Soluble interleukin-2 receptor and interleukin-4 in sera of asthmatic children before and after a prednisolone course.

BACKGROUND: Cytokine-mediated interactions among inflammatory cells may play a role in the pathogenesis of bronchial asthma. OBJECTIVE: To understand the role of soluble interleukin-2 receptor (sIL-2R) and interleukin-4 (IL-4) in the disease activity of acute asthma, changes in serum concentrations of sIL-2R and IL-4 elaborated by activated T-lymphocyte before and after prednisolone therapy with clinical improvement were determined in the present study. METHODS: Circulating levels of sIL-2R and IL-4 in sera from 15 normal control subjects and in sera from 20 allergic asthmatic children with acute exacerbation and in a stable condition were determined by using commercially available ELISA kits. RESULTS: The mean concentration of serum sIL-2R was significantly higher in acute exacerbation than in children with stable asthma (368.9 +/- 395.4 pg/mL vs 291.2 +/- 361.0 pg/mL; P < .01) or in control subjects (124.6 +/- 17.8 pg/mL; P < .001). The mean concentration of serum IL-4 was higher in acute exacerbation (5.82 +/- 1.10 pg/mL) and in stable asthmatic patients (6.73 +/- 2.83 pg/mL) versus control group subjects (5.54 +/- 1.20 pg/mL). However, the difference was not statistically significant among the three study groups. CONCLUSIONS: This study provides further evidence that changes in serum IL-2R may serve as an objective indicator for clinical outcome of allergic asthmatic patients.     

A randomized, double‐blind trial of the effect of glucocorticoid, antileukotriene and bβ‐agonist treatment on IL‐10 serum levels in children with asthma

BACKGROUND: Levels of an immunoregulatory and anti-inflammatory cytokine IL-10 are reduced in asthmatic airways, potentially contributing to more intense inflammation. Triamcinolone has anti-inflammatory properties and the anti-inflammatory effects of montelukast and formoterol have been discussed. OBJECTIVE: The purpose of this study was to define the effect of treatment with triamcinolone, montelukast and formoterol on the serum level of IL-10, eosinophil blood counts, eosinophil cationic response (ECP) and clinical parameters (symptom score, FEV1 and PC20H) in children with moderate asthma. METHODS: An 8-week, placebo-controlled and randomized, double-blind trial was carried out. The subjects were 91 children with moderate atopic asthma who were allergic to dust mite. Patients were randomly allocated to receive 400 microg triamcinolone (n = 19), 5 or 10 mg (according to age) montelukast (n = 18), 24 microg formoterol (n = 18) or placebo (n = 36). RESULTS: Seventy-nine children completed the study. After treatment with triamcinolone and montelukast the level of IL-10 in blood serum significantly increased, eosinophil blood counts and ECP levels significantly decreased and all clinical parameters improved; treatment with formoterol had no effect on IL-10 level, eosinophil blood counts in serum and bronchial hyper-reactivity; ECP level significantly decreased after treatment and asthma symptoms and FEV1 improved significantly. Mean IL-10 levels in serum before and after treatment with triamcinolone were 7.23 pg/mL with 95% CI, 6.74 -7.72% and 14.24 pg/mL with 95% CI, 11.6-16.88%, respectively (P < 0.001); with montelukast they were 6.59 pg/mL with 95% CI, 6.26-7.23% and 10.94 pg/mL with 95% CI, 8.24-12.65%, respectively (P < 0.002); with formoterol they were 7.06 pg/mL with 95% CI, 6.61-7.52% and 7.04 pg/mL with 95% CI, 6.15-7.93%. We found statistically significant correlations between serum level of IL-10 and serum level of ECP after treatment with triamcinolone and montelukast. CONCLUSION: This study demonstrates that one possible way by which triamcinolone and montelukast contribute to inhibition of inflammation is by increasing IL-10 levels.     

Correlation of nasal inflammation and nasal airflow with forced expiratory volume in 1 second in patients with perennial allergic rhinitis and asthma.

BACKGROUND: Allergic rhinitis and asthma are frequently associated and are characterized by TH2-dependent inflammation. Nasal and bronchial obstruction largely depend on allergic inflammation. OBJECTIVE: To evaluate the relationships among nasal eosinophil counts, interleukin 4 (IL-4) and interferon-gamma (IFN-gamma) levels, nasal airflow, and forced expiratory volume in 1 second (FEV1) in patients with perennial allergic rhinitis and asthma. METHODS: Eight men and 7 women (mean +/- SD age, 24.8 +/- 4.7 years) with perennial allergic rhinitis and asthma were evaluated. All 15 patients had a moderate-to-severe grade of nasal obstruction. Total symptom score, rhinomanometry, nasal lavage, nasal scraping, and spirometry were evaluated in all patients. Eosinophils were counted using conventional staining; IL-4 and IFN-gamma levels were measured by immunoassay in fluids recovered from nasal lavage. RESULTS: Significant positive relationships were demonstrated between eosinophil infiltration and IL-4 levels, nasal airflow and IFN-gamma levels, FEV1 and IFN-gamma levels, and nasal airflow and FEV1 (P < .001 for all). Significant negative relationships were demonstrated between eosinophil infiltration and IFN-gamma levels, IL-4 and IFN-gamma levels, eosinophil infiltration and nasal airflow, IL-4 values and nasal airflow, nasal eosinophil counts and FEV1, and IL-4 values and FEV1 (P < .001 for all). CONCLUSIONS: There is a close association between TH2 cytokines and eosinophil infiltration in the nose. There is also clear evidence concerning the relationships among eosinophil infiltration, IL-4 and IFN-gamma levels, and nasal airflow. Nasal eosinophil, IL-4, and IFN-gamma levels correlate with FEV1. Finally, nasal airflow is related to FEV1. These findings constitute the first evidence of a relationship between TH2-related nasal inflammation and nasal and bronchial airflow in patients with perennial allergic rhinitis and asthma.     

Upregulation of Th1 cytokine profile (IL-12, IL-18) in bronchoalveolar lavage fluid in patients with pulmonary sarcoidosis.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, is characterized by a predominantly Th1 cytokine milieu, which is involved in its immunopathogenesis. The role of novel immunologic markers reflecting T cell activity of the sarcoid immunologic response needs to be determined. The present study aims to evaluate the role of the Th1 cytokine pattern by estimating the local and systemic levels of interleukin-12 (IL-12) and IL-18 in bronchoalveolar lavage fluid (BALF), induced sputum, and serum of patients with pulmonary sarcoidosis. We studied prospectively 20 patients (12 women, 8 men) of median age 46 years (range 25-65) with sarcoidosis and 10 normal subjects (5 women, 5 men) of median age 39 years (range 26-60). IL-12 and IL-18 levels were measured using ELISA kits. The IL-12 BALF levels were significantly higher in sarcoidosis patients than in healthy subjects (5.64 +/- 0.21 pg/mL vs. 5.16 +/- 0.15 pg/mL, p < 0.001). In addition, IL-18 levels were significantly increased in BALF samples (47.69 +/- 6.29 pg/mL vs. 16.73 +/- 3.00 pg/mL, p < 0.001). A statistically significant decrease in IL-12 serum levels was detected in the sarcoid population compared with controls (5.77 +/- 0.50 pg/mL vs. 7.87 +/- 2.00 pg/mL, p < 0.001). No significant differences were detected in IL-12 and IL-18 levels between patients and controls in induced sputum samples. Our data suggest a potential role of IL-12 and IL-18 in the local immunologic response in pulmonary sarcoidosis. Further large-scale studies are needed to define the precise role of IL-12 and IL-18 in the immunopathogenesis of this disorder.     

Squamous cell carcinoma-related antigen in children with acute asthma.

BACKGROUND: Increased serum levels of squamous cell carcinoma-related antigen (SCCA) have been observed in patients with allergic disorders, such as atopic dermatitis and bronchial asthma. T(H)2 cytokines, which are known to be involved in the pathogenesis of allergic disorders, stimulate new synthesis of SCCA in cultured human airway epithelial cells. OBJECTIVE: To investigate whether SCCA levels increase during acute exacerbations of asthma in children and whether the T(H)2 cytokines, interleukin 4 (IL-4) and IL-13, are associated with SCCA levels. METHODS: Serum levels of SCCA, IL-4, and IL-13 were measured by enzyme immunoassay during the acute phase of an asthma exacerbation (on hospital admission) and in the recovery phase (after symptoms had subsided). RESULTS: In the 35 children who participated in this study, serum levels of SCCA were significantly elevated in the acute phase (mean +/- SD, 3.09 +/- 2.03 ng/mL) compared with the recovery phase (mean +/- SD, 1.47 +/- 0.64 ng/mL) of an asthma exacerbation (P < .001). In 12 children, the IL-13 levels were observed to correlate with SCCA levels during the recovery phase (r = 0.68, P = .02) but not during the acute phase of an asthma exacerbation. CONCLUSIONS: Serum SCCA levels increase during the acute phase of an asthma exacerbation. During this phase, the increased synthesis of SCCA is not associated with IL-13 but rather mediated by other undefined stimuli. IL-13 may contribute to the basal production of SCCA in asthmatic children.     

Intravenous immunoglobulin treatment in women with recurrent abortions: increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood

PROBLEM: The aim of this study was to investigate changes in peripheral blood Th1/Th2 cytokine levels and lymphocyte ratios after massive intravenous immunoglobulin (MIVIg) treatment for women with recurrent spontaneous abortion (RSA) of unexplained etiology. METHOD OF STUDY: Serum Th1 (IFN-gamma, TNF-alpha) and Th2 cytokine (IL-4, IL-10) levels were assessed by ELISA methods (n = 9) and peripheral blood Th1/Th2 lymphocyte ratios (n = 4) by flow cytometry before and after MIVIg treatments in women with four or more consecutive RSA. RESULTS: Pre-treatment serum IFN-gamma (0.06 +/- 0.09 pg/mL, mean +/- SD), TNF-alpha (0.21 +/- 0.45 pg/mL), IL-4 (0.70 +/- 1.16 pg/mL), and IL-10 (1.12 +/- 1.67 pg/mL) increased to 0.17 +/- 0.16 pg/mL, 0.77 +/- 0.28 pg/mL, 1.82 +/- 0.89 pg/mL, and 3.44 +/- 0.48 pg/mL, respectively, after MIVIg treatments (P < 0.05). CD4-positive IFN-gamma/IL-4 lymphocyte ratios (17.3 +/- 9.1) were reduced to 11.5 +/- 7.1 after treatment (P < 0.05). CONCLUSIONS: Massive intravenous immunoglobulin treatments increased peripheral blood cytokine levels and decreased Th1/Th2 lymphocyte ratios; thus, MIVIg treatments modify the peripheral Th1/Th2 balance.     

Interleukin-18 is high in the serum of IVF pregnancies with ovarian hyperstimulation syndrome

PROBLEM: The presence of interleukin-18 (IL-18) in serum and pre-ovulatory follicular fluid (FF) and its possible correlation to in-vitro fertilization/embryo transfer (IVF/ET) outcome and ovarian hyperstimulation syndrome (OHSS) development. METHOD OF STUDY: A prospective study was carried out. Assays for serum and pooled pre-ovulatory FF levels of IL-18 were performed on 30 patients who underwent oocyte retrieval for IVF/ET. RESULTS: Mean serum and FF levels of IL-18 were 370.4 +/- 224 and 228.9 +/- 208 pg/mL, respectively (r = 0.77, P < 0.0001). Levels of FF IL-18 were comparable between the two ovaries (right = 221 +/- 166.8 pg/mL, left = 237 +/- 171.9 pg/mL; r = 0.7550, P = 0.49). A positive correlation was found between IL-18 FF levels and number of retrieved oocytes (r = 0.45; P = 0.019). In three patients (10%) who developed OHSS, the mean serum level of IL-18 at day of ovum pickup was significantly higher compared with patients without OHSS (620 +/- 196 pg/mL versus 345 +/- 251 pg/mL, respectively, P = 0.04). CONCLUSIONS: Both pre-ovulatory FF and serum levels of IL-18 correlate with the number of retrieved oocytes. The serum IL-18 level at day of ovum pickup may predict consequent development of OHSS. Further investigations are warranted to determine the role of IL-18 in the folliculogenesis and OHSS pathogenesis.     

Thrombopoietin and interleukin-6 levels in Henoch-Sch?nlein purpura.

BACKGROUND AND PURPOSE: Depending on the severity of the illness, thrombocytosis is found in about 60% to 70% of patients with Henoch-Sch?nlein purpura (HSP). Whether thrombocytosis is the result of an inflammatory reaction mediated by thrombopoietin (TPO) or other inflammatory cytokines such as interleukin (IL)-6 remains unknown. METHODS: Thirty two patients who met the diagnostic criteria for HSP were included. They were divided into two groups - HSP patients with thrombocytosis (n = 14) and those without thrombocytosis (n = 18) with a platelet count of 400,000/microL. Eight normal healthy controls were also included. TPO and IL-6 serum levels during the acute phase were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with platelet counts greater than 400,000/microL in the acute stage had significantly lower TPO levels than patients with platelet counts lower than 400,000/microL (310 +/- 65.6 pg/mL vs 608 +/- 97.8 pg/mL, p=0.013). However, HSP patients with or without thrombocytosis had similar TPO levels as the healthy controls (441 +/- 176 pg/mL, p=0.89 and 0.29, respectively). IL-6 serum levels were significantly elevated in HSP patients during the acute stage of HSP (28.6 +/- 61.7 pg/mL vs 3.16 +/- 1.35 pg/mL, p=0.049). In patients with complications of glomerulonephritis or gastrointestinal hemorrhage (n = 12), IL-6 levels were significantly lower than in those without such complications (8.07 +/- 3.79 pg/mL vs 40.9 +/- 16.9 pg/mL, p=0.007). CONCLUSIONS: This study showed that thrombocytosis in HSP patients is a type of inflammatory reactive thrombocytosis, and that IL-6 may also play a role in the pathogenesis of HSP.     

Elevated serum melatonin is associated with the nocturnal worsening of asthma

BACKGROUND: Increased airway inflammation at night contributes to the nocturnal worsening of asthma. In vitro studies have shown exogenous melatonin to be pro-inflammatory in asthma, but it is unknown whether endogenous melatonin levels are a controller of airway inflammation in nocturnal asthma. OBJECTIVE: Our aim was to determine 24-hour patterns of serum melatonin and their relationship to overnight decline in physiology in subjects with nocturnal asthma, non-nocturnal asthma, and in healthy controls. METHODS: Observational study of pulmonary physiology and melatonin levels in patients with nocturnal asthma (n = 7), non-nocturnal asthma (n = 13), and healthy controls (n = 11). Subjects maintained a constant sleep-wake regimen for 7 days. On day 8, serum melatonin was measured every 2 hours by radioimmunoassay and analyzed by cosinor modeling. The correlation between serum melatonin levels and overnight change in spirometry was evaluated by Spearman's rank correlation analysis. RESULTS: In subjects with nocturnal asthma, peak melatonin levels were significantly elevated compared with healthy controls (67.6 +/- 5.0 pg/mL versus 53.5 +/- 4.0 pg/mL, P =.03). Melatonin acrophase was delayed in nocturnal asthma (02:54 versus 01:58 in healthy controls, P =.003, and 02:15 in non-nocturnal asthma, P =.01). In subjects with nocturnal asthma, increasing melatonin levels were significantly and inversely correlated with overnight change in FEV(1) (r = -.79, P =.04), a relationship that was not observed in non-nocturnal asthma or healthy controls. CONCLUSIONS: Nocturnal asthma is associated with elevation and phase delay of peak serum melatonin levels. Elevated melatonin levels might contribute to the pathogenesis of nocturnal asthma.     

Effect of desloratadine on epithelial cell granulocyte-macrophage colony-stimulating factor secretion and eosinophil survival

BACKGROUND: Second-generation antihistamines are H(1) receptor antagonists and may have additional anti-inflammatory effects. OBJECTIVE: The aims of the study were to evaluate the effect of desloratadine (DL) on cytokine secretion by epithelial cells from both nasal mucosa (NM) and polyps (NP), and on eosinophil survival primed by epithelial cell secretions. METHODS: Epithelial cells were cultured and stimulated with fetal bovine serum (FBS), IL-1beta or TNF-alpha with and without DL for 24 h. Culture supernatant cytokines concentration were measured by ELISA. Peripheral blood eosinophils were incubated with human epithelial cell conditioned media (HECM) and DL. Eosinophil survival was assessed by Trypan blue dye exclusion. Results are expressed as mean+/-SEM of cytokine concentration (pg/mL) or eosinophil survival index (%). RESULTS: FBS increased granulocyte-macrophage colony-stimulating factor (GM-CSF), vascular endothelial growth factor (VEGF), IL-6, IL-8, and TGF-beta(1) secretion in epithelial cell cultures from both NM and NP. Only GM-CSF secretion was significantly (P<0.05) inhibited by a dose-response of DL compared with positive controls, in both NM (10(-5) m: 125+/-36 pg/mL, 10(-6) m: 95+/-22 pg/mL vs. control: 256+/-91 pg/mL, n=6) and NP (10(-5) m: 80+/-29 pg/mL, 10(-6) m: 109+/-45 pg/mL vs. control: 333+/-212 pg/mL, n=6). DL also showed an inhibitory effect on HECM-induced eosinophil survival from both NM and NP. At 72 h, DL significantly (P<0.01) inhibited eosinophil survival induced by HECM from NM (10(-5) m: 19.9+/-5.5%, n=9; 10(-6) m: 28.7+/-7.7%, n=9) and NP (10(-5) m: 6.2+/-2.8%, n=11) compared with HECM alone (NM: 42.1+/-7.3%; NP: 45.3+/-8.1%). CONCLUSION: The inhibitory effects of DL on epithelial cell GM-CSF secretion and on eosinophil survival induced by epithelial cell secretions, suggest that this H(1) antagonist may regulate eosinophil inflammation in upper airways.     

A single nasal allergen challenge increases induced sputum inflammatory markers in non-asthmatic subjects with seasonal allergic rhinitis: correlation with plasma interleukin-5

BACKGROUND: Seasonal allergic rhinitis (SAR) is a risk factor for asthma in affected individuals. Nasal allergic inflammation enhances bone-marrow eosinophil production, mainly via IL-5, and rhinitis patients have increased airway inflammation during the pollen season. OBJECTIVE: To assess the impact of nasal allergy on sputum inflammatory markers. METHODS: In an open-labelled, randomized, placebo-controlled cross-over study with 16 non-asthmatic SAR patients (median age 25 years, 56% males), the effect of a single nasal allergen challenge performed out of season on induced sputum inflammatory parameters was evaluated. SAR patients were identified by history, skin-prick test and specific IgE. All patients had normal lung function/bronchial hyper-responsiveness out of season and a negative asthma/wheezing history. Sputum cells and supernatant levels of ECP, sICAM, IL-5 and IL-10, and plasma levels of IL-5 and ECP, were measured before and 24 h after nasal allergen challenge. After a washout period of at least 4 weeks, the procedure was repeated with placebo challenge (diluent). RESULTS: Nasal allergen challenge led to an increase in sputum ECP (pre = 60 +/- 12, post = 212 +/- 63 micro g/L, P = 0.02 vs. placebo), and sICAM (4.8 +/- 2.7 to 6.5 +/- 2.9 ng/mL, P = 0.02 vs. placebo), whereas IL-10 decreased after provocation (44 +/- 11 to 29 +/- 6 pg/mL, P = 0.06 vs. placebo). Sputum IL-5 was undetectable in all patients. The absolute number of blood and sputum eosinophils did not change significantly after allergen or placebo challenge (P > 0.07, both comparisons). Plasma levels of IL-5 increased after allergen challenge (8.7 +/- 2.9 to 14.5 +/- 3.9 pg/mL, P = 0.001), and the increase in plasma IL-5 was positively correlated with the rise in sputum ECP in a subgroup of 'responders' (n = 12, r = 0.71, P = 0.01). CONCLUSIONS: A single nasal allergen challenge in SAR patients increased markers of allergic inflammation in the lower respiratory tract, possibly via pronounced activation of inflammatory cells through circulating immediate-type reaction cytokines like IL-5. These findings may provide additional explanatory data for the high susceptibility of SAR patients to incident asthma.     

Developmental cytokine response profiles and the clinical and immunologic expression of atopy during the first year of life

BACKGROUND: Allergic diseases have been linked to abnormal patterns of immune development, and this has stimulated efforts to define the precise patterns of cytokine dysregulation that are associated with specific atopic phenotypes. OBJECTIVE: Cytokine-response profiles were prospectively analyzed over the first year of life and compared with the clinical and immunologic expressions of atopy. METHODS: Umbilical cord and 1-year PBMCs were obtained from 285 subjects from allergic families. PHA-stimulated cytokine-response profiles (IL-5, IL-10, IL-13, and IFN-gamma) were compared with blood eosinophil counts and total and specific IgE levels (dust mites, cat, egg, Alternaria species, peanut, milk, and dog) at age 1 year and at the development of atopic dermatitis and food allergy. RESULTS: For the cohort as a whole, cytokine responses did not evolve according to a strict TH1 or TH2 polarization pattern. PHA-stimulated cord blood cells secreted low levels of IL-5 (2.1 pg/mL), moderate levels of IFN-gamma (57.4 pg/mL), and greater amounts of IL-13 (281.8 pg/mL). From birth to 1 year, IL-5 responses dramatically increased, whereas IL-13 and IFN-gamma responses significantly decreased. Reduced cord blood secretion of IL-10 and IFN-gamma was associated with subsequent sensitization to egg. In addition, there was evidence of TH2 polarization (increased IL-5 and IL-13 levels) associated with blood eosinophilia and increased total IgE levels by age 1 year. CONCLUSION: These findings demonstrate that cytokine responses change markedly during the first year of life and provide further evidence of a close relationship between TH2 skewing of immune responses and the incidence of atopic manifestations in children.     

Maternal serum levels of interferon-gamma and interleukin-2 soluble receptor-alpha predict the outcome of early IVF pregnancies

BACKGROUND: Elevated maternal serum levels of interleukin-2 soluble receptor-alpha (IL-2 sRalpha), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) have been associated with pregnancy loss. The aim of our study was to evaluate the predictive value of these cytokines in the outcome of early IVF pregnancies. METHODS: One hundred and fifty-nine consecutive IVF patients who were subsequently diagnosed to have a biochemical pregnancy (n = 23), a first-trimester miscarriage (n = 19) or a normal term delivery (n = 117) were included in this study. Serum was collected from the initial pregnancy test, 11 days after a day 3 embryo transfer, and all samples were analysed for IL-2 sRalpha, TNF-alpha and IFN-gamma by commercially available enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: IL-2 sRalpha levels were significantly higher in patients with an early pregnancy loss compared with patients with a normal term delivery (849.5 +/- 69.6 versus 693.5 +/- 31.2 pg/ml, P = 0.02), and a cut-off point of IL-2 sRalpha >1000 pg/ml predicted a poor pregnancy outcome (44.4 versus 22.7% pregnancy loss, IL-2 sRalpha >or=1000 versus IL-2 sRalpha <1000 pg/ml; P = 0.02). IFN-gamma-positive patients had twice the risk for poor IVF pregnancy outcome compared with IFN-gamma-negative subjects (40.8 versus 20.0%, respectively; P < 0.02), including a significantly lower implantation rate (37.6 +/- 0.05 versus 50.0 +/- 0.03%, respectively; P = 0.02). There was no difference in pregnancy outcome based upon serum levels, or the ability to detect the presence of TNF-alpha. No differences in levels of these cytokines were found based on the aetiology of the patients' infertility. CONCLUSIONS: Elevated maternal serum levels of IL-2 sRalpha and IFN-gamma as early as 11 days after embryo transfer are associated with poor IVF pregnancy outcome.     

Th1 cytokine pattern in sarcoidosis is expressed by bronchoalveolar CD4+ and CD8+ T cells

The pathogenesis of pulmonary sarcoidosis has been related to an increased production of Th1-like cytokines. However, cytokine expression in sarcoidosis has not been systematically studied at a single-cell level. We therefore investigated the expression of IL-2, IL-4, IL-13, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) intracellularly in bronchoalveolar lavage (BAL) and peripheral blood CD3+ T lymphocytes from patients with pulmonary sarcoidosis (radiologic stage II-III, n = 8) and normal controls (n = 9) by flow cytometry. In contrast to IL-4 and IL-13, the percentage of T lymphocytes expressing intracellular IL-2 (49.3 +/- 21.3% versus 14.5 +/- 15.6%), IFN-gamma (75.5 +/- 14.9% versus 32.6 +/- 18.7%) and TNF-alpha (68.3 +/- 18.7% versus 36.8 +/- 20.8%) was significantly higher in patients with sarcoidosis than in normal controls (each P < 0.005). In contrast to BAL lymphocytes, expression of these cytokines in peripheral blood lymphocytes did not differ between patients with sarcoidosis and normal controls. Close correlations were observed between the percentages of BAL lymphocytes expressing intracellular IL-2, IFN-gamma and TNF-alpha, but not for IL-4 or IL-13. Analysis of the expression of these cytokines in T lymphocyte subsets revealed IL-2, IFN-gamma, and TNF-alpha in CD4+ as well as CD8+ T lymphocytes, suggesting a contribution of TC1 cells to the production of proinflammatory cytokines in sarcoidosis. We conclude that a Th1-like cytokine pattern can be observed in CD4+ as well as in CD8+ BAL T lymphocytes in patients with pulmonary sarcoidosis.     

Serum concentrations of interferon-γ and intercellular adhesion molecule-1 eight years after an early respiratory syncytial virus infection

BACKGROUND: Respiratory syncytial virus (RSV) infection may influence the development of recurrent wheezing and atopy, but the mechanisms are unclear. OBJECTIVE: The purpose was to evaluate serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), CD14, IgE, IL-5 and IFN-gamma in children 6-10 years after an RSV infection and their correlation with subsequent asthma and atopy. METHODS: Fifty-one subjects admitted to hospital for RSV infection during the first year of life and controls matched for birth date and sex underwent clinical examinations including lung function, skin prick and blood tests. RESULTS: The RSV subjects had significantly higher serum concentrations of IFN-gamma and sICAM-1 than the controls (for IFN-gamma 224.9 pg/mL (standard deviation (SD) 271.3) vs. 187.1 pg/mL (372.9), difference 37.8 pg/mL, 95% confidence interval (CI) -90.3 to 166.0, P = 0.05; for sICAM-1 170.2 ng/mL (SD 63) vs. 147.8 ng/mL (SD 57), difference 22.4 ng/mL, 95% CI -1.4 to 46.1, P = 0.04). The RSV subjects with asthma had significantly higher concentrations of IFN-gamma than the controls with asthma, and the RSV subjects with wheezing during the previous 12 months had significantly higher concentrations of both IFN-gamma and sICAM-1 than the controls with wheezing. CONCLUSIONS: Children hospitalized for RSV infection in infancy still differ in IFN-gamma and sICAM-1 production 6-10 years after the infection. The data suggest that the pathomechanism of asthma and wheezing after an early RSV infection may be different from that of children without an early RSV infection.     

Sex-related differences in immune development and the expression of atopy in early childhood

BACKGROUND: Sex and age are known to influence the clinical expression of asthma and allergic diseases. OBJECTIVE: We sought to evaluate whether immune response profiles also vary by sex and age. METHODS: We performed a prospective birth cohort study (Childhood Origins of Asthma) designed to evaluate interactions among age, sex, immune responses, and virus infections on the development of asthma and allergic diseases. Two hundred eighty-nine subjects were enrolled at birth, and 275 maintained prospective follow-up for 3 years. Cytokine response profiles at birth, 1, and 3 years of age; rates of wheezing, atopic dermatitis, and viral illnesses; and biomarkers of atopy, including total and specific IgE levels and peripheral eosinophil counts, were evaluated. RESULTS: PHA-induced IFN-gamma responses were higher in boys at 1 year of age (median, 35 vs 19 pg/mL; P < .001) and at 3 years of age (median, 282 vs 181 pg/mL; P = .07). Among children who wheezed during the third year of life, boys had increased IFN-gamma, IL-5, and IL-13 responses at age 3 years (P < .001, P = .008, and P = .01, respectively). Boys also demonstrated increased rates of sensitization (P = .05 at year 1), total IgE levels (P = .03 at year 1 and P = .006 at year 3), and peripheral eosinophil counts (2.62 vs 1.85; P = .05 at year 3). CONCLUSION: Sex-specific differences in immune responses develop during early childhood; some of these differences developmentally proceed, whereas others occur in parallel to the clinical expression of various atopic phenotypes. CLINICAL IMPLICATIONS: The differential expression of atopic diseases between boys and girls in early childhood is accompanied by sex-specific differences in immune response profiles.     

Eosinophilia, interleukin-5, and tumour necrosis factor-alpha in asthmatic children

BACKGROUND: There are few paediatric studies of the interrelationships between inflammatory markers and asthma severity. We therefore assessed the relationships between eosinophil-associated markers, cytokines, and asthma severity in asthmatic children aged 8-12 years. METHODS: Forty-five children were tested twice, 2 weeks apart. Asthma severity was measured in terms of symptoms, lung function, medication needs, and histamine responsiveness. Peripheral inflammatory markers measured included eosinophil numbers, serum ECP, IL-5, and TNF-alpha and mononuclear cell IL-5, and TNF-alpha production. RESULTS: Histamine responsiveness was correlated with circulating eosinophils (r = 0.56, P = 0.0001) and serum ECP (r = 0.54, P = 0.003). Eosinophilia was increased in children with severe as opposed to mild airway hyperresponsiveness (P = 0.02) and those who lost days at school as opposed to those who did not (P = 0.01). There were no other associations between markers of asthma severity and inflammation. Children taking inhaled corticosteroids had lower serum IL-5 levels than those on beta-agonists +/- cromolyn (mean and 95% CI: 20.5 [11.7-35.7] pg/ml vs 64.3 [26.6-155.4] pg/ml; P = 0.04). Cellular IL-5 production correlated with serum TNF-alpha (r = 0.63, P = 0.0062) and IL-5 (r = -0.59, P = 0.005). CONCLUSION: Serum levels of TNF-alpha and IL-5 were not related to peripheral eosinophilia and asthma severity in these children but were related to their own cellular production ex vivo. This study confirms that eosinophilia is the index of inflammation that is most closely related to the clinical severity of childhood asthma.     

Association of interleukin-5 and eotaxin with acute exacerbation of asthma

BACKGROUND: Airway eosinophilia is frequently observed during acute exacerbation of asthma. Interleukin-5 (IL-5) and eotaxin are directly involved in the airway eosinophilia found in persistent asthma. Interrelation between these cytokines is expected to occur in acute exacerbation of asthma. Thus, we evaluated the relevance of interaction between eotaxin and IL-5 in the airway inflammation of acute exacerbation. METHODS: We measured the number of inflammatory cells and the amount of eotaxin and IL-5 in sputum from 22 healthy subjects, 21 asthmatics with acute exacerbation and 16 patients with mild persistent asthma, and reassessed these values in 7 subjects with acute exacerbation after 7 days' treatment with systemic steroid (2 mg/kg/day). Sources of IL-5 and eotaxin were investigated by immunohistochemical staining of sputum cells of 4 cases from each group. RESULTS: Both IL-5 and eotaxin levels were higher in patients with acute exacerbation of asthma than in patients with persistent asthma and normal subjects. IL-5 and eotaxin levels were significantly correlated with eosinophil percentages in mild persistent asthma. Eotaxin staining was found mainly on macrophages and occasionally on eosinophils. Steroid treatment markedly decreased eosinophil percentages and IL-5 levels within 7 days but did not alter eotaxin levels. CONCLUSIONS: Both IL-5 and eotaxin are associated with acute exacerbation of asthma. IL-5 rather than eotaxin is effectively decreased by the inhibitory effect of steroid in acute exacerbation.     

IFN-gamma-induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations

BACKGROUND: Rhinovirus-induced acute asthma is the most frequent trigger for asthma exacerbations. OBJECTIVE: We assessed which inflammatory mediators were released from bronchial epithelial cells (BECs) after infection with rhinovirus and then determined whether they were also present in subjects with acute virus-induced asthma, with the aim to identify a biomarker or biomarkers for acute virus-induced asthma. METHODS: BECs were obtained from bronchial brushings of steroid-naive asthmatic subjects and healthy nonatopic control subjects. Cells were infected with rhinovirus 16. Inflammatory mediators were measured by means of flow cytometry with a cytometric bead array. Subjects with acute asthma and virus infection were recruited; they were characterized clinically by using lung function tests and had blood taken to measure the inflammatory mediators identified as important by the BEC experiments. RESULTS: IFN-gamma-induced protein 10 (IP-10) and RANTES were released in the greatest quantities, followed by IL-6, IL-8, and TNF-alpha. Dexamethasone treatment of BECs only partially suppressed IP-10 and TNF-alpha but was more effective at suppressing RANTES, IL-6, and IL-8. In acute clinical asthma serum IP-10 levels were increased to a greater extent in those with acute virus-induced asthma (median of 604 pg/mL compared with 167 pg/mL in those with non-virus-induced acute asthma, P < .01). Increased serum IP-10 levels were predictive of virus-induced asthma (odds ratio, 44.3 [95% CI, 3.9-100.3]). Increased serum IP-10 levels were strongly associated with more severe airflow obstruction (r = -0.8; P < .01). CONCLUSIONS: IP-10 release is specific to acute virus-induced asthma. CLINICAL IMPLICATIONS: Measurement of serum IP-10 could be used to predict a viral trigger to acute asthma.