Role of Toll-like receptors in airway inflammation

Toll-like receptors (TLRs) are germline-encoded pathogen-recognition receptors that detect different microbial structures and activate the immune system. The human TLR family presently comprises ten members (TLR1-TLR10), each with distinct properties. Although the TLRs protect the host from infection, they have become increasingly implicated in the pathogenesis of various inflammatory diseases, including asthma and allergy. The aim of this thesis was to characterize the presence and function of TLRs in different cell types involved in upper airway inflammation, with special emphasis on recurrent tonsillar infection and allergic rhinitis. We also sought to map cellular and molecular changes occurring as a result of allergen-specific immunotherapy. In the first two studies, a distinct expression of TLRs was demonstrated in subsets of B and T lymphocytes isolated from human tonsils. The expression levels seemed to be affected by ongoing tonsillar infection. This was most evident in T cells. By studying the functional activity of the expressed receptors, it was found that the corresponding ligands promoted B cell activation. These data indicate that TLRs have a direct role not only in activation of the innate part of our immune system, but also of the adaptive branch. In the next two studies, presence of the virus-sensing receptors TLR3, TLR7 and TLR9 was shown in eosinophils. Stimulation with the cognate ligands gave rise to an activation manifested by an increased eosinophil survival, release of damaging mediators and ability to migrate to inflamed areas. It was also found that the response was higher in atopic patients with allergic rhinitis than in healthy subjects, and in the presence of a Th2-like cytokine milieu. Thus, activation of eosinophils via these TLRs might engender a link between viral infection and allergic exacerbations. In the following work, the effect of nasal administration with the TLR9 agonist CpG was described in healthy subjects and in patients with allergic rhinitis. CpG exposure resulted in an increased nasal resistance, production of nasal nitric oxide, infiltration of inflammatory cells and release of pro-inflammatory Th1-type cytokines. These responses were generally more marked among the healthy subjects, most likely due to the ongoing persistent inflammation seen in the allergic group. Taken together, these results show that CpG induces a local inflammation that skews the immune response towards a Th1-like phenotype. Lastly, cellular and molecular effects induced by rush immunotherapy were analyzed in patients with birch pollen-induced allergic rhinitis. The clinical improvements seen as a result of three years of treatment were mirrored by several changes in antibody and receptor levels. Of these, a reduction in serum allergen-specific IgE antibodies, correlating with cell-bound IgE and IgG expression, along with a general activation of T cells were most prominent. The novel findings in this report included a shift in monocyte populations and decrease in levels of TLR2 and TLR4. To summarize, the results presented in this thesis demonstrate a role for TLRs in lymphocyte and eosinophil biology, as well as an involvement in tonsillar and allergic inflammation. Although their exact role in airway inflammation is unclear, the TLR system holds great promise in the development of new therapeutic alternatives for allergic and inflammatory diseases

Fuktinducerade deformationer hos trä.

This essay describes computer programs for simulation of mechano-sorptive effects in wooden materials, i.e. the interaction between moisture changes and mechanical leading. Further on, three exaroples of deformation in wooden structures due to moisture variations are presented

Grågäss vid Sörfjärden 2010-2012

Under 2012 avslutades en treårig studie av grågässens numerär och rörelsemönster i jordbrukslandskapet kring Sörfjärden mellan Strängnäs och Eskilstuna. Avsikten var att kartlägga grågässens nyttjande av åkermark i området och ge underlag för en välgrundad målsättning för grågässens populationsstorlek, men även kunskap om skadeförebyggande arbete. Inom studiens ram har fyra aktiviteter genomförts: • Veckovisa räkningar av antalet grågäss längs en inventeringsrutt runt Sörfjärden. • Anläggning och skötsel av en avledningsåker (gåsbetesåker). • Studier av grödo- och betespreferenser. • Studier av hur gässen utnyttjar avledningsåkern och känsligheten för störningar från en angränsande väg. Inventeringarna visar, som förväntat, att spannmåls- och baljväxtodlingar i strandnära lägen är attraktiva och särskilt utsatta för skaderisker i samband med grågässens födosök. Skaderiskerna är dock främst begränsade till vår- och försommar då växtligheten på höst- eller vårsådda fält är späd. De förebyggande åtgärder som vidtagits (stängsling, gåsbetesåker, skrämsel och skyddsjakt) har dock varit tillräckliga hittills och inga ekonomiska ersättningskrav för skördeskador har rests under den aktuella treårsperioden. Gåsbetesåkern vid Fältstation Rördrommen har varit välbesökt under vår och försommar fram till grågässens ruggning i juni (ca 30 % av de totalt observerade gässen). Under sensommaren och hösten har spillsäden på skördade åkrar förmodligen varit mer attraktiv då besöksfrekvensen vid gåsbetesåkern minskat. Växtligheten på den naturgödslade gåsbetesåkern har tidvis varit mycket frodig. För att underlätta för gässen att landa skapades vid några tillfällen landningsbanor på åkern. I övrigt så har skötseln efter sådden 2010 bestått i ensilageskördar och gödsling. Inblandningen av cikoria i utsädet vid gåsbetesåkerns anläggning 2010 har inte gett några klara utslag vad avser betespreferenser inom ramen för detta försök. Man kan dock konstatera att grågässen betar späda växtdelar på cikoriaplantan med god aptit. Spillningsräkning över åkern har bekräftat att störningarna från en angränsande lokal väg och bebyggelse i direkt anslutning till åkern inte hindrat gässen från att beta i vägens närhet. Resultat och erfarenheter från detta projekt har tidigare redovistas i två årsrapporter för åren 2010 och 2011. Denna rapport omfattar hela projektperioden och överlappar därmed delvis de tidigare sammanställningarna

Diminished levels of nasal S100A7 (psoriasin) in seasonal allergic rhinitis: an effect mediated by Th2 cytokines

<p>Abstract</p> <p>Background</p> <p>S100A7 is an antimicrobial peptide involved in several inflammatory diseases. The aim of the present study was to explore the expression and regulation of S100A7 in seasonal allergic rhinitis (SAR).</p> <p>Methods</p> <p>Nasal lavage (NAL) fluid was obtained from healthy controls before and after lipopolysaccharide (LPS) provocation, from SAR patients before and after allergen challenge, and from SAR patients having completed allergen-specific immunotherapy (ASIT). Nasal biopsies, nasal epithelial cells and blood were acquired from healthy donors. The airway epithelial cell line FaDu was used for <it>in vitro </it>experiments. Real-time RT-PCR and immunohistochemistry were used to determine S100A7 expression in nasal tissue and cells. Release of S100A7 in NAL and culture supernatants was measured by ELISA. The function of recombinant S100A7 was explored in epithelial cells, neutrophils and peripheral blood mononuclear cells (PBMC).</p> <p>Results</p> <p>Nasal administration of LPS induced S100A7 release in healthy non-allergic subjects. The level of S100A7 was lower in NAL from SAR patients than from healthy controls, and it was further reduced in the SAR group 6 h post allergen provocation. In contrast, ASIT patients displayed higher levels after completed treatment. S100A7 was expressed in the nasal epithelium and in glands, and it was secreted by cultured epithelial cells. Stimulation with IL-4 and histamine repressed the epithelial S100A7 release. Further, recombinant S100A7 induced activation of neutrophils and PBMC.</p> <p>Conclusions</p> <p>The present study shows an epithelial expression and excretion of S100A7 in the nose after microbial stimulation. The levels are diminished in rhinitis patients and in the presence of an allergic cytokine milieu, suggesting that the antimicrobial defense is compromised in patients with SAR.</p

Holistic monitoring of freshwater and terrestrial vertebrates by camera trapping and environmental DNA

The anthropogenic impact on the world's ecosystems is severe and the need for non-invasive, cost-effective tools for monitoring and understanding those impacts are therefore urgent. Here, we combine two such methods in a comprehensive multi-year study; camera trapping (CT) and analysis of environmental DNA (eDNA), in river marginal zones of a temperate, wetland Nature Park in Denmark. CT was performed from 2015 to 2019 for a total of 8778 camera trap days and yielded 24,376 animal observations. The CT observations covered 87 taxa, of which 78 were identified to species level, and 73 were wild native species. For eDNA metabarcoding, a total of 114 freshwater samples were collected from eight sites in all four seasons from 2017 to 2018. The eDNA results yielded a total detection of 80 taxa, of which 74 were identified to species level, and 65 were wild native species. While the number of taxa detected with the two methods were comparable, the species overlap was only 20%. In combination, CT and eDNA monitoring thus yielded a total of 115 wild species (20 fishes, 4 amphibians, one snake, 23 mammals, and 67 birds), representing half of the species found via conventional surveys over the last ca. 20 years (83% of fishes, 68% of mammals, 67% of amphibians, 41% of birds, and 20% of reptiles). Our study demonstrates that a holistic approach combining two non-invasive methods, CT, and eDNA metabarcoding, has great potential as a cost-effective biomonitoring tool for vertebrates

Dental and Periodontal Health in Acute Intermittent Porphyria

In the inherited metabolic disorder acute intermittent porphyria (AIP), high sugar intake prevents porphyric attacks due to the glucose effect and the following high insulin levels that may lower AIP disease activity. Insulin resistance is a known risk factor for periodontitis and sugar changes diabetogenic hormones and affects dental health. We hypothesized differences in homeostasis model assessment (HOMA) scores for insulin resistance in AIP cases vs. controls and in those with periodontitis. Our aim was to systematically study dental health in AIP as poor dental health was previously only described in case reports. Further, we aimed to examine if poor dental health and kidney failure might worsen AIP as chronic inflammation and kidney failure might increase disease activity. In 47 AIP cases and 47 matched controls, X-rays and physical examination of clinical attachment loss (CAL), probing pocket depth (PPD), and decayed missing filled teeth (DMFT) were performed. Dietary intake was evaluated through a diet logbook. Plasma cytokines and diabetogenic hormones were measured using multiplex technology and urine porphobilinogen and kidney and liver function by routine methods. An excel spreadsheet from the University of Oxford was used to estimate HOMA scores; beta cell function, HOMA%B (%B), insulin sensitivity, HOMA%S (%S), and insulin resistance HOMA-IR (IR), based on glucose and plasma (P) C-peptide. The Wilcoxon matched-pairs signed rank test, the Mann–Whitney U-test, and Spearman’s nonparametric correlation were used. Insulin (p = 0.007) and C-peptide (p = 0.006) were higher in the AIP cases with periodontitis versus those without. In AIP patients, the liver fibrosis index 4 correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.006); the estimated glomerular filtration rate correlated with DMFT (p < 0.001) and CAL ≥4 mm (p = 0.02). CAL ≥4 mm was correlated with chemokine ligand 11 and interleukin (IL)-13 (p = 0.04 for both), and PPD >5 mm was correlated with plasminogen activator inhibitor-1 (p = 0.003) and complement component 3 (p = 0.02). In conclusion, dental health in AIP cases was correlated with insulin resistance, inflammatory markers, and biomarkers of kidney and liver function, demonstrating that organ damage in the kidney and liver are associated with poorer dental health

Changes in life expectancy and disease burden in Norway, 1990–2019: an analysis of the Global Burden of Disease Study 2019

Bill & Melinda Gates FoundationpublishedVersio