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Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis. © 2018 The Author(s), Funding: Novo Nordisk, Denmark; SHARE (Synergy in human and animal research) University of Copenhagen; The Warwara Larsen Foundation, The Carlsberg Foundation; The Karen A. Tolstrup Foundation; The A.P. Møller Foundation.

BACKGROUND: T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247. METHODS: DNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations. RESULTS: Our study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247. CONCLUSIONS: Several risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosoma

Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.

This thesis investigated the possibilities to resume cultivation of an old manor house built of timber and what this would mean from an energy and moisture perspective. The building in this case study is named Sofiedals mansion and was built in 1858 in Valbo 11 kilometers west of Gävle. The structure of the house was documented and used as a starting-point for carrying out calculations focused on energy and moisture aspects. With the help of a number of computer programs and a conducted air tightness test, the buildings energy consumption were calculated and compared with the current building regulations. In addition, the building was analyzed considering energy retrofitting and what it meant for moisture problems. The energy retrofitting consisted of additional insulation, decreasing the buildings permeability through air sealing; window and door replacements. When a building is equipped with natural ventilation it is difficult to know its precise performance and how an energy retrofitting affects it. Therefore a sensitivity-analysis was performed on four different types of ventilation performance and how they affected the buildings energy as well as its building components moisture performance. The proposed suggestion for an energy retrofitting was made with a potential buyer in mind. Therefore general problems have been documented to demonstrate other measures to be taken into consideration when cultivating the building. The investigation showed that the buildings energy consumption needs to be reduced by approximately 45% to achieve the goal of Swedens current building regulations. Depending on the presumed ventilation performance, the energy consumption and moisture content in the building components varied. The conducted sensitivity analysis showed that a vapour barrier is required to make the building safe from moisture problems. In order to achieve the building regulations energy demands a specific energy consumption of 110kWh/m 2 each year was required. Cur, Detta examensarbete undersökte möjligheterna kring att återuppta brukandet av en äldre herrgårdsbyggnad uppbyggd av timmer och vad detta skulle innebära ur ett energi- samt fuktperspektiv. Byggnaden som undersöktes heter Sofiedals herrgård och är uppförd år 1858 i Valbo 11 kilometer väst om Gävle. Husets uppbyggnad dokumenterades och användes som utgångspunkt för att kunna genomföra beräkningar inriktade på energi och fuktaspekter. Med hjälp av ett antal datorprogram och en tillhörande lufttäthetsprovning kunde husets nuvarande energianvändning beräknas och jämföras med dagens gällande byggregler. Därutöver undersöktes hur byggnaden påverkades ur energi- och fuktsynpunkt genom en energieffektivisering i form av tilläggsisolering, lufttätning, fönster- och dörrbyten. Eftersom det är svårt att kontrollera självdragsventilationens exakta prestanda har en luftflödesanalys gjorts beträffande fyra olika luftomsättningars påverkan av fukt och energiförhållanden för byggnaden. Åtgärdsförslag gällande en energieffektivisering projekterades med en potentiell köpare som bakgrund. Därför har även allmänna problem dokumenterats för att påvisa andra åtgärder som behöver vidtas. Undersökningen visade att byggnadens energianvändning behövde sänkas med ungefär 45 % för att uppnå Boverkets krav. Beroende på vilken ventilationsomsättning som antogs varierade både energianvändningen samt den relativa ånghalten i konstruktionen. En utförd luftflödesanalys visade att vid monterad ångspärr kommer konstruktionen vara fuktsäker. För att uppnå Boverkets energikrav krävs en specifik energianvändning på 110kWh/m 2·år. I dagsläget uppnår byggnaden inte kraven. Eftersom byggnaden beräknades till nästan 200 kWh/ m2∙år måste den genomgå omfattande renoveringsåtgärder.