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Notes: Background:  Allergic asthma is an increasingly common disease of complex inheritance. Several studies have suggested candidate regions, but genetic heterogeneity, ethnic differences and varying study designs may in part explain the lack of identified and confirmed susceptibility genes. Investigation of different populations will further clarify the topic. We therefore evaluated allergic asthma and increased total and specific IgE in 39, 45 and 57 sib-pairs from 100 Danish allergy families. Methods:  Affected sib-pairs meeting a narrow phenotype definition were selected for the three phenotypes atopy, allergic asthma and increased total IgE. We performed a total genome scan using 446 microsatellite markers and obtained nonparametric linkage results from the MAPMAKER/SIBS computer program. Results:  Our study revealed four candidate regions (MLS 〉 2) on chromosome 1p36, 3q21–q22, 5q31 and 6p24–p22, and 15 candidate regions (1 〈 MLS 〈 2) that may contain susceptibility genes for asthma and atopy. We did not find linkage to the candidate genes TNF-β, FcER1β and Il4R-α, except for weak support for linkage of the asthma phenotype to TNF-β (MLS = 1.18). Conclusions:  We found evidence for two new asthma and atopy loci, 1p36 and 3q21–q22, and supported linkage in the Danish population to seven previously reported candidate regions.

Notes: T lymphocytes play a major role in many immune responses. In the last decade, special focus has been on the function of Th1 and Th2 effector cells. Now the importance of regulatory CD4+CD25+ T cells in maintenance of the immunological homeostasis emerges. Sarcoidosis is a multisystem granulomatous disorder often affecting the lungs. The typical sarcoid granulomas consists of epitheloid cells, macrophages and lymphocytes, mainly CD4+ T cells of Th1 phenotype. We have cultured T cells from bronchial biopsies of patients with sarcoidosis as well as from controls in high levels of interleukin 2 (IL-2) and IL-4 and demonstrate spontaneously arising CD4+ CD25+ populations and high concentrations of IL-10 in these cultures. The main difference between cultures of sarcoid origin compared to controls is a very much higher concentration of the inflammatory cytokines IL-6 and TNF-α in cultures of sarcoid origin.

Notes: Combining inhaled long-acting β-2 agonist (LABA) and inhaled corticosteroid (ICS) seems to offer asthma control at a lower dose of ICS than achieved by ICS alone. Fine mapping of T-cell surface markers by flow cytometry offers a detailed status of the individual's inflammatory response. The frequency of MT2 (CD4+CD45RA–CD62L+CD11adim) and MT1 (CD4+CD45RA–CD62L–CD11abright) cells in peripheral blood, and their ratio, has been shown to differ predictably in atopics and patients with leprosy, where MT2 correlates with a Th2 phenotype and MT1 with a Th1 phenotype. Stable asthmatics, requiring fluticasone propionate (FP) 750–1000 µg daily or equivalent, were randomized to receive, double-blinded, either Seretide®[salmeterol and fluticasone propionate (SFC, n = 16)] 50 µg/500 µg bd or FP 500 µg bd (n = 17). If asthma was controlled based on lung function and symptoms at clinic visits every 6 weeks, ICS dose was tapered until asthma exacerbated or 0 µg was reached. The frequency and ratio of MT2 and MT1 T cells of the patients was monitored at 6 week intervals. As treatment tapered, the frequency of MT2 cells decreased (P = 0038 from first to final visit), whereas that of MT1 cells increased. The ratio of MT2/MT1 decreased (P = 0049 from first to final visit). In patients receiving LABA + ICS, the fall in MT2/MT1 ratio appeared to be more pronounced than in patients receiving ICS alone. Thus, the MT2 phenotype may be associated with stable asthma, whereas an imminent exacerbation may associate with an increase in the MT1 phenotype. LABA may allow for a greater effect of FP on the MT ratio.

Notes: Background Atopy is closely associated with the cellular T helper type-2 (Th2) phenotype, that is dominated by the pleiotrophic cytokine IL-4. The cellular source of IL-4 has yet to be determined, although basophils have been proposed. Eosinophils and mast cells are likely contenders investigated here, and the eosinophil-like leukaemia line AML14.3D10 is compared to eosinophils as an in vitro culturable model for eosinophils. Lectins can cross-link-specific surface glycoproteins and are found in the ingested (processed foods) and inhaled (airborne pollen grains) human environment. Therefore it is of interest to determine whether lectins can elicit the release of IL-4 from Th2-associated granulocytes other than basophils.Method This study investigated the ability of eosinophils, AML14.3D10 and mast cells to secrete preformed IL-4 in response to stimulation with lectins, and explored molecular mechanisms underlying the interaction.Results Purified eosinophils and basophils, and cultured mast cells and AML14.3D10 cells were incubated with 1 µm lectin. Agglutination was scored by microscopy. IL-4 secretion was measured by enayme-linked immunosorbent assay. Biotinylated lectins were used to determine binding to cells by flow cytometry and in lectin blots of sodium dodecyl sulphate (SDS) gels.Discussion Purified human eosinophils, AML14.3D10 cells and cultured mast cells secrete IL-4 with a pattern similar to that found in basophils when stimulated with a panel of reactive and unreactive lectins. The lectin SNA induces IL-4 secretion from mast cells and basophils, but not from eosinophils or AML14.3D10. Eosinophils appear to secrete only pre-formed IL-4, whereas mast cells may synthesize IL-4 on ligation with the lectin LCA. Lectins that agglutinate the granulocytes investigated do not necessarily induce secretion of IL-4. Lectins that elicit secretion of IL-4 bind more to eosinophils than unreactive lectins as determined by flow cytometry and lectin blotting of SDS gels.Conclusion As granulocytes with functions related to that of basophils, eosinophils, AML14.3D10 and cultured mast cells respond to stimulation with lectins similarly to basophils. This emphasizes the possibility that eosinophils and mast cells may be linked in their cellular heritage as the cellular partners, and lectins as ligands, may contribute to the maintenance of a Th2-favoured microenvironment that is thought to underlie the allergic march.

Notes: Background: Several susceptibility genes for atopy have been suggested in recent years. Few have been investigated as intensively as the interleukin-4-receptor α (IL4Rα) gene on chromosome 16. The results remain in dispute. Therefore, in a robust design, we tested for association of type I allergy to the IL4R variations I50V and Q576R, and investigated chromosome 16 for atopy candidate regions in general. Methods: We identified 100 Danish allergy sib-pair families. Five conservative phenotypes for type I allergy were defined and evaluated. The IL4R variations were genotyped in trios and evaluated by the transmission disequilibrium test (TDT). Multipoint linkage analysis and exclusion mapping were conducted with sib-pairs analyzed for 17 microsatellite markers. Results: No evidence for association or linkage to the IL4R polymorphisms was found (P values: 0.12–0.90). Linkage analysis did not support linkage of any of the phenotypes to chromosome 16. Major parts of chromosome 16 were excluded as candidate regions harboring oligogenes for type I allergy. Conclusions: We found chromosome 16 unlikely to harbor strong candidate genes for type I allergy. The role of the IL4Rα gene in the inheritance of atopy was insignificant in the Danish population. The use of conservative allergy phenotypes in the search for genes predisposing to atopic disease was discussed.

Notes: Background:  The aim of this clinical trial was to investigate whether repeated inhalation of the new inhaled steroid ciclesonide reduces the early-phase (EAR) and late-phase (LAR) reactions after allergen challenge in patients with mild allergic asthma. Also, this study provides further data on safety and tolerance of ciclesonide.Methods:  The study was designed as a double-blind placebo-controlled randomized crossover trial. Following a baseline period, patients were randomized to either of two treatment sequences (ciclesonide/placebo, placebo/ciclesonide) each of which lasted for one week and were separated by 3–5 weeks from the alternate treatment sequence. Patients received 800 µg ciclesonide twice daily by means of a Cyclohaler. At the end of each treatment patients were subjected to an allergen challenge.Results:  Thirteen asthmatic patients (mean FEV1 of 91% predicted) who experienced an EAR and LAR after allergen challenge participated in the study. The time-average FEV1 decreases 0–2 h (2–12 h) after allergen challenge as measure of the EAR (LAR) were significantly reduced (P 〈 0.05, one-sided) from 0.426 L to 0.233 L (EAR) and from 0.443 L to 0.213 L (LAR), respectively. Thus, the study results suggest that ciclesonide significantly lowered the extent of EAR and LAR compared to placebo. Ciclesonide was well tolerated and no drug-related adverse events were reported. Cortisol excretion in 24-h urine showed no significant difference between ciclesonide and placebo.Conclusions:  The study supports the efficacy and safety of ciclesonide.