Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.

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Eosinophilic airway inflammation and structural airway changes are present in school age asthmatics. When these changes occur, and their relationship, are controversial. Some structural airway changes, up-regulation of collagens 1 and 111, and increased distance between alveolar tethering points, may be antenatal, and independent of inflammation. We have established that there is no eosinophilic inflammation or reticular basement membrane thickening in wheezing infants median age one year; but by age three years, both are present. This accords with cohort studies, showing that children who become persistent wheezers have a drop in lung function in the pre-school years. Thereafter, lung function tracks into middle age, so the preschool years represent window during which an intervention might have long term benefit. Supportive are measurements in blood and bronchoalveolar lavage fluid, implicating the neutrophil as the key inflammatory cell in early wheeze. Models of the pathophysiology of asthma include (1) that eosinophilic inflammation is the primary event, and leads to remodelling as a secondary event, which itself results in progressive airflow obstruction (the least likely model); (2) eosinophilic inflammation is the primary event, but remodelling is protective, preventing worsening AHR. It should be noted that these first two are not mutually exclusive; rbm thickening may be protective, but other components of remodeling, for example increased ASM, may have adverse effects; (3) eosinophilic inflammation and airway remodelling are parallel processes, driven by some underlying 'asthma factor'; and (4) the primary abnormality is not airway inflammation, but some form of disordered airway repair.

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In bronchial asthma, respiratory virus infection involves several issues: 1) respiratory virus infection in infancy is a risk factor for, and may predispose to, the development of asthma later in life; 2) respiratory virus infection is associated with the acute exacerbation of bronchial asthma; and, 3) glucocorticosteroids (GC) are not adequate for controlling asthma-related symptoms upon respiratory virus infection. Various cells, inflammatory mediators and cytokines participate in the production of airway inflammation upon respiratory virus infection. Bronchial epithelial cells are a site of infection and replication of respiratory virus. They actively participate in the production of airway inflammation: 1) they produce various proinflammatory cytokines, chemokines and mediators; and, 2) they undergo apoptosis, thereby impairing the repair process. It is therefore important to understand the role of bronchial epithelial cells in the pathophysiology of bronchial asthma. In this review, the interaction between viral infection and asthma is discussed to elucidate the role of bronchial epithelial cells in viral infection.

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The respiratory tract opens to the external environment at the oral side edge, and the other edge of the respiratory tract connects to the closed space (alveoli), and so to preserve the sterility in the terminal respiratory tract is critical for protection against pathogens. The recognition machinery for the invasion of microbes is indispensable for the preservation of the sterility in the lungs. Our general understanding of how microbes are recognized by the innate immune system has increased considerably over the past several years, and the contribution of Toll-Like Receptors (TLRs) to innate immunity is now well documented. In the meantime, it has come to understand that many inflammatory processes may depend on TLR signaling, it has been considered to be involved in the pathogenesis of airway inflammatory diseases such as airway infections, bronchial asthma, and occupational airway diseases. In this review, we focus on physiological roles of TLRs in defense mechanisms of the airways, and pathophysiological roles on airway diseases.

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Atopic dermatitis (AD) is a chronic inflammatory skin disorder with an increasing prevalence in industrialized countries. AD belongs to the group of allergic disorders that includes food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Recent breakthroughs in genetic methodology have greatly augmented our understanding of the contribution of genetics to susceptibility to AD. A candidate gene association study is a general approach to identify susceptibility genes. Fifty three candidate gene studies (50 genes) have identified 19 genes associated with AD risk in at least one study. Significant associations between single nucleotide polymorphisms (SNPs) in chemokines (chymase 1-1903A > G), cytokines (interleukin13 Arg144Gln), cytokine receptors (interleukin 4 receptor 1727G > A) and SPINK 1258G > A have been replicated in more than one studies. These SNPs may be promising for identifying at-risk individuals. SNPs, even those not strongly associated with AD, should be considered potentially important because AD is a common disease. Even a small increase in risk can translate to a large number of AD cases. Consortia and international collaborative studies, which may maximize study efficacy and overcome the limitations of individual studies, are needed to help further illuminate the complex landscape of AD risk and genetic variations.

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Background: Uteroglobin-related protein 1 (UGRP1) is a secretory protein expressed in the airways and is speculated to have anti-inflammatory activity. In the mouse, its gene expression is down-regulated by interleukin (IL)-5 and -9, and up-regulated by IL-10. However, the precise role of UGRP1 in human inflammatory airway diseases such as asthma has not been clarified. The objectives of this study were to establish an ELISA system to quantify UGRP1 protein, and to examine whether plasma UGRP1 levels are associated with the G-112A polymorphism, asthma susceptibility, and its severity.
Methods: 152 asthma patients and 103 normal controls were involved in this study. Mice were immunized with recombinant UGRP1 and hybridoma cell lines were established. A sandwich ELISA system was established by using two monoclonal antibodies recognizing different epitopes. Plasma UGRP1 levels were measured with the ELISA system and the G-112A allele was detected by using real-time PCR.
Results: An ELISA system was established that allowed determination of UGRP1 levels within the range of 9.6-1250pg/ml. The mean plasma UGRP1 levels for subjects with -112A allele were significantly lower than those without it (p = 0.025). Although there was no significant difference in the plasma UGRP1 levels between asthma patients and controls (p = 0.13), severe asthma patients without oral corticosteroid had significantly lower plasma UGRP1 levels compared to mild- or moderate- asthma patients and controls (p = 0.004, 0.03 and 0.003, respectively).
Conclusions: The ELISA system for quantifing UGRP1 protein was established, and plasma UGRP1 levels were associated with the G-112A UGRP1 gene promoter polymorphism and the severity of asthma.

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Background: An imbalanced prevalence of allergic diseases occurs in the region of South East Asia. It has been suggested that a change in lifestyle associated with improved hygiene and modernization has altered the composition of human gastrointestinal microbiota, and hence susceptibility to allergy.
Methods: This cross-sectional study was designed to investigate the differences between fecal microbiota in children living in areas with contrasting socioeconomic development. Fecal samples from 73 young children (age 3.0 ± 0.5) from rural Thailand and 69 age-matched children from urban Singapore were collected and studied using selective culture. Clinical data were also collected using modified ISAAC questionnaires, aiming to identify the key differences in the demographic as well as clinical features between the two study groups.
Results: The two contrasting populations studied differed significantly in multiple lifestyle factors such as family size, antibiotic use and sources of drinking water in the households. Rural children harbored significantly higher counts of lactic acid bacteria (LAB) [7.1 (6.4, 8.3) vs 6.0 (5.3, 7.0)logCFU/g, p < 0.001)], coliforms [8.9 (7.3, 10.2) vs 6.9 (5.7, 7.7)logCFU/g, p < 0.001)] as well as staphylococci [5.3 (4.8, 6.3) vs 4.3 (3.6, 5.0)logCFU/g, p < 0.001)] than their urban counterparts. However, enterococcal counts did not differ between the two groups. No single lifestyle factor could be identified to have caused such differences.
Conclusions: Certain fecal microbial counts were higher in rural children compared with urban children in South East Asia. Several contrasting home environmental conditions and practices were also identified. These may serve as a basis for future investigation of lifestyle factors underlying the global gradient of the increasing trends of allergic diseases.

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Background: The fibrotic process in airway remodeling of asthma may be characterized by an exaggerated deposition of extracellular matrix (ECM) components such as fibronectin and type I, III and IV collagen. In the present study, we established airway remodeling model mice and examined the mechanism of fibrotic change by measuring chemotactic activity of lung fibroblasts and quantifying collagen content in lung tissues.
Methods: Airway remodeling model mice were made by ovalbumin (OA) sensitization and inhalation. Bronchoalveolar lavage (BAL) and bronchial biopsy were performed. Cell migration was assessed by the Boyden's chamber technique. The collagen content of lung tissue was measured using ELISA.
Results: The chemotactic activity in lung fibroblasts toward the mouse BAL fluid (BALF) was significantly increased in OA-inhaled mice. Total soluble collagen content was significantly increased in OA-inhaled mice. We observed markedly increased collagen deposition around the airway wall in OA-inhaled mice, which was not shown in saline-inhaled mice. Furthermore, fibronectin in the BALF of OA-inhaled mice was significantly higher than that in the control mice.
Conclusions: The total soluble collagen content increased during the fibrotic change of airway remodeling in asthma. Furthermore, migration of fibroblasts may play a key role in this remodeling process, and fibronectin and type I and IV collagen seem to be chemotactic factors for the fibroblasts.

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Background: Wild birch trees grow in limited areas in Japan and are not a common aero-allergen. However, many patients who do not live in the area show positive birch pollen Radioallergosorbent Test (RAST). Therefore, being sensitized by another tree pollen which is closely related to birch may result in showing a specific IgE antibody to birch. Alder is a one of these trees and in the past it grew widely in Japan. However, there is no available RAST data as to the correlations between alder and alder-related trees.
Methods: We measured the alder specific IgE (CAP-RAST, Phadea) in stored sera which was positive in birch RAST (228 samples), beech RAST (36 samples), oak RAST (152 samples) and cedar RAST (411 samples) and examined correlations between the RAST of alder and other trees.
Results: The correlation coefficient value of birch was very high (0.971). The other coefficient values of beech and oak were high (0.884 in beech and 0.895 in oak) but were slightly lower than that of the birch. This means that in terms of allergenicities, birch pollen is almost the same as alder and beech and oak are partly different from the alder.
Conclusions: The Japanese respond to alder pollen just same as they do to birch pollen in forming specific IgE antibody. In clinical practice, positive alder RAST has the same meaning as positive birch RAST.

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Background: Pollen is an important trigger of allergic rhinitis, conjunctivitis, and/or asthma, and an exacerbating factor in atopic dermatitis. Although it is proposed that protease activity from allergen sources, such as mites, enhances allergenicity, little information is available on that from relevant allergenic pollens such as Japanese cedar and Japanese cypress pollens, which are the major cause of pollinosis in Japan.
Methods: We analyzed the protease activities derived from allergenic pollen of Japanese cedar, Japanese cypress, and Rocky mountain juniper, which belong to the Cupressaceae/Taxodiaceae family, and white birch and short ragweed, using synthetic substrates and class-specific inhibitors.
Results: We found that the pollen of the three members of the Cupressaceae/Taxodiaceae family contained serine protease activity, that the pollen of white birch and short ragweed contained not only serine protease activity but also cysteine protease activity, that all five types of pollen tested contained at least one other type of serine protease, whose sensitivity to a serine protease-specific inhibitor was relatively low, and that the content and releasability of the pollen-derived proteases differed according to the plant families.
Conclusions: Clinically relevant allergenic pollens tested in the present study can release serine and/or cysteine endopeptidases. Information on the spectrum of the endopeptidase activities from these allergenic pollen grains will be useful for investigating their contribution to the pathogenesis of allergies.

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Background: Birch pollen is the major allergen in pollinosis in northern Japan. IgE reactivity to individual birch pollen allergens has been shown to differ between populations of birch pollen-allergic patients living in different countries. In this study, we examined the IgE profiles to recombinant birch pollen allergens in birch-sensitive patients living in Sapporo.
Methods: This study used the sera of 40 patients with specific IgE toward birch pollen extract. Their sera were analyzed for specific IgE reactivity to individual birch pollen allergens (recombinant Bet v 1, Bet v 2 and Bet v 4) and natural birch pollen extract using Pharmacia CAP System^TM.
Results: Of 40 sera with positive CAP results for natural birch pollen extract, 39 (97.5%) had specific IgE towards Bet v 1; 6 (15%) contained specific IgE against Bet v 2. Bet v 4 reactivity was documented in only one subject (2.5%).
Conclusions: The present data suggest that the specific IgE reactivity profiles to birch pollen allergen in birch-sensitive patients in Sapporo correspond to those in Scandinavia, possibly due to the heavy birch pollen exposure in this area. This observation provides useful information for future birch allergen-specific immunotherapy in Japan.

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Background: Food-dependent exercise-induced anaphylaxis (FDEIA) is a distinct form of common food allergy characteristically induced by a combination of causative food ingestion and physical exercise. Recent investigations have documented that aspirin consumption, in place of exercise, also induces allergic symptoms.
Case Summary: A 63-year-old man began low dose aspirin therapy on September 2005. Since January 2006, he had repeated episodes of generalized urticaria and lost consciousness while he was exercising after eating wheat. He was strongly positive for ω-5 gliadin in a cap-system fluorescent enzyme immunoassay. Therefore, a diagnosis of wheat-dependent exercise-induced anaphylaxis was made.
Discussion: Patients with aspirin-provoked FDEIA have been reported previously as taking ordinary doses of aspirin for reducing pain, inflammation and fever. However, in our patient, low dose aspirin therapy for reducing cardiovascular risk possibility induced FDEIA. Growing numbers of elderly people take low doses of aspirin for prevention of cerebral or myocardial infarction. Therefore, physicians should remember that aspirin consumption, even at low doses, is a risk factor for FDEIA.

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Background: IgM deficiency is a rare primary immunodeficiency. As few studies of selective IgM deficiency have been reported among the various other types of primary immunodeficiencies, the detailed pathogenesis of this disorder remains to be elucidated.
Case Summary: We clinically analyzed a 37-year-old woman who presented with IgM and IgG4 deficiency and ectopic bronchial pneumonia, and investigated immunological functions. Occlusive pneumonia was repeatedly observed in the right S6 area, and bronchoscopy revealed a polyp in the right B6 orifice, which was later identified as a fibroepithelial polyp after transbronchial endoscopic polypectomy. Two months later, pneumonia involving the right inferior lobe developed. Systemic erythema and pigmentation with bleb formation were also observed on the skin, and were thought to be drug-induced exanthema following a biopsy. Serum levels of IgM and IgG4 were extremely low at 3.0mg/dl and less than 2.0mg/dl, respectively. Circulating CD20 positive B cells were mildly reduced and memory B cells were markedly decreased. The majority of B cells expressed IgM on their surface. There were no abnormalities in cell counts of neutrophils, T cells, NK cells and monocytes. Chemotaxins, bactericidal activity and phagocytosis of neutrophils were normal.
Discussion: There have been no case reports of selective IgM deficiency with concurrent IgG4 deficiency, various dermal symptoms and a bronchial polyp, as demonstrated in our patient.

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