-driven pathology in addition to inflammation may increase the effectiveness of asthma treatment.     

A clinical study of endoscopic sinus surgery for sinusitis in patients with bronchial asthma

BACKGROUND: An association between bronchial asthma and sinusitis has long been suspected. Our aim is to study the clinical features of chronic sinusitis associated with bronchial asthma as two manifestations of one airway disease. METHODS: We conducted a prospective analysis of the outcome of 88 patients, with or without bronchial asthma, who underwent endoscopic sinus surgery (ESS) for chronic sinusitis. Patients were divided into two groups by the presence or absence of asthma and were evaluated. One surgeon performed the ESS, and the same postoperative treatment was given to both groups. The postoperative outcomes of symptoms and objective findings related to sinusitis were evaluated numerically, with a maximum score of 2 points for each examination item. Twenty-eight patients with asthma symptoms were assessed before and after surgery, using peak flow (liter/second) and medication scores (according to US Food and Drug Administration) to determine whether bronchial asthma was improved by first-time ESS. RESULTS: The outcomes of ESS were significantly worse in the asthma group, especially the endonasal findings. Patients suffering from chronic sinusitis and bronchial asthma showed improvement following ESS in terms of their asthma symptoms, peak flow and medication score. Patients with a good ESS result tended to have the greatest improvement in their asthma. CONCLUSIONS: We conclude that sinusitis and asthma are closely related to each other, acting as two manifestations of one airway disease. We recommend treating cases of sinusitis complicated by asthma as a single disease of the entire respiratory tract.     

Characterization of T cell subpopulations involved in the pathogenesis of asthma and allergic diseases

Allergic asthma is a complex and heterogeneous disease which is characterized by intermittent reversible airway obstruction, chronic inflammation of the airways, bronchial hyperreactivity and an infiltration of lymphocytes and eosinophils into the airway submucosa. Animal models and clinical studies in humans have indicated an important role for T helper type 2 lymphocytes, producing IL-4, IL-5 and IL-13, in the pathogenesis of this disorder. However, although IL-4 and IL-13 have strong anti-inflammatory properties, the physiologic anti-inflammatory Th2 response does not seem to be operational in allergic asthma. Moreover, the induction of a Th1 response seems to aggravate, rather than ameliorate, its inflammatory character. This article will focus on the involvement of T lymphocyte subpopulations in the pathogenesis of allergic asthma and allergic diseases. In addition, a potential role of the subpopulation(s) of T regulatory cells in the induction and/or maintaince of the disease process will be discussed.     

Blocking induction of T helper type 2 responses prevents development of disease in a model of childhood asthma

Early-life respiratory viral infections are linked to subsequent development of allergic asthma in children. We assessed the underlying immunological mechanisms in a novel model of the induction phase of childhood asthma. BALB/c mice were infected neonatally with pneumonia virus of mice, then sensitized intranasally with ovalbumin following recovery. Animals were challenged with low levels of aerosolized ovalbumin for 4 weeks to induce changes of chronic asthma, then received a single moderate-level challenge to elicit mild acute allergic inflammation. To inhibit the initial induction of a T helper type 2 (Th2) response, we administered neutralizing antibodies against interleukin (IL)-4 or IL-25, then assessed development of airway inflammation and remodelling. Anti-IL-4 administered during chronic challenge prevented development of chronic and acute allergic inflammation, as well as goblet cell hyperplasia/metaplasia, but features of remodelling such as subepithelial fibrosis and epithelial hypertrophy were unaffected. In contrast, anti-IL-25 had limited effects on the airway inflammatory response but prevented key changes of remodelling, although it had no effect on goblet cells. Both antibodies suppressed development of a Th2 response, while anti-IL-25 also promoted a Th17 response. In further experiments, anti-IL-25 was administered in early life alone, and again had limited effects on airway inflammation, but prevented development of airway wall remodelling. We conclude that in this murine model of childhood asthma, administration of anti-IL-4 or anti-IL-25 prevents development of some key features of asthma, suggesting that suppression of development of a Th2 response during the neonatal period or later in childhood could be effective for primary prevention.     

Atrial natriuretic peptide/natriuretic peptide receptor A (ANP/NPRA) signaling pathway: a potential therapeutic target for allergic asthma

Allergic asthma is a chronic inflammatory disease of airway and immune disorder is an acknowledged mechanism. Numerous data demonstrate Th1/Th2 cells play an important role in the development of allergic asthma. Atrial natriuretic peptide (ANP) is a multifunctional hormone secreted by cardiac atria, lung, and so forth, which has been recognized for several decades due to its general effects on cardiovascular system, and natriuretic peptide receptor A (NPRA) is the major effecting receptor for ANP. In recent years, more and more studies suggest that ANP/NPRA signaling pathway is implicated in modulation of immnue and inflammatory reaction. Moreover, there are some reports about significant changes of ANP production in peripheral blood from asthmatics in acute exacerbation compared with patients during the remission and the healthy. Nevertheless, it is unknown that why ANP shows an observable change and what role ANP plays in asthma until now. We propose that ANP/NPRA signaling pathway is involved in immune dysfunction and airway inflammation of allergic asthma based on our experimental results, which suggests ANP/NPRA signaling pathway may be a potential therapeutic target for allergic asthma.     

A revisit to cockroach allergens

Among cockroaches (CR) that live in people's homes, two species, i.e., German CR (Blattella germanica) and American CR (Periplaneta americana) predominate in temperate and tropical areas, respectively. CR is an important source of inhalant indoor allergens that sensitize atopic subjects to (localized) type I hypersensitivity or atopy including allergic rhinitis and atopic asthma. In Thailand the predominant CR species is P. americana. CR allergens are found throughout CR infested houses; the number found in kitchens correlates with the degree of CR infestation while sensitization and reactivation of the allergic morbidity are likely to occur in the living room and bedroom. Levels of the CR allergens in homes of CR allergic Thais, measured by using locally made quantification test kits, revealed that the highest levels occur in dust samples collected from the wooden houses of urban slums and in the cool and dry season. CR allergens are proteins that may be derived from any anatomical part of the insect at any developmental stage. The allergens may be also from CR secretions, excretions, body washes or frass. The proteins may be the insect structural proteins, enzymes or hormones. They may exist as dimers/multimers and/or in different isoforms. Exposure to CR allergens in infancy leads to allergic morbidity later in life. Clinical symptoms of CR allergy are usually more severe and prolonged than those caused by other indoor allergens. The mechanisms of acute and chronic airway inflammation and airway hyper-responsiveness (AHR) have been addressed including specific IgE- and non-IgE-mediated mechanisms, i.e., role of protease-activated receptor-2 (PAR2). Participation of various allergen activated-CD4+ T cells of different sublineages, i.e., Th2, Th17, Th22, Th9, Th25, Tregs/Th3 as well as invariant NKT cells, in asthma pathogenesis have been mentioned. The diagnosis of CR allergy and the allergy intervention by CR population control are also discussed.     

Asthma in children

Asthma is the most common chronic disease in childhood characterized by chronic bronchial inflammation of variable intensity accompanied by spontaneous or drug reversible airflow obstruction. The onset of asthma, clinical presentation and response to therapy are influenced by numerous genetic and environmental factors. Asthma in childhood is characterized by its heterogeneity in terms of possible etiology, degree of inflammation and airway obstruction, lung function as well as the natural course of disease that may persist and continue to adulthood. Protective factors linked to early life experiences have also been delineated which may impact the development of asthma. Pathophysiological mechanisms of allergic reaction as an excessive inflammation driven by T-helper-2 (Th2) immunity, offer poor understanding of the heterogeneity of clinical disease. A recently introduced approach defines asthma as a syndrome that comprises of several subtypes or endotypes based on entirely novel pathways to disease. Timely diagnosis and adequate treatment are necessary to prevent irreversible airway remodeling and consequent decrease in pulmonary function.     

Role of respiratory viral infections in the development of atopic conditions

PURPOSE OF REVIEW: Respiratory viral infections are implicated in both protection from, and inception of, allergic airway disease. Severe lower respiratory tract viral infections are associated with recurrent wheeze, asthma and atopy. It is unclear if this association is causal and the underlying mechanisms governing this are unknown. Whilst respiratory viral infections are the major precipitants of acute exacerbations of wheezing illness, early life infections are also clearly associated with protection from allergic diseases. This article aims to review the current understanding of the complex relationship between lower respiratory tract viral infections and their impact upon development of atopy in the airway. RECENT FINDINGS: Clinical studies and animal models have further demonstrated that lower respiratory tract viral infections are strongly associated with development of recurrent wheeze and asthma with human rhinoviruses being shown to be the most prevalent cause of lower respiratory tract viral infections in infants, along with associated asthma development. A case-control study provided evidence of a contributory role for respiratory viral infections within this association, whilst recent experimental studies provide a possible mechanistic insight. SUMMARY: Progress into understanding the relationship between respiratory viral infections and allergic airway disease is essential for development of treatments aimed at treating common risk factors mediating association but not cause. Recent findings may have begun to identify key pathways open to therapeutic intervention.     

Relationship Between Atopy and Bronchial Hyperresponsiveness

Both atopy and bronchial hyperresponsiveness (BHR) are characteristic features of asthma. They are also found among non-asthmatic subjects, including allergic rhinitis patients and the general population. Atopy and BHR in asthma are closely related. Atopy induces airway inflammation as an IgE response to a specific allergen, which causes or amplifies BHR. Moreover, significant evidence of the close relationship between atopy and BHR has been found in non-asthmatic subjects. In this article, we discuss the relationship between atopy and BHR in the general population, asthmatic subjects, and those with allergic rhinitis. This should widen our understanding of the pathophysiology of atopy and BHR.     

Exacerbated Th2-mediated airway inflammation and hyperresponsiveness in autoimmune diabetes-prone NOD mice: a critical role for CD1d-dependent NKT cells

The NOD mouse has proved to be a relevant model of insulin-dependent diabetes mellitus, closely resembling the human disease. However, it is unknown whether this strain presents a general biastoward Th1-mediated autoimmunity or remains capable of mounting complete Th2-mediated responses. Here, we show that NOD mice have the capacity to develop a typical Th2-mediated disease, namely experimental allergic asthma. In contrast to what might have been expected, they even developed a stronger Th2-mediated pulmonary inflammatory response than BALB/c mice, a strain that shows a typical Th2 bias in this model. Thus, after allergen sensitization and intra-nasal challenge, the typical features of experimental asthma were exacerbated in NOD mice, including enhanced bronchopulmonary responsiveness, mucus production and eosinophilic inflammation in the lungs as well as specific IgE titers in serum. These hallmarks of allergic asthma were associated with increased IL-4, IL-5, IL-13 and eotaxin production in the lungs, as compared with BALB/c mice. Notwithstanding their quantitative and functional defect in NOD mice, CD1d-dependent NKT cells contribute to aggravate the disease, since in OVA-immunized CD1d(-/-) NOD mice, which are deficient in this particular T cell subset, airway eosinophilia was clearly diminished relative to NOD littermates. This is the first evidence that autoimmune diabetes-prone NOD mice can also give rise to enhanced Th2-mediated responses and might thus provide a useful model for the study of common genetic and cellular components, including NKT cells that contribute to both asthma and type 1 diabetes.