Vα14 natural killer T (NKT) cells produce large amounts of both IL-4 and IFN-γ upon stimulation with a ligend, α-galactosylceramide (α-GalCer), and play a crucial role in various immune responses, including allergic reactions. Interestingly, Vα14 NKT cells are not essential for the induction of specific IgE response but they instead tend to induce suppression of specific IgE upon α-GalCer activation in vivo. The suppression in the IgE production is not detected either in Vα14 NKT cell-deficient mice or in IFN-γ-deficient mice. Therefore, activated Vα14 NKT cells are able to exert a potent suppressive activity on Th2 cell differentiation and subsequent IgE production by producing a large amount of IFN-γ. In an OVA-induced asthma model, α-GalCer administration inhibited airway inflammation and airway hyperreactivity by IFN-γ from activated Vα14 NKT cells, thus suggesting the negative regulation of Th2-responses by the activated Vα14 NKT cells.

View full abstract

Allergic bronchial asthma is a complex inflammatory diseases originated from dysregulated immune responses in the respiratory mucosa. The inflammatory state in asthmatic lung is characterized by massive infiltration with eosinophils, lymphocytes, and mast cells in the airway mucosa leading to airway hyperseisitivity, goblet cell hyperplasia and mucus overproduction. The inflammatory process is thought to be the result of intensive T helper (Th) 2-biased immune response. Over the past several years, there has been enormous progress in understanding the mechanisms for development of Th2-biased responses after inhaled exposure to allergens and the characteristics of CD4+ T cells prominently involved in this process. Recently, a new population of T cells, invariant natural killer T (iNKT) cells has been shown to play an important role in the pathogenesis of mouse model of allergic airway inflammation. iNKT cells are one of the most potent immune modulators through a massive production of a various cytokines including IL-4 and IFN-γ upon activation, and are involved in a variety of immunoregulations including infection, autoimmunity, and tumor surveillance. The potent pathogenic role of iNKT cells in the development of bronchial asthma is due to their ability to produce predominant Th2 cytokines in a given condition. The involvement of iNKT cells in the pathogenesis of asthma might have been underestimated in the past studies demonstrating the involvement of CD4+ T cells in asthma because of the difficulty in the detection of iNKT cells. Meanwhile, growing evidences have demonstrated that iNKT cells could be a promising target for immune-based therapies for autoimmune diseases, tumor, and infection due to the invariance of their TCR usage, the restriction to the evolutionally-conserved non-polymorphic antigen-presenting molecule CD1d, and their outstanding ability to produce both Th1- and Th2-cytokines. In this review, we will overview current understanding of the pathophysiological roles of iNKT cells in asthma. We would also discuss on possible therapeutic approaches to bronchial asthma employing glycolipid ligands for iNKT cells.

View full abstract

Background: Guidelines and literature debate the importance of testing for bronchial reversibility and its total significance is unclear. Clinically, patients with greater reversibility have higher fluctuations in respiratory symptoms, and hence may have a reduced health-related quality of life (HRQoL). On the other hand, they may have a better HRQoL as medications may be more effective in this population. Presently, there are no reports concerning the relationship between HRQoL as an indicator of therapy and reversibility. We hypothesized that the reversibility of airflow limitation might be correlated with the HRQoL in COPD.
Methods: We examined 63 subjects with COPD (mean age: 71.7 years). Reversibility was measured by the change in FEV₁ and FVC after the inhalation of salbutamol (300μg), and we investigated the relationship between the reversibility and the parameters of HRQoL, which included St. George's Respiratory Questionnaire (SGRQ), Visual analogue scale-8 (VAS-8), Short-Form 36-Item Health Study, Basic activities of daily living, Instrumental activities of daily living, and the Oxygen cost diagram.
Results: Post-bronchodilator FEV₁, % predicted was positively correlated with both the total scores of SGRQ and VAS-8 (p < 0.0001 and p < 0.006, respectively). Furthermore, the reversibility of FVC was positively correlated with all items of the SGRQ, except for impact (total score: p < 0.02; symptoms: p < 0.02; activity, p < 0.05; total score of VAS-8: p < 0.02). However, the reversibility of FEV₁ was neither correlated with the total score nor any items in the scales.
Conclusions: Those who have FVC that respond to bronchodilator at rest might result in an improvement of HRQoL after treatment.

View full abstract

Background: The gene encoding CD14 is a positional candidate gene for allergic diseases as it is localized on chromosome 5q31, a region that is linked to atopy-related phenotypes.
Although it has been shown that a polymorphism in the 5' region of the CD14 gene is associated with food allergy in white subjects, it is not clear whether this association is also present in the Japanese population.
Methods: Eighty-eight children with food allergy were recruited along with 101 children controls without food allergy. DNA samples from these subjects were genotyped by PCR-based restriction fragment length polymorphism (RFLP) assay to investigate the relationship between two polymorphisms in the 5' region of the CD14 gene (C-159T and C-550T) and food allergy.
Results: There was no association among the CD14 alleles, dominant model or recessive model of either polymorphism with food allergy.
Conclusions: The CD14-159 and -550 polymorphisms might not play a major role in the pathogenesis of food allergy in Japanese children.

View full abstract

Background: Psychological stress has long been recognized to be associated with asthma symptoms. There appear to be individual differences in the susceptibility to even the same kind of stress, and furthermore, stress responses are different between the types of the stress, acute and chronic, even in the same person. However, the mechanisms linking stress to asthma are not well defined. Psychological stress upregulates the expression of endogenous opioids. The opioids stimulate the hypothalamus-pituitary-adrenal axis and sympathetic and adrenomedullary system, through the activation of μ-opioid receptor (MOR) to release stress hormones, such as cortisol and catecholamines, respectively. These hormones can modulate immune responses via the induction of Th1 immunity.
Methods: Female BALB/c and C57BL/6, wild and MOR-deficient, mice sensitized with ovalbumin (OVA) were exposed to OVA with or without either acute or chronic restraint stress. Airway inflammation was evaluated by the measurement of the number of inflammatory cells and cytokine contents in bronchoalveolar lavage fluids.
Results: In BALB/c mice, but not in C57BL/6 mice, the number of total cells, eosinophils and lymphocytes in the acute stress group were significantly decreased compared with those in the non-acute stress group. In contrast, chronic stress significantly increased the cell numbers and the contents of IL-4 and IL-5 in both mouse strains. Furthermore, these exacerbations were abolished in MOR-deficient mice.
Conclusions: These results suggest that acute stress modifies the allergic airway responses distinctively depending on the genetic background, and MOR is involved in the chronic psychological stress-induced exacerbation of allergic airway inflammation.

View full abstract

Background: Exhaled nitric oxide (eNO) is a useful marker of eosinophilic airway inflammation in asthma patients. There is no study to show the relationship between the eNO measured by using an off-line method and the degree of reversibility of airflow limitation in Japanese asthma patients. We sought to investigate the relationship between the eNO level measured by using an off-line method and the degree of reversibility of bronchial constriction in Japanese asthma patients.
Methods: The study population comprised 97 asthma patients in our outpatient clinic with some patients in both groups who received inhaled corticosteroid treatment. We measured eNO levels, forced expiratory volume in one second (FEV₁) before and after treatment, reversible airway obstruction (ΔFEV₁) after inhalation of bronchodilator, and other parameters.
Results: eNO was significantly correlated with peripheral blood eosinophil counts in asthma patients (in steroid-naïve asthma patients, r = 0.544, p < 0.0001; in asthma patients treated with inhaled corticosteroid, r = 0.463, p = 0.026), and subjects with severe eosinophilia in sputum showed high levels of eNO (mild eosinophilia versus severe, p = 0.0152). Among patients with obstructive impairment, eNO levels were correlated with ΔFEV₁ regardless of whether patients received (r = 0.527, p = 0.0435) or did not receive (r = 0.64, p = 0.0056) inhaled corticosteroid. In subjects with normal pulmonary function, there was no significant relationship between eNO and ΔFEV₁ with or without inhaled corticosteroid.
Conclusions: In patients with obstructive impairment, eNO reflects the degree of reversible airflow limitation. In subjects with normal pulmonary function, eNO may facilitate the diagnosis and management of asthma, rather than indicate reversible bronchial obstruction. eNO measurement by off-line methods is applicable as a potential tool for the diagnosis of asthma and management of asthma patients.

View full abstract

Background: To clarify the role of eosinophils in the pathogenesis of Kimura's disease and the values of measuring serum levels of eosinophil cationic protein (ECP) for monitoring disease activity might be very important, but there are few reports about this matter.
Methods: A total 14 serum and 7 tissue samples from patients with Kimura's disease were studied. The concentrations of ECP and cytokines (interleukin-4 (IL-4), granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin 5 (IL-5)) in sera from patients with Kimura's disease were measured by enzyme-linked immunosorbent assay (ELISA). The density of eosinophils and the degree of activation of eosinophils in the tissue were also studied immunohistochemically.
Results: The concentration of ECP in sera from patients with Kimura's disease was significantly higher than that in the control group (p < 0.05). At the time of the remission, a significant decrease of ECP was observed. In interfollicular areas, most infiltrated eosinophils were positive for EG2 antibody (64.0-94.0%) and the mean percentage of EG2-positive eosinophils was 75.7%. The concentrations of IL-4, GM-CSF, and IL-5 in sera from patients with Kimura's disease were within normal ranges or below the detectable level in all sera examined.
Conclusions: Our findings suggest that eosinophils play an important role in the pathogenesis of Kimura's disease and ECP may be used as an additional parameter of disease activity.

View full abstract

Background: Previous studies show that 6-9% of young adults in Reykjavik are sensitised to the house dust mite (HDM) Dermatophagoides pteronyssinus (D. pteronyssinus). However, only negligible amounts of HDM and HDM allergens were detected in their homes. The study investigates what characterizes these individuals.
Methods: We investigated all participants in the European Community Respiratory Health Surveys I and II (ECRHS I and II) with D. pteronyssinus specific IgE, in the years 1991-92. A grass positive but D. pteronyssinus negative control group was recruited from the same cohort. A detailed questionnaire was administered and the specific IgE (Pharmacia CAP system) against six D. pteronyssinus cross-reactive allergens was measured.
Results: Of 601 ECRHS I participants with available IgE results, 88% returned for ECRHS II, 8.4 years later. Of 49 individuals with D. pteronyssinus specific IgE in ECRHS I, 24 had become negative in ECRHS II. Compared with controls, HDM sensitive subjects were more often men who had lived on farms or kept aquaria fish in childhood. Of those with specific IgE against D. pteronyssinus in ECRHS I and II, 75% had detectable IgE antibodies (≥0.35kU/l) to cross-reactive allergens compared with none in the control group (p < 0.0001): Lepidoglyphus destructor (L. destructor) (67%), shrimp (58%), cockroach (33%), mosquito (17%), tropomyosin (17%) and blood worm (4%).
Conclusions: Icelanders with specific IgE to D. pteronyssinus are more often men who spent time on farms in childhood and today have high prevalence of IgE antibodies cross-reactive to D. pteronyssinus.

View full abstract

Background: Galectin-3 is a β-galactoside-binding protein which is implicated in diverse physiological and pathological processes including human liver cirrhosis and a mouse lung fibrosis model. The aim of this study is to determine whether galectin-3 is involved in human lung fibrosis.
Methods: We measured galectin-3 concentration in bronchoalveolar lavage fluid (BALF) and examined its expression in alveolar macrophages from patients with interstitial lung disorders using ELISA and immunohistochemical staining, respectively. Using monocyte/macrophage cell lines in vitro, we examined the effect of cytokines on galectin-3 expression, and the opposite similarly by RT-PCR and Western blotting. Finally, we performed Micro Boyden chamber assay and Sircoll assay to determine whether galectin-3 induces migration and collagen synthesis, respectively, in fibroblasts.
Results: Galectin-3 was specifically increased in BALF from patients with idiopathic pulmonary fibrosis (IPF) and interstitial pneumonia associated with collagen vascular disease (CVD-IP). Galectin-3 levels in BALF seemed to be lower in IPF and CVD-IP patients receiving corticosteroid therapy. Alveolar macrophages from IPF patients expressed more galectin-3 compared with those from control. Galectin-3 expression was induced by tumor necrosis factor-alpha (TNF-α) and interferon (IFN)-γ in a monocytic cell line U937. Galectin-3 also induced mRNA expression and protein production of TNF-α and interleukin (IL)-8 in a macrophage cell line THP-1. This lectin stimulated NIH-3T3 fibroblast to induce migration and collagen synthesis in vitro.
Conclusions: These results suggest that galectin-3 is involved in the pathogenesis of human IPF and CVD-IP by activating macrophages and fibroblasts.

View full abstract

Background: Japanese cedar pollinosis (JCPsis) affects nearly one in six Japanese. Oral administration of Bifidobacterium longum BB536 has been shown to be effective in relieving JCPsis symptoms during the pollen season.
Methods: This double- two-way crossover study was designed to evaluate the efficacy of BB536 on reducing symptoms in JCPsis patients exposed to Japanese cedar pollen (JCP) in an environmental exposure unit (EEU) outside of the normal JCP season. After a 1-week run-in period, subjects (n = 24) were randomly allocated to receive BB536 powder (approximately 5 × 10¹⁰) or placebo twice a day for 4 weeks. After a 2-week washout period, subjects were crossed over to another 4 weeks of intake. At the end of each intake period, subjects received controlled JCP exposure for 4 hours in the EEU. Symptoms were self-rated 30 minutes before and every 30 minutes during the exposures. From the first day of exposure through the next 5 successive days, participants self-rated their delayed symptoms and medication uses. Blood samples were taken before the exposures. The mean JCP levels for exposures were 6500 to 7000grains/m³ air.
Results: In comparison with placebo, BB536 intake significantly reduced the ocular symptom scores during JCP exposures. Evaluating delayed symptoms after exposures indicated that scores for disruption of normal activities were significantly lower in the BB536 group compared with the placebo group. Prevalence of medication use was markedly reduced by BB536 intake.
Conclusions: These results suggest the potential beneficial effect of BB536 in relieving symptoms of JCP allergy

View full abstract