Mithilfe einer epidemilogischen Datenerhebung bei niedergelassenen Pneumologen, sollte die Prävalenz des Emphysems bei COPD GOLD III/IV Patienten in Deutschland abgeschätzt werden und eine mögliche Korrelation zwischen Phänotyp und Lungenfunktion dargestellt werden.

Introduction Cortisol exerts effects on the brain via two different receptors, producing complex and sometimes opposite effects on the brain structures involved with the different cognitive functions. Objective To scrutinize the interrelationships between cortisol, cognition and dementia. Methods Review of the literature and new own findings. Results Animal and clinical studies showed an association between increased cortisol and poorer overall cognitive performance, declarative memory, language, processing speed, executive functioning, spatial memory, as well as social memory. High cortisol may exhibit neurotoxic effects on the hippocampus, and exacerbate oxidative injury and amyloid β peptide toxicity. Increased CSF cortisol levels have been found in subjects with dementia and Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD) compared to control subjects with normal cognition. In MCI due to AD, high CSF cortisol may also predict a more rapid cognitive decline. Higher cortisol levels have been also observed in delirium. Increased cortisol levels interact with inflammatory mediators, neurotransmitters, and growth factors, and may mediate the effects of depression, stressful life events, and personality traits, sleep disturbances, and cardiovascular risk factor on cognitive performance and cognitive decline. Conclusions High cortisol levels may exert deleterious effects on cognition and exacerbate AD pathology. Further studies are needed to explore glucocorticoid-based interventions in the management of cognitive disorders. Disclosure of interest The authors have not supplied their declaration of competing interest.

Allergic asthma is a chronic disease of the airways associated with airway hyperresponsiveness, a variable degree of airflow obstruction, airway remodelling and a characteristic airway inflammation. Factors of the vitamin D axis, which include vitamin D metabolites and vitamin D binding protein (VDBP), have been linked to asthma, but only few data exist about their regulation in the lung during acute allergen-induced airway inflammation. Therefore, we analysed the regulation of factors of the vitamin D axis during the early- and late-phase reaction of allergic asthma. Fifteen patients with mild allergic asthma underwent segmental allergen challenge. VDBP was analysed in bronchoalveolar lavage fluid (BALF) and serum using the enzyme-linked immunosorbent assay (ELISA) technique. 25-hydroxyvitamin D3 [25(OH)D3] and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] were analysed by a commercial laboratory using the liquid chromatography-mass spectrometry (LC/MS) technique. VDBP (median 23, range 02-71g/ml), 25(OH)D3 (median 0060, range<0002-3210ng/ml) and 1,25(OH)2D3 (median<01, range<01-28pg/ml) were significantly elevated in BALF 24h but not 10min after allergen challenge. After correction for plasma leakage using the plasma marker protein albumin, VDBP and 25(OH)D3 were still increased significantly while 1,25(OH)2D3 was not. VDBP and 25(OH)D3 were correlated with each other and with the inflammatory response 24h after allergen challenge. Serum concentrations of all three factors were not influenced by allergen challenge. In conclusion, we report a significant increase in VDBP and 25(OH)D3 in human BALF 24h after allergen challenge, suggesting a role for these factors in the asthmatic late-phase reaction.

Zusammenfassung Das Marie-Bamberger-Syndrom (Synonym: hypertrophe pulmonale Osteoarthropathie) tritt mit einer Inzidenz von 1 – 5 % bei Patienten mit nichtkleinzelligem Bronchialkarzinom (NSCLC) auf. In seiner vollständigen Form treten Trommelschlegelfinger (meist ohne Vorliegen einer Zyanose) und Knochen- und Gelenkschmerzen auf. Anhand der hier dargestellten Fälle wird verdeutlicht, dass dieses paraneoplastische Syndrom zeitlich vor typischen Tumorsymptomen auftritt, jedoch auch heute noch selten erkannt wird. Wird die Symptomkonstellation Trommelschlegelfinger und Knochenschmerz frühzeitig erkannt, lässt sich ein NSCLC in einem früheren Tumorstadium diagnostizieren – daher ist es von großer klinisch-praktischer Bedeutung. Neben der Falldarstellung gibt der Artikel einen Überblick über die aktuellen Vorstellungen zur Pathogenese und Therapie dieses Syndroms.

Hypertrophic pulmonary osteoarthropathy (often referred to as Marie-Bamberger syndrome) occurs in 1 - 5 % of all patients with non-small cell lung cancer (NSCLC) as a paraneoplastic syndrome. The complete syndrome is characterised by clubbing of the fingers and toes (often without hypoxia) and pain in the joints and tubular bones. On the basis of four clinical cases, this article shows that this syndrome can precede tumour-specific symptoms and that it is still often overlooked by physicians. An early suspicion of this syndrome is of great clinical value because it can lead to a diagnosis of NSCLC at an earlier tumour stage. In addition to the case reports, the current literature on hypertrophic pulmonary osteoarthropathy is reviewed in this article, with special reference to pathogenetic concepts und to therapeutic options.

Lipopolysaccharides (LPS) have been associated with a protective role in the development of asthma while higher levels of endotoxin have been linked with more severe asthma. LPS recruit neutrophils and eosinophils and activate macrophages via the CD14 receptor. The soluble CD 14 receptor (sCD14) has been found in bronchoalveolar lavage fluid in different diseases including allergic asthma. To elucidate the kinetics and the regulation of sCD14 concentrations in BAL in asthma, 18 patients with allergic asthma underwent segmental allergen challenge at different time points (10 min, 18, 42 and 162 h). In addition, CD14+ peripheral blood mononuclear cell (PBMC-CD14+) cultures from seven allergic and seven non-allergic subjects were stimulated with LPS, leukotrien D-4 (LTD4), a combination of LPS and LTD4, IL-17 and LTD4 in presence of the leukotriene-receptor antagonist (LTRA) Montelukast for 6, 12 and 24 h. sCD14 concentrations in BAL and the supernatants were measured by ELISA. sCD14 concentrations in BAL were significantly increased 18 h after allergen challenge and peaked at 42 h. At 162 h, concentrations had returned to baseline levels. In PBMC-CD14+ cultures, sCD14 levels increased significantly 24 h after stimulation with LTD4 and Montelukast was able to block LTD4-induced stimulation. Allergen challenge leads to a significant increase in sCD14 concentrations in BAL and might modulate the allergen-induced inflammation. In addition, LTD4 might play a role in the release of sCD14, and it could be speculated that sCD14 reduction by LTRA might contribute to the mechanisms of LTRA in the treatment of allergic asthma.

Airway dendritic cells (DCs) play a key role in smoke-related lung diseases; however, the acute effects of tobacco smoke on human airway DCs in vivo are unknown.A total of 16 smokers underwent bronchoalveolar lavage at two time-points: directly after a 4-h period of nonsmoking (no smoke exposure); and directly after a 4-h period during which eight cigarettes were smoked (acute smoke exposure). Using flow cytometry, myeloid DCs (mDCs) and plasmacytoid DCs (pDCs), as well as function-associated surface molecules on mDCs, were analysed in bronchoalveolar lavage fluid (BALF) and in blood.The numbers of macrophages, lymphocytes, neutrophils, eosinophils and pDCs were unchanged in BALF following acute smoke exposure, as compared to no smoke exposure. In contrast, there was a strong increase in mDC number in BALF and a concomitant decrease in mDC number in blood following acute smoke exposure. In addition, acute smoke exposure led to an increase in the expression of the surface molecules blood dendritic cell antigen 1 and 4 and a decrease in the expression of the lung homing receptor, CC chemokine receptor 5, on mDCs in BALF.Acute tobacco smoke inhalation results in an immediate and selective recruitment of mDCs into human airways, which might reflect the very early reaction of the adaptive immune system to smoke exposure.

SummaryBackground Plasmacytoid dendritic cells (pDCs) are involved in a variety of immune functions. However, the expression of cytotoxic granule proteins like granzymes and perforin in human pDCs is still poorly understood.Objective The aim of this study was to systematically analyse the expression and regulation of cytotoxic granule proteins in human pDCs.Methods The expression of cytotoxic proteins was analysed by RT‐PCR, flow cytometry, and fluorescence microscopy. The functional expression of these proteins was confirmed in a flow‐cytometry‐based cytotoxicity assay using K562 cells as targets. In order to analyse the regulation of pDC‐derived cytotoxic proteins in infectious and allergic diseases, human pDCs were analysed after stimulation with toll‐like receptor (TLR)7/9 ligands and in the human asthma model of segmental allergen challenge.Results Granzyme B (GrB), but not the granzymes A, H, K, M or perforin, was specifically expressed by human pDCs and this GrB expression was up‐regulated by IL‐3 stimulation. In addition, IL‐3‐stimulated pDCs were found to kill K562 cells in a GrB‐ and caspase‐dependent manner. TLR7/9 ligands significantly suppressed GrB expression in pDCs. In contrast, there was an up‐regulation of GrB in endobronchial pDCs 24 h after allergen challenge, and this was accompanied by enhanced GrB concentrations in bronchoalveolar lavage fluid.Conclusion We report the selective expression of GrB in human pDCs and show for the first time pDC‐mediated GrB‐ and caspase‐dependent cytotoxicity against target cells. In addition, the regulation of GrB expression was investigated in vitro and in vivo providing an evidence for a specific role of pDC‐derived GrB in allergic inflammation. Cite this as: K. Bratke, J. Nielsen, F. Manig, C. Klein, M. Kuepper, S. Geyer, P. Julius, M. Lommatzsch and J. C. Virchow, Clinical & Experimental Allergy, 2010 (40) 1015–1024.

To the Editor:Yerkovich et al1Yerkovich S.T. Roponen M. Smith M.E. McKenna K. Bosco A. Subrata L.S. et al.Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response.J Allergy Clin Immunol. 2009; 123: 209-216Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar report a house dust mite (HDM) allergen–mediated upregulation of thrombomodulin (blood dendritic cell antigen 3, CD141) on myeloid dendritic cells (mDCs) that is associated with a TH2-polarized immune response. In accordance with that study, we previously described the allergen (HDM, birch, and rye)–enhanced expression of thrombomodulin on peripheral blood (PB) and bronchoalveolar lavage (BAL) fluid–derived mDCs using the human asthma model of segmental allergen challenge.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar Here we report the allergen-induced upregulation of thrombomodulin on BAL-derived plasmacytoid dendritic cells (pDCs) in this asthma model.Ten patients with mild allergic asthma (3 female and 7 male patients; median age, 27 years; age range, 20–39 years; median total IgE level, 298 kU/L; IgE range, 57-770 kU/L) were recruited for the study on the basis of previously described criteria.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar All patients provided written informed consent, and the study protocol was approved by the local ethics committee. Segmental allergen challenge was performed as previously described.3Lommatzsch M. Julius P. Kuepper M. Garn H. Bratke K. Irmscher S. et al.The course of allergen-induced leukocyte infiltration in human and experimental asthma.J Allergy Clin Immunol. 2006; 118: 91-97Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Patients were challenged with HDM (n = 6) or birch (n = 4) allergen, and the individual provocation dose was calculated as previously described (median allergen dose, 155.5 allergen units; range, 0.06–2180.0 allergen units).4Nassenstein C. Braun A. Erpenbeck V.J. Lommatzsch M. Schmidt S. Krug N. et al.The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma.J Exp Med. 2003; 198: 455-467Crossref PubMed Scopus (134) Google Scholar BAL fluid samples were taken 10 minutes and 24 hours after allergen and saline challenge, respectively, and pDCs were identified by means of flow cytometry as lineage-negative HLA-DR+CD123+ cells, as previously reported.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar Thrombomodulin expression was determined by using a specific allophycocyanin-labeled antibody (clone AD5-14H12; Miltenyi Biotech, Bergisch Gladbach, Germany).Twenty-four hours after allergen challenge, pDC numbers were significantly decreased in PB, whereas in BAL fluid from allergen-challenged lung segments significantly higher pDC numbers could be detected compared to BAL fluid from saline-challenged control segments (Fig 1, A). No change in thrombomodulin expression on PB pDCs could be detected 24 hours after allergen challenge (Fig 1, B). Ten minutes after allergen challenge, cell numbers in BAL fluid samples were too low to measure thrombomodulin on pDCs. Twenty-four hours after allergen challenge, thrombomodulin expression on BAL fluid pDCs was significantly higher compared with that seen in saline-challenged control segments (Fig 1, B).Thus our data emphasize the in vivo relevance of allergen-enhanced thrombomodulin expression. However, in extending the findings of Yerkovich et al,1Yerkovich S.T. Roponen M. Smith M.E. McKenna K. Bosco A. Subrata L.S. et al.Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response.J Allergy Clin Immunol. 2009; 123: 209-216Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar this is not restricted to mDCs but also present on pDCs. In addition, we can add to their data by showing that thrombomodulin upregulation is not restricted to HDM allergen but also occurs in response to pollen allergens, such as birch and rye. To the Editor: Yerkovich et al1Yerkovich S.T. Roponen M. Smith M.E. McKenna K. Bosco A. Subrata L.S. et al.Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response.J Allergy Clin Immunol. 2009; 123: 209-216Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar report a house dust mite (HDM) allergen–mediated upregulation of thrombomodulin (blood dendritic cell antigen 3, CD141) on myeloid dendritic cells (mDCs) that is associated with a TH2-polarized immune response. In accordance with that study, we previously described the allergen (HDM, birch, and rye)–enhanced expression of thrombomodulin on peripheral blood (PB) and bronchoalveolar lavage (BAL) fluid–derived mDCs using the human asthma model of segmental allergen challenge.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar Here we report the allergen-induced upregulation of thrombomodulin on BAL-derived plasmacytoid dendritic cells (pDCs) in this asthma model. Ten patients with mild allergic asthma (3 female and 7 male patients; median age, 27 years; age range, 20–39 years; median total IgE level, 298 kU/L; IgE range, 57-770 kU/L) were recruited for the study on the basis of previously described criteria.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar All patients provided written informed consent, and the study protocol was approved by the local ethics committee. Segmental allergen challenge was performed as previously described.3Lommatzsch M. Julius P. Kuepper M. Garn H. Bratke K. Irmscher S. et al.The course of allergen-induced leukocyte infiltration in human and experimental asthma.J Allergy Clin Immunol. 2006; 118: 91-97Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Patients were challenged with HDM (n = 6) or birch (n = 4) allergen, and the individual provocation dose was calculated as previously described (median allergen dose, 155.5 allergen units; range, 0.06–2180.0 allergen units).4Nassenstein C. Braun A. Erpenbeck V.J. Lommatzsch M. Schmidt S. Krug N. et al.The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 are survival and activation factors for eosinophils in patients with allergic bronchial asthma.J Exp Med. 2003; 198: 455-467Crossref PubMed Scopus (134) Google Scholar BAL fluid samples were taken 10 minutes and 24 hours after allergen and saline challenge, respectively, and pDCs were identified by means of flow cytometry as lineage-negative HLA-DR+CD123+ cells, as previously reported.2Bratke K. Lommatzsch M. Julius P. Kuepper M. Kleine H.D. Luttmann W. et al.Dendritic cell subsets in human bronchoalveolar lavage fluid after segmental allergen challenge.Thorax. 2007; 62: 168-175Crossref PubMed Scopus (107) Google Scholar Thrombomodulin expression was determined by using a specific allophycocyanin-labeled antibody (clone AD5-14H12; Miltenyi Biotech, Bergisch Gladbach, Germany). Twenty-four hours after allergen challenge, pDC numbers were significantly decreased in PB, whereas in BAL fluid from allergen-challenged lung segments significantly higher pDC numbers could be detected compared to BAL fluid from saline-challenged control segments (Fig 1, A). No change in thrombomodulin expression on PB pDCs could be detected 24 hours after allergen challenge (Fig 1, B). Ten minutes after allergen challenge, cell numbers in BAL fluid samples were too low to measure thrombomodulin on pDCs. Twenty-four hours after allergen challenge, thrombomodulin expression on BAL fluid pDCs was significantly higher compared with that seen in saline-challenged control segments (Fig 1, B). Thus our data emphasize the in vivo relevance of allergen-enhanced thrombomodulin expression. However, in extending the findings of Yerkovich et al,1Yerkovich S.T. Roponen M. Smith M.E. McKenna K. Bosco A. Subrata L.S. et al.Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response.J Allergy Clin Immunol. 2009; 123: 209-216Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar this is not restricted to mDCs but also present on pDCs. In addition, we can add to their data by showing that thrombomodulin upregulation is not restricted to HDM allergen but also occurs in response to pollen allergens, such as birch and rye. Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune responseJournal of Allergy and Clinical ImmunologyVol. 123Issue 1PreviewDendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce TH2-polarized responses in atopic individuals. It has been suggested that intrinsic properties of allergens can directly stimulate TH2 polarizing functions of DCs, but little is known of the underlying mechanisms. Full-Text PDF

Airway dendritic cells (DCs) are key regulators of pulmonary immune responses. However, information is limited regarding the characteristics of airway DCs in human lung diseases. Plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were analysed using four-colour flow cytometry in bronchoalveolar lavage fluid (BALF) from nonsmoking controls and patients with sarcoidosis, idiopathic pulmonary fibrosis (IPF) and pneumonia (in the presence or absence of immunosuppression). Compared with controls, immunocompetent patients with pneumonia displayed strongly enhanced pDC counts in BALF. In contrast, pDC counts in BALF from immunocompromised patients with pneumonia were even lower than in controls. This discrepancy was not explained by a different chemotactic milieu in the airways; all patients with pneumonia were characterised by strongly increased concentrations of the pDC-attracting chemokine, CXC chemokine ligand 10, in BALF. Patients with IPF were characterised by normal percentages of DC subtypes. However, the mDCs of patients with IPF were not as mature (CD83-positive) as those of controls. Patients with sarcoidosis displayed a unique increase in CD1a-negative mDCs in the airways. In addition, there was altered expression of costimulatory molecules (increased CD80 and decreased CD86 expression) on mDCs in patients with sarcoidosis. These data suggest that inflammatory diseases of the human lung are associated with a differential phenotype and recruitment of airway dendritic cells.

Airway dendritic cells (DCs) control pulmonary immune responses to inhaled particles. However, the profile of function-associated surface molecules on airway DCs in smokers is unknown. In this study, function-associated surface molecules were analyzed using four-color flow cytometry on myeloid DCs (mDCs) in bronchoalveolar lavage fluid (BALF) of cigarette smokers and never-smokers. Furthermore, the lung function was assessed directly before bronchoscopy in all participants. There was a 7-fold increase in total cell numbers in BALF of smokers, as compared with never-smokers. The percentage of mDCs among BALF cells and the expression of the maturation marker CD83 on mDCs did not differ between smokers and never-smokers. However, there was a strong increase in the expression of Langerin and CD1a (markers of Langerhans cells) on mDCs of smokers. Furthermore, mDCs of smokers were characterized by an increased expression of antigen presentation markers such as CD80 and CD86. By contrast, mDCs of smokers displayed a decreased expression of the lymph node homing receptor CCR7, as compared with mDCs of never-smokers. Decreased expression of CCR7 on mDCs, but not any of the other surface molecules studied, was specifically associated with airway obstruction and pulmonary hyperinflation in smokers. In conclusion, our data suggest that smoking affects the expression profile of function-associated surface molecules on airway mDCs. We provide the first evidence that a reduced CCR7 expression on airway mDCs is associated with airflow limitation in smokers.

BACKGROUND:Granzymes are a subfamily of serine proteases involved in the pathogenesis of many inflammatory disorders. In contrast with granzyme A and B, the role of granzyme K (GrK) in human lung diseases is unknown. Therefore, the release and expression of GrK in allergic asthma, chronic obstructive pulmonary disease (COPD) and bronchopneumonia were investigated.METHODS:Soluble GrK was quantified using an enzyme linked immunosorbent assay in the bronchoalveolar lavage fluid of patients with allergic asthma (before and after segmental allergen challenge), and in patients with mild COPD, pneumonia and in healthy controls. The molecular form of GrK was analysed by western blot. Flow cytometry was performed to determine the cellular expression of GrK.RESULTS:Compared with healthy controls, there were normal levels of soluble GrK in the bronchoalveolar lavage fluid of patients with COPD, and patients with allergic asthma before allergen challenge. In contrast, soluble GrK was strongly increased in the bronchoalveolar lavage fluid of patients with acute bronchopneumonia. In patients with allergic asthma, there was a significant increase in soluble GrK as well as in GrK expressing CD8(+) T cells in the bronchoalveolar lavage fluid 24 h and 72 h after allergen challenge. After allergen challenge, soluble GrK correlated with the percentage of GrK expressing CD8(+) T cells. Finally, it was shown that the endobronchial release of the CCR5 ligand CCL3 might be a mechanism for the recruitment of GrK(+)CD8(+) T cells after allergen challenge.CONCLUSION:These data provide the first evidence that expression of GrK is upregulated in acute airway inflammation, both in infectious and non-infectious diseases.

BACKGROUND:Dendritic cells control pulmonary immune reactions. Characteristics of dendritic cells in human bronchoalveolar lavage fluid (BALF) after allergen challenge are unknown.METHODS:7 patients with allergic asthma (median 23 years, range 19-25 years) underwent segmental challenge and were lavaged 10 min and 24 h after challenge. Dendritic cell subsets and surface markers in BALF and in peripheral blood were analysed using four-colour flow cytometry.RESULTS:Plasmacytoid dendritic cells (pDCs, median 0.06%, range 0.01-0.08%) and myeloid dendritic cells (mDCs, median 0.47%, range 0.27-0.87%) were detectable in BALF from control segments. CD1a-positive dendritic cells in BALF were identified as a subpopulation of mDCs. Both pDCs (median 0.56%, range 0.09-1.83%) and mDCs (median 1.82%, range 0.95-2.29%) increased significantly in BALF 24 h (p = 0.018 compared with the control segments for pDCs and mDCs), but not 10 min, after allergen challenge. The percentage increase in pDCs was higher than that of mDCs after allergen challenge, as reflected by an enhanced pDC:mDC ratio after allergen challenge. In peripheral blood, there was a significant decrease in mDCs (p = 0.038) and a trend to a decrease in pDCs (p = 0.068) 24 h after allergen challenge. Analysis of dendritic cell surface molecules showed that after allergen challenge, BALF dendritic cells have a less mature phenotype compared with BALF dendritic cells from control segments.CONCLUSION:Using a comprehensive strategy to analyse dendritic cell subsets in human BALF, we have shown for the first time that both myeloid and plasmacytoid dendritic cells accumulate in the airway lumen after allergen challenge in patients with asthma.

Background: Segmental allergen challenge is widely used to study mechanisms of human allergic asthma. Despite the relatively large dissemination, limited information is available about the safety of this method.Objective: Observational, retrospective study to report the adverse events of segmental allergen challenge in a large group of volunteers with asthma.Methods: In total, 78 cases from several studies performed between 1994 and 2007 were pooled for this analysis. Volunteers underwent allergen challenge using either a fixed dose of allergen (7 cases) or an individually standardized allergen dose defined by an inhaled allergen test before the challenge (71 cases). A subgroup of 13 volunteers underwent repeated challenges, with more than 6 months between the challenges.Results: With a fixed dose instilled during bronchoscopy, 43% of the participants developed wheezing and coughing, requiring 2-6 puffs of a beta(2)-agonist after segmental allergen challenge. In volunteers with individually standardized doses, a beta(2)-agonist was required in only 19% of the cases. No severe adverse events occurred in all cases studied. Volunteers who underwent repeated challenges did not develop more adverse events than those who underwent 1 challenge.Conclusions: Segmental allergen challenge is a safe tool to study the mechanisms of human allergic asthma, even when repeated challenges are performed in the same patient. It is associated with only a few, tolerable adverse events, especially when the dose of allergen is standardized individually.

Histamine, leukotriene C4, IL-4, and IL-13 are major mediators of allergy and asthma. They are all formed by basophils and are released in particularly large quantities after stimulation with IL-3. Here we show that supernatants of activated mast cells or IL-3 qualitatively change the makeup of granules of human basophils by inducing de novo synthesis of granzyme B (GzmB), without induction of other granule proteins expressed by cytotoxic lymphocytes (granzyme A, perforin). This bioactivity of IL-3 is not shared by other cytokines known to regulate the function of basophils or lymphocytes. The IL-3 effect is restricted to basophil granulocytes as no constitutive or inducible expression of GzmB is detected in eosinophils or neutrophils. GzmB is induced within 6 to 24 hours, sorted into the granule compartment, and released by exocytosis upon IgE-dependent and -independent activation. In vitro, there is a close parallelism between GzmB, IL-13, and leukotriene C4 production. In vivo, granzyme B, but not the lymphoid granule marker granzyme A, is released 18 hours after allergen challenge of asthmatic patients in strong correlation with interleukin-13. Our study demonstrates an unexpected plasticity of the granule composition of mature basophils and suggests a role of granzyme B as a novel mediator of allergic diseases.

Die allergische Entzündung ist durch eine Infiltration von Leukozyten in das bronchoalveoläre Kompartiment gekennzeichnet. Die Lungenfunktionsveränderungen im Verlauf sind hinreichend bekannt. Bisher gibt es aber nur wenig Informationen zur Kinetik der Leukozyteninfiltration. In dieser Studie wurden die Zellzahlen in der bronchoalveolären Lavage bis zu einer Woche nach segmentaler Allergenprovokation beim Menschen und im Mausmodell bis zu 3 Wochen nach Allergenprovokation (AP) untersucht. In beiden Modellen zeigte die Infiltration von neutrophilen Granulozyten ein Maximum bei etwa 18 Stunden nach AP, während eosionphile Granulozyten bei Menschen einen Peak bei 42 Stunden und im Mausmodell erst nach 4 Tagen aufwiesen. Makrophagen waren in beiden Modellen über einige Tage erhöht in der BAL zu finden, während Lymphozyten im humanen Modell ein Maximum nach 18 Stunden, hingegen im Mausmodell erst nach 2 Wochen aufwiesen. Diese Ergebnisse zeigen eine Parallelität der beiden Modelle hinsichtlich des frühen Einstroms Neutrophiler und des späteren Maximums eosinophiler Granulozyten in der BAL nach AP. Hingegen scheint die Kinetik der lymphozytären Infiltration stark vom gewählten Asthmamodell abhängig zu sein. Darüber hinaus stimmt das Maximum der Eosinophileninfiltration (2–4 Tage nach AP) nicht mit dem Maximum der in der Literatur beschriebenen Bronchokonstriktion überein (0–12 Stunden). Somit scheinen die maximale Zellinfiltration und das Maximum der Bronchokonstriktion zeitlich nicht überein zu stimmen.

PURPOSE:To test the hypothesis that long-term immunological response may be different after accustomed concentric and unaccustomed eccentric exercise in endurance-trained men. METHODS:Fourteen highly endurance-trained male runners performed two bouts of high-intensity exercise with at least 2-wk intervals between bouts. Concentric exercise consisted of a 60-min level run with a targeted heart rate of 80% VO2 peak. Eccentric exercise was conducted lying on a specially designed exercise rack, eliciting eccentric action of the musculus quadriceps femoris. Blood samples were taken before and 1, 6, 24, 72, and 144 h after exercise to determine creatine kinase (CK), C-reactive protein (CRP), and interleukin-6 (IL-6). Lymphocyte subset distribution was assessed using flow cytometry. RESULTS:We found a significant (P < 0.05) increase of CD4 (eccentric: 17%; concentric: 20%), CD3+/CD4+ (16 vs 19%), CD25+ (45 vs 29%), CD25+/CD4+ (27 vs 50%), HLA-DR+ (20 vs 15%), HLA-DR+/CD4+ (16 vs 67%), and CD19+/CD45+ (52 vs 103%) positive lymphocytes 1 h after both exercise bouts. However, eccentric exercise resulted in a significantly higher and longer (6 h) increase of CD25+/CD4+ and HLA-DR+/CD8+ lymphocytes and a peak increase of CK at 72 h. IL-6 and CRP increased only after concentric exercise within the first 24 h. Both exercises resulted in a decrease of monocyte activation (LFA-1: CD18+/CD11a+) after 6 h, with an increase for the eccentric exercise part after 24 h (P < 0.05). CONCLUSION:Accustomed concentric exercise mainly induced an acute-phase response, with increased CRP, IL-6, and activation of CD4 lymphocyte subsets. Unaccustomed eccentric exercise provided a delayed increase in CK and activation of monocytes and CD4+ and CD8+ subsets. Therefore, the immunological reaction depends not only on the type of contraction but also on the adaptation to the exercise.