Pathogenesis Of Nonatopic Asthma Research Articles

The Association of Lung Function, Bronchial Hyperresponsiveness, and Exhaled Nitric Oxide Differs Between Atopic and Non-atopic Asthma in Children.

PurposeAlthough many previous studies have attempted to identify differences between atopic asthma (AA) and non-atopic asthma (NAA), they have mainly focused on the difference of each variable of lung function and airway inflammation. The aim of this study was to evaluate relationships between lung function, bronchial hyperresponsiveness (BHR), and the exhaled nitric oxide (eNO) levels in children with AA and NAA.MethodsOne hundred and thirty six asthmatic children aged 5-15 years and 40 normal controls were recruited. Asthma cases were classified as AA (n=100) or NAA (n=36) from skin prick test results. Lung function, BHR to methacholine and adenosine-5'-monophosphate (AMP), eNO, blood eosinophils, and serum total IgE were measured.ResultsThe AA and NAA cases shared common features including a reduced small airway function and increased BHR to methacholine. However, children with AA showed higher BHR to AMP and eNO levels than those with NAA. When the relationships among these variables in the AA and NAA cases were evaluated, the AA group showed significant relationships between lung function, BHR to AMP or methacholine and eNO levels. However, the children in the NAA group showed an association between small airway function and BHR to methacholine only.ConclusionsThese findings suggest that the pathogenesis of NAA may differ from that of AA during childhood in terms of the relationship between lung function, airway inflammation and BHR.

Does IFN-γ play a role on the pathogenesis of non-atopic asthma in Latin America children?

In this work we explore differences in blood cells and cytokine profiles in children according to atopic status and asthma (atopic or non-atopic). The study involved measurement of Th1(IFN-γ) and Th2 (IL-5 and IL-13) cytokines in Dermatophagoides pteronyssinus stimulated peripheral blood leukocytes, blood cell count, skin prick test and specific IgE against common aeroallergens. Atopic status was associated with eosinophilia and production of Th2 type cytokines. Atopic asthma was associated with eosinophilia and non-atopic asthma was associated with IFN-γ and elevated monocytes in blood. IFN-γ and monocytes might play a role in immunopathology of non-atopic asthma in Latin American children.

Association between genetic variations of the transforming growth factor β receptor type III and asthma in a Korean population

Transforming growth factor-beta (TGF-ß) and its receptors have been suggested to play key roles in the pathogenesis of asthma. The aim of this study was to evaluate the effects of genetic variations in the TGF-ß receptor type III (TGFBR3) on asthma and on its related phenotypes in the general population. A cohort of 2,118 subjects aged from 10 to 18 years responded to a questionnaire concerning asthma symptoms and risk factors. Methacholine airway hyperresponsiveness (AHR), skin test responses to common aeroallergens, and serum total IgE levels were evaluated in the cohort. A total of 19 SNPs for TGFBR3 were found using direct re-sequencing in 24 healthy adults. Of these, informative SNPs [+44T>C (S15F) and +2753G>A at 3'UTR] were selected and scored using the high throughput single base extension method. Atopy was identified in subjects with 44T>C allele [P=0.04, OR (95% CI)=0.79 (0.62-0.99)] and in subjects with Ht1 (CG) more frequently than in subjects with other haplotypes [P=0.04, OR (95% CI)=1.27 (1.01-1.59)]. The A allele in 2753G>A was more common in subjects with non-atopic asthma [OR (95% CI)=1.76 (1.01-3.05)]. A significant association was found between non-atopic asthma and 44T_2753A [OR (95% CI) =2.16 (1.22-3.82)]. Genetic variations in TGFBR3 appear to be associated with a genetic predisposition to development of asthma and to phenotypes of asthma. Also, the minor allele 2753G and the haplotype TA in the TGFBR3 gene were associated with a pathogenesis of non-atopic asthma.

Key role for mast cells in nonatopic asthma.

The mechanisms involved in nonatopic asthma are poorly defined. In particular, the importance of mast cells in the development of nonatopic asthma is not clear. In the mouse, pulmonary hypersensitivity reactions induced by skin sensitization with the low-m.w. compound dinitrofluorobenzene (DNFB) followed by an intra-airway application of the hapten have been featured as a model for nonatopic asthma. In present study, we used this model to examine the role of mast cells in the pathogenesis of nonatopic asthma. First, the effect of DNFB sensitization and intra-airway challenge with dinitrobenzene sulfonic acid (DNS) on mast cell activation was monitored during the early phase of the response in BALB/c mice. Second, mast cell-deficient W/W(v) and Sl/Sl(d) mice and their respective normal (+/+) littermate mice and mast cell-reconstituted W/W(v) mice (bone marrow-derived mast cells-->W/W(v)) were used. Early phase mast cell activation was found, which was maximal 30 min after DNS challenge in DNFB-sensitized BALB/c, +/+ mice but not in mast cell-deficient mice. An acute bronchoconstriction and increase in vascular permeability accompanied the early phase mast cell activation. BALB/c, +/+ and bone marrow-derived mast cell-->W/W(v) mice sensitized with DNFB and DNS-challenged exhibited tracheal hyperreactivity 24 and 48 h after the challenge when compared with vehicle-treated mice. Mucosal exudation and infiltration of neutrophils in bronchoalveolar lavage fluid associated the late phase response. Both mast cell-deficient strains failed to show any features of this hypersensitivity response. Our findings show that mast cells play a key role in the regulation of pulmonary hypersensitivity responses in this murine model for nonatopic asthma.

Intracellular IL-5 and T-lymphocyte subsets in atopic and nonatopic bronchial asthma

Background: Allergen-stimulated IL-5 production by CD4+ T cells is the key issue in atopic asthma. On the other hand, virus-specific CD8+ T cells produce IL-5 and might play an important role in the pathogenesis of nonatopic asthma. Objectives: We sought to compare the IL-5-producing T-lymphocyte subsets in the peripheral blood of atopic and nonatopic asthmatic subjects, especially the contribution of IL-5-producing CD8+ T cells in nonatopic asthma. Methods: Heparinized blood samples were obtained from subjects with atopic asthma (n = 10), subjects with nonatopic asthma (n = 10), and healthy subjects (n = 10) and stimulated with ionomycin and phorbol myristate acetate in the presence of brefeldin A. Two-color flow cytometric analysis with mAbs to cell-surface antigens and intracellular IL-5 was used to detect the IL-5-producing T-cell subsets. Results: A higher percentage of IL-5-producing CD3+ T cells was detected in subjects with atopic and nonatopic asthma than that seen in the healthy subjects. The percentage of IL-5-producing CD4+ T cells was significantly higher in subjects with atopic asthma than in the healthy subjects. The percentage of IL-5-producing CD8+ T cells was significantly higher in subjects with nonatopic asthma than in the healthy subjects. The percentage of IL-5-producing CD8+ T cells was higher in subjects with nonatopic asthma than in those with atopic asthma, but the difference was not statistically significant. Conclusions: CD4+ T cells are the major source of IL-5 among CD3+ lymphocytes in subjects with atopic asthma. On the other hand, increased IL-5 production by CD8+ T cells, as well as by CD4+ T cells, is a characteristic feature of nonatopic asthma. (J Allergy Clin Immunol 2002;109:294-8.)

Increased levels of circulating autoantibodies to cultured human bronchial epithelial cell in adult patients with nonatopic asthma.

The pathogenetic mechanism of nonatopic asthma has not yet been defined. The idea of a possible involvement of autoimmunity in the pathogenesis of nonatopic asthma has been proposed by earlier studies. To evaluate the possible involvement of autoimmune response against bronchial epithelial cell in the pathogenesis of nonatopic asthma, we measured circulating autoantibodies to cultured human bronchial epithelial cell (BEAS-2B cell line) using enzyme-linked immunosorbent assay. We used stored serum samples form 38 age-matched healthy controls, 26 adult patients with atopic asthma, 16 adult patients with nonatopic asthma, and 12 adult patients with systemic lupus erythematosus. Levels of IgG autoantibodies to bronchial epithelial cell were significantly higher in patients with nonatopic asthma (mean+/-SD of absorbance values; 0.135+/-0.030) and systemic lupus erythematosus (0.293+/-0.181) than in healthy controls (0.112+/-0.016) and patients with atopic asthma (0.116+/-0.031) (p<0.05). This study showed that levels of circulating IgG autoantibodies to bronchial epithelial cell were increased in adult patients with nonatopic asthma. Further studies are needed to evaluate the possible involvement of autoimmune mechanism in the pathogenesis of nonatopic asthma.

Presence of circulating autoantibodies against bronchial epithelia cell in patients with nonatopic asthma.

Allergic response to common environmental agents has been regarded as a main pathogenetic mechanism of bronchial asthma. However, allergic sensitization (atopy) can not be detected in a siginificant number of adult asthmatic patients. The etiology of nonatopic asthma has not yet been defined. To evaluate the possible involvement of autoimmune response against bronchial mucosa in the pathogenesis of nonatopic asthma, we performed indirect immunofluorescence staining of fresh frozen human bronchial mucosa tissue using serum samples from patients with atopic and nonatopic asthma, healthy controls, and patients with systemic lupus erythematosus. On immunostaining, circulating IgG autoantibodies against bronchial mucosa were detected in 2 (9.1%) of 22 patients with nonatopic asthma and in none of 22 patients with atopic asthma and of 22 healthy controls. IgG autoantibodies from the two patients with nonatopic asthma predominantly stained the cytoplasmic membrane of basal cells in bronchial epithelium. Serum samples from 10 patients with systemic lupus erythematosus immunostained the nucleus of epithelial cells in whole layer of bronchial epithelium. This study showed the presence of circulating IgG autoantibodies against the bronchial epithelial cell in a small portion of patients with nonatopic asthma. Further studies may be necessary to evaluate the possible involvement of autoimmune mechanism in the pathogenesis of nonatopic asthma.

アレルギー性肺疾患における末梢気道領域の免疫応答に関する研究

The distribution of immunoglobulin containing cells and interstitial deposition of immunoglobulins and complement were observed aroud small airway areas of bronchial asthmatics. Transbronchial lung biopsy was performed to obtain peripheral lung tissues of bronchial asthmatics in non-attack stage. The peroxidase antiperoxidase technique was applied to detect IgG, IgA, IgM, IgE antibodies and C1q using routinely processed paraffin sections.The proportion of IgA containing cells was lower in the peripheral airway of bronchial asthmatics than in normal peripheral lungs.In atopic asthmatics, the proportion of IgE containing cells was higher than that in non-atopic asthmatics and normal controls.In non-atopic asthmatics, the proportion of IgG containing cells was higher than that in atopic asthmatics and normal controls.In non-atopic asthmatics, interstitial depositon of IgG antibody to alveolar septa and bronchiolar mucosa was characteristic.These findings suggest that the IgG antibody plays an important role in the pathogenesis of non-atopic asthma, whereas the IgE antibody is involved in atopic asthma.