Asthma and rhinitis have different genetic profiles for IL13, IL17A and GSTP1 polymorphisms.

BACKGROUND: Asthma and rhinitis have a complex etiology, depending on multiple genetic and environmental risk factors. An increasing number of susceptibility genes are currently being identified, but the majority of reported associations have not been consistently replicated across populations of different genetic backgrounds. PURPOSE: To evaluate whether polymorphisms of IL4R (rs1805015), IL13 (rs20541), IL17A (rs2275913) and GSTP1 (rs1695) genes are associated with rhinitis and/or asthma in adults of Portuguese ancestry. METHODS: 192 unrelated healthy individuals and 232 patients, 83 with rhinitis and 149 with asthma, were studied. All polymorphisms were detected by real time polymerase chain reaction (PCR) using TaqMan assays. RESULTS: Comparing to controls, significant association with asthma was observed for GSTP1 rs1695 AA genotype (odds ratio (OR) - 1.96; 95% CI - 1.18 to 3.25; p=0.010). The association sustains for allergic asthma (OR - 2.17; 95% CI - 1.23 to 3.80; p=0.007). IL13 rs20541 GG genotype was associated with less susceptibility to asthma (OR - 0.55, 95% CI - 0.33 to 0.94, p=0.028). Among patients, IL17A rs2275913 AA genotype was less associated with asthma than with rhinitis (OR - 0.20; 95% CI of 0.07 to 0.56; p=0.002). A similar association was found for IL13 rs20541 GG genotype (OR - 0.48; 95% CI of 0.25 to 0.93; p=0.031). There were no significant differences in the distribution of allelic and genotypic frequencies between patients and controls for the IL4R polymorphism' analyzed. CONCLUSION: These results support the existence of a significant association between GSTP1 rs1695 and IL13 rs20541 SNPs, with susceptibility to asthma, in the population studied. Different genotype profiles of IL17A and IL13 genes seem to influence the clinical pattern of disease expression mainly confined to the upper airways, as rhinitis, or including the lower airways, as asthma.

Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy.

OBJECTIVE: To provide evidence of the existence of membrane progesterone receptor alpha (mPRα) on regulatory T cells (Treg) in peripheral blood during pregnancy, postulating a possible explanation for the effect of progesterone on preterm birth. DESIGN: Cross-sectional study. SETTING: Tertiary Obstetric Department in a University Hospital. POPULATION: Healthy pregnant women. METHODS: Treg cells from peripheral blood samples were studied by flow cytometry using multiple monoclonal antibody expression. MAIN OUTCOME MEASURES: Evaluate the number and percentage of CD4(+) CD25(high) CD127(low) , the number and percentage of Treg cells among the total CD4(+) T cells, and the percentage and mean fluorescence intensity (MFI) of mPRα in that population, using several gating strategies. RESULTS: 43 peripheral blood samples were collected from healthy women during pregnancy, whose median gestational age was 28.7 ± 7.1 (16-40) weeks. The percentage of CD4(+) in the total lymphocytes was 43% (32-51) and the percentage of CD4(+) CD25(high) CD127(low) was 4.8% (1.6-5.9), with only 45% (16-72) of those cells expressing the intracellular marker FoxP3 (Treg cell pool). We confirmed the existence of mPRα in that specific population because 8.0% (2.02-33) of the Treg cells were marked with the specific monoclonal antibody, with an mPRα(+) MFI of 719 (590-1471). CONCLUSIONS: This research shows that Treg cells express mPRα during pregnancy, which might play an important role in immune modulation by progesterone.

Leptin and resistin in overweight patients with and without asthma

BACKGROUND: Excess body mass increases the risk of development of asthmatic symptoms and their severity and decreases the treatment effectiveness. One of the hypotheses explaining the link between the two diseases concerns the adipokines, hormones produced by adipose tissue with a proinflammatory character. The aim of this study was to compare the levels of the adipokines (leptin and resistin) between overweight asthmatic patients, asthmatic patients with normal weight and overweight patients without asthma. METHODS: 80 peripheral blood samples were collected from patients and blood serum extracted. Three groups were selected: overweight asthmatic patients (BMI ≥ 25), overweight patients without asthma and asthmatic patients with normal weight (BMI < 25). Waist circumference of the patients was measured (cut-off points were 80 cm for women and over 94 cm for men) and a skin prick test performed. Comparison of adipokine concentration between the 3 groups was made and association between these concentrations and the measurements was performed. RESULTS: Although the concentrations of both adipokines were slightly higher for overweight asthmatic patients compared to overweight healthy patients, these differences were not significant. A significant association was found between leptin concentration and both BMI (p < 0.01) and waist circumference (p < 0.01). A difference for this cytokine was also found between asthmatic and non-asthmatic female patients (p < 0.05). CONCLUSIONS: As expected overweight patients with BMI ≥ 25 and patients with increased waist circumference showed higher leptin levels. We suggest that the studied cytokines, with a stronger indication for leptin, can elicit asthmatic inflammation in obese phenotype of asthma that affects more frequently women

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Leptin and resistin in overweight patients with and without asthma.

BACKGROUND: Excess body mass increases the risk of development of asthmatic symptoms and their severity and decreases the treatment effectiveness. One of the hypotheses explaining the link between the two diseases concerns the adipokines, hormones produced by adipose tissue with a proinflammatory character. The aim of this study was to compare the levels of the adipokines (leptin and resistin) between overweight asthmatic patients, asthmatic patients with normal weight and overweight patients without asthma. METHODS: 80 peripheral blood samples were collected from patients and blood serum extracted. Three groups were selected: overweight asthmatic patients (BMI≥25), overweight patients without asthma and asthmatic patients with normal weight (BMI<25). Waist circumference of the patients was measured (cut-off points were 80cm for women and over 94cm for men) and a skin prick test performed. Comparison of adipokine concentration between the 3 groups was made and association between these concentrations and the measurements was performed. RESULTS: Although the concentrations of both adipokines were slightly higher for overweight asthmatic patients compared to overweight healthy patients, these differences were not significant. A significant association was found between leptin concentration and both BMI (p<0.01) and waist circumference (p<0.01). A difference for this cytokine was also found between asthmatic and non-asthmatic female patients (p<0.05). CONCLUSIONS: As expected overweight patients with BMI≥25 and patients with increased waist circumference showed higher leptin levels. We suggest that the studied cytokines, with a stronger indication for leptin, can elicit asthmatic inflammation in obese phenotype of asthma that affects more frequently women.

The association of asthma, nasal allergies, and positive skin prick tests with obesity, leptin, and adiponectin.

BACKGROUND: Cross-sectional and longitudinal reports show that obese adults have more asthma than non-obese adults. A proposed mechanism is via effects of adipokines (leptin and adiponectin) on the immune system. OBJECTIVE: We wished to measure the associations of asthma and other atopic diseases with serum adipokine levels and to find whether the associations with asthma were strong enough to rule out the possibility that they are secondary to the association of fatness measures with asthma. METHODS: The Global Asthma and Allergy Network of Excellence (GA(2) LEN) clinical follow-up survey is a clinical survey, embedded in a larger multi-centre cross-sectional postal survey, involving, with a case/control design, enrichment of the sample with subjects with asthma and chronic rhinosinusitis (CRS). We recorded serum leptin or adiponectin in 845 men and 1110 women in 15 centres and also anthropometric measures of fatness including body mass index and waist/hip ratio, current asthma, and specific skin prick and IgE sensitisation. We used inverse sampling-probability-weighted rank and regression statistics to measure population associations of disease outcomes with adipokines in males and females, adjusting for confounders (area, age, smoking history, and number of elder siblings) and also mutually adjusting associations with adipokines and fatness measures. RESULTS: One thousand nine hundred and fifty-five subjects aged 16-77 years had information on leptin or adiponectin levels. Leptin and leptin/adiponectin ratio were positively associated with the level of asthma, especially in females (Somers' D of leptin by asthma score, 0.20; 95% CI, 0.08-0.30; P = 0.00079). These associations were attenuated after adjusting for confounders and became non-significant after additionally adjusting for fatness measures and multiple comparisons. CONCLUSIONS AND CLINICAL RELEVANCE: Asthma levels are positively associated with serum leptin. However, we cannot rule out the possibility that this association is secondary to associations of both with fatness measures.

Aging and asthma - changes in CD45RA, CD29 and CD95 T cells subsets

Background Aging is associated with thymus involution leading to a reduction in naive T cells and to an accumulation of effector-memory cells. Apoptosis is a key mechanism to clear the immune system from activated and harmful cells. In asthma the stimulation of T cells by environmental antigens can decrease naive cells and sustain activated cells. The aim of this work was to evaluate the imbalance between CD45RA and CD29 cells during the aging process and their changes in elderly asthma and to evaluate how elderly and chronic diseases like asthma can affect susceptibility to apoptosis. Methods Elderly and young adult healthy volunteers and elderly asthmatic patients were submitted to skin prick tests, immunoglobulin determination and flow cytometry analyses of CD3, CD4, CD8, CD45RA, CD29, and CD95. Results Serum IgE was increased in allergic patients (p=0.0001). Asthmatics presented an increase in CD4 cells (p<0.05). CD45RA was significantly decreased in elderly individuals (p<0.05) and this decrease was higher in asthmatics (p<0.05). CD29 was increased in elderly healthy individuals compared to the control young group (p=0.0001). A negative correlation between CD29 and CD45RA (p<0.05) was observed. CD95 lymphocytes increased in elderly (p=0.0001) and a positive correlation between age and CD95 (p<0.05) was found. Asthmatic patients showed significant decreases in CD95 (p=0. 0001). Conclusions Naive cells are key cells in the defence against infections and their decrease in the elderly and in asthma is a bad prognosis factor. The reduction of apoptosis markers can promote the persistence of activated cells involved in chronic conditions(AU)

Aging and asthma - changes in CD45RA, CD29 and CD95 T cells subsets.

BACKGROUND: Aging is associated with thymus involution leading to a reduction in naive T cells and to an accumulation of effector-memory cells. Apoptosis is a key mechanism to clear the immune system from activated and harmful cells. In asthma the stimulation of T cells by environmental antigens can decrease naive cells and sustain activated cells. The aim of this work was to evaluate the imbalance between CD45RA and CD29 cells during the aging process and their changes in elderly asthma and to evaluate how elderly and chronic diseases like asthma can affect susceptibility to apoptosis. METHODS: Elderly and young adult healthy volunteers and elderly asthmatic patients were submitted to skin prick tests, immunoglobulin determination and flow cytometry analyses of CD3, CD4, CD8, CD45RA, CD29, and CD95. RESULTS: Serum IgE was increased in allergic patients (p=0.0001). Asthmatics presented an increase in CD4 cells (p<0.05). CD45RA was significantly decreased in elderly individuals (p<0.05) and this decrease was higher in asthmatics (p<0.05). CD29 was increased in elderly healthy individuals compared to the control young group (p=0.0001). A negative correlation between CD29 and CD45RA (p<0.05) was observed. CD95 lymphocytes increased in elderly (p=0.0001) and a positive correlation between age and CD95 (p<0.05) was found. Asthmatic patients showed significant decreases in CD95 (p=0. 0001). CONCLUSIONS: Naive cells are key cells in the defence against infections and their decrease in the elderly and in asthma is a bad prognosis factor. The reduction of apoptosis markers can promote the persistence of activated cells involved in chronic conditions.

Regulatory T cells in elderly patients with asthma.

BACKGROUND: Airway walls in asthma present an accumulation of activated cells that determine bronchial structural changes and disease progression and severity. During the aging process, the immunoinflammatory response changes as a consequence of chronic antigenic stress. OBJECTIVE: To evaluate T-cell subsets with regulatory functions associated with asthma in elderly patients METHODS: A group of 153 individuals (95 with controlled asthma and 58 healthy controls) aged over 65 years was studied. Blood samples were collected for flow cytometry analyses of CD3, CD4, CD8, CD56, CD56CD8, CD3CD4CD25, CD3CD4CD25CD127, CD4HLA-DR and TCRgamma delta. RESULTS: Asthmatic patients showed a statistically significant increase in CD4+ T cells. CD3CD4CD25high and CD3CD4CD25highCD127high cells were also significantly increased in asthmatic patients, while CD3CD4CD25highCD127low cells had similar values in asthmatics and in the control group. CD4HLA-DR cells were within the normal range in both groups. A positive correlation between CD3CD4CD25highCD127low and CD4HLA-DR was observed and gamma delta T cells were significantly decreased in the asthmatic patients compared to the controls. CONCLUSIONS: Since T cells with regulatory functions were within normal ranges or reduced in asthmatic patients compared to healthy controls, at least in basal conditions, it can be speculated that they probably play a limited role in chronic asthma in elderly patients.These data suggest an absence of a modulatory effect on the inflammatory response that characterizes asthma and allergy, which in turn would facilitate the persistence of disease in this population. Underlying inflammatory processes that are involved in chronic diseases associated with aging could provide an additional explanation for the attenuated differences observed between asthmatic and nonasthmatic individuals.

Recommendations for assessing patient-reported outcomes and health-related quality of life in patients with urticaria: a GA(2) LEN taskforce position paper.

The aim of this Global Allergy and Asthma European Network (GA(2)LEN) consensus report is to provide recommendations and suggestions for assessing patient-reported outcomes (PROs) including health-related quality of life in patients with urticaria. We recommend that PROs should be used both in clinical trials and routine practice for the evaluation of urticaria patients. We suggest that PROs should be considered as the primary outcome of future clinical trials. Two validated and disease-specific instruments for assessing PROs are available, the urticaria activity score (for symptoms) and the chronic urticaria questionnaire on quality of life CU-Q(2)oL. This latter tool, CU-Q(2)oL, is available in many languages and should be preferred, where available, over more generic instruments for assessing urticaria-specific effects on quality of life. CU-Q(2)oL is only suited for the investigation of patients with chronic spontaneous urticaria. Similar instruments for other forms of urticaria have yet to be developed and validated. Also, tools for assessing other chronic spontaneous urticaria PROs besides quality of life and symptoms are needed.

FoxP3, GATA-3 and T-bet expression in elderly asthma.

BACKGROUND: Asthma is a chronic inflammatory disorder in which Th2, Th1 and suppressive T cells (Tregs) play a role. The transcription factor FoxP3 plays a role in Treg differentiation while T-bet is important for Th1 and GATA-3 for Th2 differentiation from naïve T cells. Recent data show that age-related deregulation of Treg cells is a mechanism of senescence affecting several chronic diseases. It is crucial to understand the behaviour of these cell populations in asthma for elderly patients. OBJECTIVE: To evaluate FoxP3, GATA-3 and T-bet gene expression under basal conditions and after in vitro activation in a group of elderly asthmatic compared with age-matched healthy individuals. METHODS: Thirty-two elderly asthmatics and 17 healthy elderly individuals were selected. Serum total IgE was measured, and peripheral blood mononuclear cells (PBMCs) were isolated and stimulated in vitro with anti-CD3/anti-CD28, followed by mRNA isolation. After reverse transcription, real-time quantitative PCR was performed and relative quantification was determined 2(-ΔΔCt)(2(-ΔΔCt) method). RESULTS: The mean values and standard deviation of FoxP3, GATA-3 and T-bet relative expression for control vs. asthma were 10.2±6.8 vs. 4.8±3.8, 2.4±2.9 vs. 1.7±0.9 and 3.3±2.1 vs. 2.1±1.5, respectively. Healthy individuals showed significantly higher expression of FoxP3 and T-bet; asthmatics had a lower T-bet/GATA-3 ratio, higher serum IgE and a positive significant correlation between total IgE and GATA-3 expression. CONCLUSION AND CLINICAL RELEVANCE: Elderly asthmatic patients have lower FoxP3 mRNA expression in PBMC, which can be associated with the sustained inflammatory process and with the decreased immune tolerance by Treg cells. The T-bet deficiency and the correlation of GATA-3 expression with the increase of IgE are characteristics of long-lasting asthma. Changes related to the immunosenescence process could provide an explanation for the minor differences observed between the groups. It is important to clarify persistent modifications in long-lasting asthma in the elderly and adequate future therapeutic approaches.

Apoptosis and asthma in the elderly.

BACKGROUND: Asthma is a chronic inflammatory disorder of the airways. The persistence of airway inflammation depends on a decrease in apoptosis of T lymphocytes and eosinophils and survival of these activated cells. T lymphocytes expressing gamma delta receptors can be identified in human lungs and play an important role in immune defence against pathogens and in the regulation of chronic inflammation. Aging is associated with evidence of some immune dysregulation. OBJECTIVE: The aim of this study was to analyze the apoptosis receptors of T lymphocytes in long-lasting asthma, to establish their correlation with activation markers such as CD25+ and human leukocyte antigen (HLA)-DR+, and to analyze the gama delta T cell expression in this disease. METHODS: A group of 64 individuals (group A) who had had asthma for more than 30 years (mean age [+/-SD] 72 +/- 5 years) and 61 healthy individuals acting as controls--group B with 41 individuals (mean age 79 +/- 7 years) and group C with 20 individuals (mean age 38 +/- 12 years) were included in the study. All subjects underwent clinical evaluation and spirometric testing. Peripheral blood cells were stained with monoclonal antibodies anti-CD3, anti-CD4, anti-CD8, anti-CD25, anti-TCR gamma delta, anti-HLA-DR and anti-CD95. Statistical comparisons were performed between the asthmatics and the elderly control group and between the elderly control group and the adult control group. RESULTS: The average percentage of predicted forced expiratory volume in the first second was 73.6 gamma delta 25.3. The mean values of T cell receptors for asthma group A vs elderly control group B vs adult control group C respectively, were the following: CD3, 74.9+/-7 vs. 74.8 +/- 8.8 (P=ns) vs. 76.7 +/- 4.2 (P=ns); CD4, 48.8 +/- 8.7 vs. 43.5 +/- 10.2 (P=ns) vs. 44.8 +/- 3.8 (P=ns); CD8, 23.3 +/- 7.9 vs. 25.7 +/- 10.2 (P=ns) vs. 25.6 +/- 4.5 (P=ns); CD25, 14.3 +/- 5.9 vs. 22.4 +/- 7.8 (P = .0001) vs. 5.5 +/- 2.4 (P = .0001); TCR gamma delta, 2.8 +/- 2.1 vs. 4.1 +/- 3.3 (P < .05) vs. 4.6 +/- 2.1 (P=ns); HLA-DR, 18.4 +/- 9.2 vs. 17.8 +/- 5.9 (P=ns) vs. 15.4 +/- 5.1 (P=ns) and CD95, 49.3 +/- 13.7 vs. 52.6 +/- 12.1 (P=ns) vs. 13.8 +/- 10.8 (P = .0001). CONCLUSIONS: The immunological and inflammatory changes related to ageing may cause an increase in CD95 and CD25 T cell expression. In asthma, blood cells may express increased activation and apoptosis markers but in elderly patients taking steroids, these receptors remain within normal ranges. The number of gamma delta T cells may be lower in long-lasting asthma, and have a limited modulatory effect on allergic inflammatory reactions. The evaluation of patients with long-lasting asthma should take into account the immunological and inflammatory changes present in the elderly in order to avoid results being misinterpreted.

Elevated neopterin levels in non-allergic asthma.

Neopterin is synthesized by human monocyte-derived macrophages upon stimulation with interferon-gamma (IFN-gamma). Measurement of neopterin concentration is useful to monitor cell-mediated (Th1-type) immune activation. In this study, we aimed to analyze the behaviour of neopterin in long lasting asthma considering its role as a marker of the Th1 environment and to establish the distinction between patients belonging either to the allergic or the non-allergic population, particularly in the elderly where asthma is often under diagnosed. Therefore we evaluated allergic parameters such as skin prick tests, IgE and hemogram (eosinophils count), and we compared our findings with neopterin values found in an age-matched control population. A group of individuals older than 65 was selected. It included 64 asthmatic patients (mean age 72+/-5 years) and 41 healthy individuals (mean age 79+/-7 years). In our study population, 42 patients presented positive skin tests, mainly to house dust mites. All patients were clinically stable and presented an average percentage of predicted forced expiratory volume in the first second (FEV1) of 73.6+/-25.3 and predicted median expiratory flow percentage (MEF50) of 38.8+/-26.7. Blood cell counts showed statistically different mean values of eosinophils between allergic and non-allergic controls (5.42+/-4.7% versus 2.8+/-2.8%; p<0.04). IgE values were increased in allergic asthmatic patients when compared with non-allergic asthmatic patients (493.2+/-549.8IU/ml versus 85.3+/-194.4IU/ml; p=0.000). Allergic asthmatic patients presented mean neopterin levels similar to those found in the control group (2.4+/-2.8ng/ml versus 2.1+/-1.9ng/ml). In contrast, in non-allergic asthmatic patients these values were higher when compared with the control group (4.0+/-4.7ng/ml versus 2.1+/-1.9ng/ml). Neopterin levels were lower in allergic asthmatic patients when compared with non-allergic asthmatic patients (2.4+/-2.8ng/ml versus 4.0+/-4.7ng/ml). Within asthmatic patients, those with higher neopterin values (>2.1ng/ml) presented lower mean IgE values (IgE

The evaluation of neopterin and antioxidants in long lasting asthma.

Asthma is a condition characterised by a chronic immunoinflammatory response to different triggers. Neopterin (NPT) is synthesised by human macrophages upon stimulation with interferon-gamma and is also capable of enhancing the oxidative potential of reactive oxygen species. NPT is useful for the monitoring of cell-mediated (Th1-type) immune activation. This study analysed the behaviour of NPT in long lasting asthma, considering its role as a marker of Th1 environment. Allergic parameters (skin prick tests, Immunoglobin E (IgE), and eosinophil count) and NPT were evaluated in an asthmatic group and in a control group. We also analysed the C Reactive Protein (CRP) concentration, Total Antioxidant Status (TAS) and Superoxide Dismutase Enzyme (SOD) in both groups. A group of individuals aged over 65 years old was selected. It included 64 asthmatic patients (72+/-5 years) and 41 healthy individuals (79+/-7 years). Blood cell counts showed statistically different median values of eosinophils (5.42+/-4.7 vs 2.8+/-2.8;p<.04), IgE (493.2+/-549.8 vs 85.3+/-194.UI/ml; p=.000) and NPT was non-statistically decreased (2.4+/-2.8 vs 4.0+/-4.7 ng/ml) in allergic asthmatic patients when compared with non-allergic asthmatic patients. Both allergic and non-allergic asthmatic patients presented a statistically significant decreased expression of TAS (0.84+/-0.14/0.86+/-0.11 vs 0.91+/-0.10 mM) and SOD (584.8+/-108.7/595.6+/-235.9 vs 822.9+/-179.5) when compared with normal control subjects. Our results suggest macrophage involvement in asthma pathogenesis. The deficit in antioxidant defence impacts negatively on this disease. The increase of NPT values in non-allergic asthma consolidates these affirmations and mapping this parameter should be part of the work of an analytical study panel as it may lead to allergic asthma being distinguished from non- allergic asthma.

Neopterin in tuberculous and neoplastic pleural fluids.

Neopterin is derived from guanosine-triphosphate, produced by stimulated macrophages under the influence of gamma interferon of lymphocyte origin. It has been suggested as an excellent marker for activation of the monocyte/macrophage axis in some clinical situations. We evaluated its concentration in the pleural effusions of 25 individuals (10 tuberculous and 15 neoplastic) as well as in the blood of 22 of them (8 tuberculous and 14 neoplastic), comparing these levels with those of a control group in 99 normal individuals. The concentration of neopterin was determined by radioimmunologic assay. This showed a significant increase (p less than 0.001) of neopterin levels in the tuberculous pleural fluid, compared to the neoplastic group (42 +/- 23/17 +/- 9 nmol/L). In the blood, values were nearly identical to the pleural fluid (41.3 +/- 25/15.8 +/- 6.9 nmol/L), although with significant differences between them and in relation to the control group (p less than 0.001), which had a normal serum value (5.11 +/- 1.92 nmol/L). We emphasize the influence of the neopterin levels in the pleural fluid on the diagnosis of causes of pleurisy and its importance as a marker of immunologic cellular activity.

[Humoral immunity and the argon-laser]. / L'immunité humorale et argon-laser.

We have done two argon-laser iridotomies 24 and 72 hours before cataract surgery, to study ocular inflammation. We have taken aqueous samples to study IgA, IgG, C3 and AAT by laser immunonephelometry. All the proteins raised in the first 24 hours (P less than or equal to 0.01) except IgA in aqueous humor, taken with control levels, but only AAT (P less than or equal to 0.05), albumine at 72 hours (P less than or equal to 0.01) in aqueous humor. We tried to understand the observed gap by immunomodulation of released mediators.