Genetic and Immunological Regulation of Neuroinflammation

Multiple Sclerosis (MS) affects young adults and is characterized by chronic inflammation and demyelination in the central nervous system that leads to progressive worsening of disease. The cause of MS is incompletely understood and there is a need for more specific and effective treatments. This thesis aimed to characterize genetically controlled pathogenic mechanisms in the model of MS, experimental autoimmune encephalomyelitis (EAE), and to translate findings from experimental models to human disease. We demonstrated that genetic risk factors and pathogenic mechanisms in EAE are similar to those of MS. The EAE-susceptible strain had increased expression of MS candidate genes Il2ra and Il7r among others and upregulation of MS-associated immunological pathways such as TH1 and TH17. Expression of Il18r1 was increased in both the susceptible strain and in periphery and cerebrospinal fluid of MS patients. This might contribute pathogenically to disease through T cell differentiation and activation. Clinically isolated syndrome (CIS) patients had elevated IL18R1 expression, thus it could potentially serve as an early disease biomarker. Using an expression quantitative trait loci (eQTL) approach we detected numerous cis-regulated positional candidate genes for EAE and defined several disease correlated gene networks enriched for pathways involved in cell-mediated immune mechanisms of relevance for both EAE and MS. Mfsd4 was identified as a candidate gene for Eae34 which conferred a functional effect on T cell proliferation and activation. The importance of autophagy related genes in the pathogenesis of neuroinflammation was investigated. Atg7 expression was higher in the EAE-resistant strain and in MS patients it associated with remission and less severe symptoms. Results presented in this thesis collectively demonstrate genetic regulation of known and novel mechanisms in EAE and MS and point to causal pathogeni

Fine-Mapping Resolves Eae23 into Two QTLs and Implicates ZEB1 as a Candidate Gene Regulating Experimental Neuroinflammation in Rat

This study was supported by grants from the Swedish Research Council, The Wadsworth Foundation, Söderbergs Foundation, Petrus and Augusta Hedlunds Foundation, Bibbi and Niels Jensens Foundation, Montel Williams Foundation, Åke-Wibergs Stiftelse, the Swedish Foundation for Neurologically Disabled and the EU 6TH Framework EURATools (LSHG-CT-2005-019015) and Neuropromise (LSHM-CT-2005-018637)

Microglial autophagy-associated phagocytosis is essential for recovery from neuroinflammation

Multiple sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation and neurodegeneration in the central nervous system (CNS). The capacity of microglia to clear tissue debris is essential for maintaining and restoring CNS homeostasis. This capacity diminishes with age, and age strongly associates with MS disease progression, although the underlying mechanisms are still largely elusive. Here, we demonstrate that the recovery from CNS inflammation in a murine model of MS is dependent on the ability of microglia to clear tissue debris. Microglia-specific deletion of the autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin and progressive MS-like disease. This impairment correlated with a microglial phenotype previously associated with neurodegenerative pathologies. Moreover, Atg7-deficient microglia showed notable transcriptional and functional similarities to microglia from aged wild-type mice that were also unable to clear myelin and recover from disease. In contrast, induction of autophagy in aged mice using the disaccharide trehalose found in plants and fungi led to functional myelin clearance and disease remission. Our results demonstrate that a noncanonical form of autophagy in microglia is responsible for myelin degradation and clearance leading to recovery from MS-like disease and that boosting this process has a therapeutic potential for age-related neuroinflammatory conditions.Swedish Research CouncilSwedish Brain FoundationSwedish Association for Persons with Neurological DisabilitiesStockholm County Council (ALF project)AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration)European Union Horizon 2020/European Research Council Consolidator Grant (Epi4MS)Knut and Alice Wallenbergs FoundationMargeretha af Ugglas FoundationAlltid Litt SterkereFoundation of Swedish MS researchNEURO SwedenKarolinska InstitutetAccepte

Alternative splicing and transcriptome profiling of experimental autoimmune encephalomyelitis using genome-wide exon arrays

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory disease causing demyelination and nerve loss in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate complex pathogenic mechanisms. Transcriptional control through isoform selection and mRNA levels determines pathway activation and ultimately susceptibility to disease. METHODOLOGY/PRINCIPAL FINDINGS: We have studied the role of alternative splicing and differential expression in lymph node cells from EAE-susceptible Dark Agouti (DA) and EAE-resistant Piebald Virol Glaxo.AV1 (PVG) inbred rat strains using Affymetrix Gene Chip Rat Exon 1.0 ST Arrays. Comparing the two strains, we identified 11 differentially spliced and 206 differentially expressed genes at day 7 post-immunization, as well as 9 differentially spliced and 144 differentially expressed genes upon autoantigen re-stimulation. Functional clustering and pathway analysis implicate genes for glycosylation, lymphocyte activation, potassium channel activity and cellular differentiation in EAE susceptibility. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that alternative splicing occurs during complex disease and may govern EAE susceptibility. Additionally, transcriptome analysis not only identified previously defined EAE pathways regulating the immune system, but also novel mechanisms. Furthermore, several identified genes overlap known quantitative trait loci, providing novel causative candidate targets governing EAE

HUR PÅVERKAR UNGDOMARS BAKGRUND DERASARBETSVÄRDERINGAR? : – En kvantitativ studie baserat på data frånUngdomsstyrelsens Attityd- och Värderingsstudie 2007.

I syfte att undersöka hur ungdomars bakgrund påverkar deras arbetsvärderingar genomfördesen kvantitativ undersökning med datamaterial hämtat från Ungdomsstyrelsens Attityd- ochVärderingsstudie från 2007. Genom att använda Herzberg’s tvåfaktorsteori som utgångspunktanalyserades datamaterialet utifrån två dimensioner av arbetsvärderingar och med hjälp avlinjär regressionsanalys. Resultatet visar att ungdomars kön och födelseland samt egna ochfaderns högsta avslutade utbildning är de viktigaste bakgrundfaktorerna som påverkar hurderas arbetsvärderingar ser ut. Olika bakgrundsfaktorer tenderar också att påverka de olikadimensionerna av arbetsvärderingarna på olika sätt

Reaction and miscibility of two diepoxides with poly(ethylene terephthalate)

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