Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma

The pathophysiology of allergic asthma is driven by T-helper 2 (Th2) immune responses following aeroallergen inhalation. The mechanisms that initiate, potentiate and regulate airways allergy are incompletely characterized. We have previously shown that Hedgehog (Hh) signaling to T-cells, via downstream Gli transcription factors, enhances T-cell conversion to a Th2 phenotype. Here, we show for the first time that Gli-dependent transcription is activated in T-cells in vivo during murine allergic airways disease (AAD) a model for the immunopathology of asthma; and that genetic repression of Gli signaling in Tcells decreases the differentiation and/or recruitment of Th2 cells to the lung. We report that T-cells are not the only cells capable of expressing activated Gli during AAD. A substantial proportion of eosinophils and lung epithelial cells, both central mediators of the immunopathology of asthma, are also able to undergo Hh/Gli signaling. Finally, we show that Shh increases Il4 expression in eosinophils. We therefore propose that Hh signaling during AAD is complex, involving multiple cell types, signaling in an auto- or paracrine fashion. Improved understanding of the role of this major morphogenetic pathway in asthma may give rise to new drug targets for this chronic condition

Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway

Electrochemical detection of Toxocara canis excretory-secretory antigens in children from rural communities in Esmeraldas Province, Ecuador: association between active infection and high eosinophilia.

BACKGROUND: The diagnosis of active Toxocara canis infections in humans is challenging. Larval stages of T. canis do not replicate in human tissues and disease may result from infection with a single T. canis larva. Recently, we developed a nanobody-based electrochemical magnetosensor assay with superior sensitivity to detect T. canis excretory-secretory (TES) antigens. Here, we evaluate the performance of the assay in children from an Ecuadorian birth cohort that followed children to five years of age. METHODS: Samples were selected based on the presence of peripheral blood eosinophilia and relative eosinophil counts. The samples were analyzed by the nanobody-based electrochemical magnetosensor assay, which utilizes a bivalent biotinylated nanobody as capturing agent on the surface of streptavidin pre-coated paramagnetic beads. Detection was performed by a different nanobody chemically labelled with horseradish peroxidase. RESULTS: Of 87 samples tested, 33 (38%) scored positive for TES antigen recognition by the electrochemical magnetosensor assay. The average concentration of TES antigen in serum was 2.1 ng/ml (SD = 1.1). The positive result in the electrochemical assay was associated with eosinophilia > 19% (P = 0.001). Parasitological data were available for 57 samples. There was no significant association between positivity by the electrochemical assay and the presence of other soil-transmitted helminth infections. CONCLUSIONS: Our nanobody-based electrochemical assay provides highly sensitive quantification of TES antigens in serum and has potential as a valuable tool for the diagnosis of active human toxocariasis

Sonic Hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation

Epithelial barrier tissues such as the skin and airway form an essential interface between the mammalian host and its external environment. These physical barriers are crucial to prevent damage and disease from environmental insults and allergens. Failure to maintain barrier function against such risks can lead to severe inflammatory disorders, including atopic dermatitis and asthma. Here, we discuss the role of the morphogen Sonic Hedgehog in postnatal skin and lung and the impact of Shh signalling on repair, inflammation and atopic disease in these tissues

Hedgehog signalling in allograft vasculopathy: a new therapeutic target?

Allograft vasculopathy (AV) leads to chronic rejection of organ transplants, but its causes are obscure. New research from the Jane-Wit laboratory showed that Sonic Hedgehog (SHH) signalling from damaged graft endothelium drives vasculopathy by promoting proinflammatory cytokine production and NLRP3-inflammasome activation in alloreactive CD4+PTCH1hiPD-1hiT memory cells, offering new diagnostic and therapeutic strategies

Hedgehog signalling promotes Th2-differentiation in naive human CD4 T-cells

Original journal article Abstract: Here we show that differentiation of human naïve CD4 T-cells to Th2 is promoted by Hedgehog signaling and attenuated by SMO-inhibition. As Hedgehog proteins are produced by epithelial tissues this finding is important to understanding atopic disease

The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL

The Pioneer Transcription Factor Foxa2 Modulates T Helper Differentiation to Reduce Mouse Allergic Airway Disease

Foxa2, a member of the Forkhead box (Fox) family of transcription factors, plays an important role in the regulation of lung function and lung tissue homeostasis. FOXA2 expression is reduced in the lung and airways epithelium of asthmatic patients and in mice absence of Foxa2 from the lung epithelium contributes to airway inflammation and goblet cell hyperplasia. Here we demonstrate a novel role for Foxa2 in the regulation of T helper differentiation and investigate its impact on lung inflammation. Conditional deletion of Foxa2 from T-cells led to increased Th2 cytokine secretion and differentiation, but decreased Th1 differentiation and IFN-γ expression in vitro. Induction of mouse allergic airway inflammation resulted in more severe disease in the conditional Foxa2 knockout than in control mice, with increased cellular infiltration to the lung, characterized by the recruitment of eosinophils and basophils, increased mucus production and increased production of Th2 cytokines and serum IgE. Thus, these experiments suggest that Foxa2 expression in T-cells is required to protect against the Th2 inflammatory response in allergic airway inflammation and that Foxa2 is important in T-cells to maintain the balance of effector cell differentiation and function in the lung

Modern pollen-vegetation relationships along a steep temperature gradient in the Tropical Andes of Ecuador

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this record.The characterization of modern pollen rain assemblages along environmental gradients is an essential prerequisite for reliable interpretations of fossil pollen records. In this study, we identify pollen-vegetation relationships using modern pollen rain assemblages in moss polsters (n = 13) and lake sediment surface samples (n = 11) along a steep temperature gradient of 7°C (3100–4200 m above sea level) on the western Andean Cordillera, Ecuador. The pollen rain is correlated to vascular plant abundance data recorded in vegetation relevées (n = 13). Results show that pollen spectra from both moss polsters and sediment surface samples reflect changes in species composition along the temperature gradient, despite overrepresentation of upper montane forest taxa in the latter. Estimated pollen transport distance for a lake (Laguna Llaviucu) situated in a steep upper montane forest valley is 1–2 km, while a lake (Laguna Pallcacocha) in the páramo captures pollen input from a distance of up to 10–40 km. Weinmannia spp., Podocarpus spp., and Hedyosmum sp. are indicators of local upper montane forest vegetation, while Phlegmariurus spp. and Plantago spp. are indicators for local páramo vegetation.Earth and Life Science council (ALW) of the Netherlands Organisation of Scientific Researc

Modelos y análisis para datos de degradación

La degradación es una debilidad que eventualmente puede causar la falla (e. g., el desgaste que sufren los neumáticos de un automóvil). Cuando es posible medirla, esta puede proporcionar mayor información que los datos de tiempo de falla, para propósitos de determinación y mejoramiento de la confiabilidad de un producto. Este artículo es de carácter divulgativo y desarrolla técnicas que son propuestas por Meeker y Escobar (1998). Se cree importante hacer conocer este tópico, hoy en la frontera de la Teoría de Confiabilidad (Lawless 2000)). En este trabajo se compara el análisis clásico aproximado de degradación con el modelo de degradación explícito. Estos últimos modelos implican la utilización de modelos físicos de degradación a los cuales se les introduce efectos aleatorios. Se implementan las técnicas para la estimación de modelos mixtos en S-PLUS siguiendo a Pinheiro y Bates (2000) y se utiliza el bootstrap para intervalos de confianza.Degradation is a weakness that eventually can cause failure (e.g. car tire wear). When it is possible to measure degradation, such measures often provide more information than failure-time data for purposes of assessing and improving product reliability. This is a paper which mainly pretends to divulge techniques that had been developed by Meeker and amp; Escobar (1998). We think it is worth to make this topics known, because they are in the research frontier of the Reliability Theory (Lawless 2000). We compare in this work the explicit degradation models with the approximate degradation analysis. The explicit degradation model requires specific models developed by engineers and physical scientists, which are treated as mixed models with random effects. To obtain ML estimates we use S-PLUS following Pinheiro and amp; Bates (2000), and also use bootstrap confidence intervals