Immune activation at the lung epithelial barrier

Dendritic cells (DCs) are commonly known as the most potent antigen presenting cells in several inflammatory diseases. In the lung the main function of DCs is to sample incoming antigens, transport them to the draining lymph nodes, where they will activate naïve T cells to become effector T cells or regulatory T cells. The outcome of the response depends on the type of antigen, the type of instructing signals encountered in the periphery but also on the nature of the dendritic cell subsets presenting the antigen to T cells. In chapter 3 we have tried to understand the immune response developed towards antigens trapped in the lung vascular filter. We have shown that these antigens were presented to T cells by interstitial lung DCs in the mediastinal lymph nodes. In addition, we found that these interstitial lung DCs secrete monocyte-chemotactic protein-1 (MCP-1) after embolic antigen exposure, leading to the recruitment of monocytes. Deletion of interstitial DCs resulted in reduced inflammatory aggregates in the lung and antigen presentation in the MLN. Adoptive transfer of purified bone marrow monocytes into DC- depleted mice resulted in conversion of injected monocytes into monocyte-derived DCs and presentation of the antigen in the MLN. In chapter 4 we describe that bile acid ursodeoxycholic acid (UDCA) has immune regulatory properties by directly acting on the nuclear farnesoid X receptor on DCs. Treatment with UDCA during the secondary immune responses resulted in reduced features of allergic airway inflammation. Recent studies revealed an important role for structural cells, especially epithelial cells, in allergic asthma. Lung epithelial cells express pattern recognition receptors (such as TLR4) and respond to allergens by producing DC-instructing factors. Chapter 5 demonstrates that exposure of lung epithelial cells to HDM leads to release of uric acid (UA). Secreted UA acts as a danger signal to promote Th2 immune responses to harmless inhaled antigens. UA-driven responses were mediated by DCs through Syk and PI3Kd signalling pathway. Treatment of mice with uricase at the time of HDM sensitization reduced the features of allergic airway inflammation. Chapter 6 shows that after HDM exposure, IL-1a is one of the key cytokines released by epithelial cells and acts in an autocrine loop to enhance Th2 inflammatory responses. Signalling through the IL-1a/IL-1RI pathway induces the secretion of various chemokines and Th2 instructing cytokines by lung epithelial cells. We found that IL-1a induced production of IL-33 and GM-CSF by lung epithelial cells. These two cytokines were found to be crucial in driving Th2 immunity to HDM. Unexpectedly, we also found that epithelial-derived thymic-stromal lymphopoietin (TSLP) did not play a role in a mild model of HDM-induced asthma. However, the use of higher doses of HDM (inducing more severe asthma features) revealed a more important role for TSLP. In conclusion, this thesis shows that lung DCs are important for the sampling of antigens in different lung compartments. In some cases, like upon exposure to inhaled allergen such as HDM, epithelial cell-derived factors control DC-induced responses. This crosstalk between epithelial cells and DCs involves cytokines such as IL-1a, IL-33 and GM-CSF but also endogenous danger signals like uric acid. Our findings place airway epithelial cells at the origin of Th2 sensitization and therefore, airway epithelial cells can be considered as a therapeutic target for allergic asthma

Accessibility to urban environments for visually impaired people : an analysis of Storängstorget in Norra Djurgårsstaden in Stockholm

Synen har en avgörande roll för hur allmänna platser upplevs och används. Synnedsättningar kan begränsa personers möjligheter att orientera sig självständigt. Svårigheterna som personer med synnedsättning upplever kan resultera i att de inte vill vistas utomhus själva, vilket i sig kan leda till isolering, utanförskap och sämre fysisk och mental hälsa. Stockholms stads övergripande målsättning gällande tillgänglighet är att alla invånare i Stockholm, oavsett funktionsförmåga, ska kunna ta del av och delta i alla samhällsområden. Den nya stadsdelen Norra Djurgårdsstaden är ett av de mest hållbarhetsprofilerade områdena i Stockholm och dess allmänna platser anses vara tillgängliga för personer med funktionsnedsättning. Syftet med arbetet är att undersöka hur tillgängligt det är på en allmän plats i Norra Djurgårdsstaden för personer med synnedsättning, avgränsat till området kring Storängstorget. Kunskap om vad som betraktas vara bra utformade utemiljöer för synnedsatta personer har erhållits från nuvarande lagar och rekommendationer samt synpunkter från synnedsatta personer. En platsanalys har utförts på Storängstorget där platsens utformning, markmaterial, utrustning och belysning analyseras gentemot kraven, rekommendationerna och synpunkterna som studerades. Resultatet visar på att området uppnår många av de krav som finns på tillgänglighet. Platsen är överskådlig, har en logisk utformning, rymliga gångbanor, bra belysning och har dessutom taktila plattor som förtydligar gångriktningar och uppmärksammar hinder. Brister som observerades är otillräckliga kontrastskillnader och avskiljningar mellan gångbanor, körbanor och utrustning samt att övergångsställen saknar en tydlig och konsekvent utformning. Att det finns brister i tillgängligheten beror sannolikt inte på en otillräcklig lagstiftning eller målsättning, utan skulle kunna förklaras av bristande kunskap eller att tillgängligheten står i konflikt med andra aspekter såsom ekonomi och fysiska förutsättningar. Tillgänglighetslösningar som tillämpas i efterhand kan bli kostsamma och oestetiska. För att undvika dyra efterkostnader och att synnedsatta personer exkluderas från allmänna platser bör tillgänglighetsfrågor beaktas under hela byggprocessen. Förutom att enbart följa lagar och krav, bör även synnedsatta personers synpunkter tas till vara. En tillgänglig utemiljö för personer med funktionsnedsättning gynnar inte bara de få, utan bidrar även till en ökad tillgänglighet och säkerhet för alla människor.Sight plays a crucial role in how public places are experienced and used. Visual impairments can limit people's ability to orient themselves independently. The difficulties which people with visual impairments experience can result in them not wanting to go outside by themselves, which may lead to isolation, exclusion, and worse physical and mental health. The aim of Stockholms stad regarding accessibility is that all residents of Stockholm, regardless of functional ability, should be able to take part and participate in all areas of society. The new district Norra Djurgårdsstaden is one of the most sustainably profiled areas in Stockholm and its public places are said to be accessible to people with disabilities. The purpose of this study is to examine how accessible a public space in Norra Djurgårdsstaden is for people with visual impairments and the area which is analyzed is Storängstorget and its vicinity. Knowledge of what is well-designed outdoor environments for visually impaired people has been obtained from current laws, recommendations, and viewpoints from visually impaired people. An inspection and analysis were carried out at Storängstorget, where the area’s design, ground materials, equipment and illumination have been analyzed and compared with the requirements, recommendations, and viewpoints. The results show that this area fulfills many of the requirements for accessibility. The area is perspicuous, has a logical design, spacious walkways, good lighting and has tactile slabs which help with navigation and inform about obstacles. Flaws which were observed at the site are insufficient contrast markings and separation between walkways, roads, and equipment. The pedestrian crossings did also lack a distinct and consistent design. The deficiencies in accessibility are probably not due to insufficient legislation or ambition but could be attributed to lack of knowledge or other conflicting aspects such as economic costs and challenging physical conditions. To avoid expensive subsequent costs and that visually impaired people are excluded from public places, accessibility issues should be considered throughout the entire construction process. In addition to observe laws and requirements, the viewpoint of visually impaired people should also be considered. An accessible outdoor environment for people with disabilities do not only benefit the few, but also enhance accessibility and safety for all people

Mutarotational Kinetics and Glass Transition of Lactose

We report for the first time real time in situ and quantitative measurements of the mutarotation reaction of lactose in the solid state. The experiments have been performed by 13C NMR. We show that mutarotation is initiated on heating the amorphous state, and reaches chemical equilibrium close above the glass transition temperature Tg. We do not observe this transformation when starting from stable crystalline states. The final ratio of and anomers is 1:1, which suggests that the energy profile of the mutarotation reaction pathway in the solid state is actually different from the mechanism proposed for aqueous solution. This chemical equipartition is reached before the crystallization into the corresponding 1:1 molecular compound. These new data clearly illustrate the interrelation between the chemical molecular properties, the physical state of the material, and the relaxational dynamics of the glass

A20 deficiency in lung epithelial cells protects against influenza A virus infection

A20 negatively regulates multiple inflammatory signalling pathways. We here addressed the role of A20 in club cells (also known as Clara cells) of the bronchial epithelium in their response to influenza A virus infection. Club cells provide a niche for influenza virus replication, but little is known about the functions of these cells in antiviral immunity. Using airway epithelial cell-specific A20 knockout (A20(AEC-KO)) mice, we show that A20 in club cells critically controls innate immune responses upon TNF or double stranded RNA stimulation. Surprisingly, A20(AEC-KO) mice are better protected against influenza A virus challenge than their wild type littermates. This phenotype is not due to decreased viral replication. Instead host innate and adaptive immune responses and lung damage are reduced in A20(AEC-KO) mice. These attenuated responses correlate with a dampened cytotoxic T cell (CTL) response at later stages during infection, indicating that A20(AEC-KO) mice are better equipped to tolerate Influenza A virus infection. Expression of the chemokine CCL2 (also named MCP-1) is particularly suppressed in the lungs of A20(AEC-KO) mice during later stages of infection. When A20(AEC-KO) mice were treated with recombinant CCL2 the protective effect was abrogated demonstrating the crucial contribution of this chemokine to the protection of A20(AEC-KO) mice to Influenza A virus infection. Taken together, we propose a mechanism of action by which A20 expression in club cells controls inflammation and antiviral CTL responses in response to influenza virus infection

Cholesterol-sensing liver X receptors stimulate Th2-driven allergic eosinophilic asthma in mice

Introduction: Liver X receptors (LXRs) are nuclear receptors that function as cholesterol sensors and regulate cholesterol homeostasis. High cholesterol has been recognized as a risk factor in asthma; however, the mechanism of this linkage is not known. Methods: To explore the importance of cholesterol homeostasis for asthma, we investigated the contribution of LXR activity in an ovalbumin- and a house dust mite-driven eosinophilic asthma mouse model. Results: In both models, airway inflammation, airway hyper-reactivity, and goblet cell hyperplasia were reduced in mice deficient for both LXR and LXR isoforms (LXR-/--/-) as compared to wild-type mice. Inversely, treatment with the LXR agonist GW3965 showed increased eosinophilic airway inflammation. LXR activity contributed to airway inflammation through promotion of type 2 cytokine production as LXR-/--/- mice showed strongly reduced protein levels of IL-5 and IL-13 in the lungs as well as reduced expression of these cytokines by CD4(+) lung cells and lung-draining lymph node cells. In line herewith, LXR activation resulted in increased type 2 cytokine production by the lung-draining lymph node cells. Conclusions: In conclusion, our study demonstrates that the cholesterol regulator LXR acts as a positive regulator of eosinophilic asthma in mice, contributing to airway inflammation through regulation of type 2 cytokine production

Processing-Induced Disorder in Pharmaceutical Materials

This chapter focuses on the major types of pharmaceutical processing methods that have been widely reported to produce disordered material either intentionally or unintentionally. Milling is one of the most frequently used unit operations used by the pharmaceutical industry for reducing the particle size of solids. Thermal processing techniques are mainly used for controlling or improving the release and the subsequent bioavailability of an active pharmaceutical ingredient (API). Techniques such as melt-mixing, spray-congealing, sintering, melt-granulation, and hot-melt extrusion (HME) have developed and evolved rapidly for large-scale pharmaceutical production. Solvent-evaporation-based methods are important processing techniques for both raw materials, such as crystallization of the raw drug, and formulation manufacturing in the pharmaceutical industry. The chapter discusses the processing that can potentially induce the formation of the disordered state during the manufacture of formulations. The widely used solvent-evaporation-based processing techniques in pharmaceutical formulation production include spray-drying, freeze-drying, film casting, and film coating

Transport and dispersion of atmospheric sulphur dioxide from an industrial coastal area during a sea-breeze event

International audienceExperimental and modelling results of the dynamics of a sea-breeze event and its effects on the three-dimensional (3-D) redistribution of the gaseous SO2 are presented within the framework of a particularly flat and industrialized coastal area of the North Sea. The measurements were carried out at ground level with the stations of the local air quality monitoring agency and with two optical remote sensing instruments. The remote sensing setup consisted of a lidar and a sodar whose measurements allowed us to determine the layers of the lower troposphere during a sea-breeze event up to 1400 m height. The experimental results and measurements of industrial SO2 in the atmosphere are compared to the numerical simulations of the 3-D atmospheric non-hydrostatic chemistry model Meso-NH-C. The transport and the dispersion of gaseous SO2 are studied above the neighbouring industrial and urban areas. We show how the evolution and the redistribution of the SO2 concentrations at ground level are related to the structure and the dynamics of the sea breeze. The gaseous SO2 is brought back inland as soon as the sea breeze commences, mixed inner the thermal internal boundary layer and transported inland by the gravity current up to the sea-breeze front, where gases and particles are uplifted. The elevation of the polluted air masses by the sea-breeze system favours the nucleation of the emitted compounds due to the increase of the relative humidity in the uplifted layer. We show how the dynamical conditions during and after the sea breeze lead to storage of SO2 near and above the emitting industrial coastal areas, and favour the formation of acidic aerosol particles

The mucosal adjuvant cholera toxin B instructs non-mucosal dendritic cells to promote IgA production via retinoic acid and TGF-β

It is currently unknown how mucosal adjuvants cause induction of secretory immunoglobulin A (IgA), and how T cell-dependent (TD) or -independent (TI) pathways might be involved. Mucosal dendritic cells (DCs) are the primary antigen presenting cells driving TI IgA synthesis, by producing a proliferation-inducing ligand (APRIL), B cell activating factor (BAFF), Retinoic Acid (RA), TGF-beta or nitric oxide (NO). We hypothesized that the mucosal adjuvant Cholera Toxin subunit B (CTB) could imprint non-mucosal DCs to induce IgA synthesis, and studied the mechanism of its induction. In vitro, CTB-treated bone marrow derived DCs primed for IgA production by B cells without the help of T cells, yet required co-signaling by different Toll-like receptor (TLR) ligands acting via the MyD88 pathway. CTB-DC induced IgA production was blocked in vitro or in vivo when RA receptor antagonist, TGF-beta signaling inhibitor or neutralizing anti-TGF-beta was added, demonstrating the involvement of RA and TGF-beta in promoting IgA responses. There was no major involvement for BAFF, APRIL or NO. This study highlights that synergism between CTB and MyD88-dependent TLR signals selectively imprints a TI IgA-inducing capacity in non-mucosal DCs, explaining how CTB acts as an IgA promoting adjuvant