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No description available.

The tyrosine kinase 2 (TYK2) gene was first implicated in autoimmune disease in 2009 when a nonsynonymous single nucleotide polymorphism (nsSNP) in TYK2 was reported to be associated with multiple sclerosis (MS). The immunological function of TYK2, as a kinase involved in signal transduction downstream of numerous different cytokine receptors, further strengthened the candidacy of the gene as an MS-relevant risk factor. More recently, this nsSNP has been associated with several other autoimmune conditions. In addition, another three different SNPs in the region have been found to be associated with a number of autoimmune diseases, sometimes in opposing directions. Considering the complex genetic association pattern that is emerging for the TYK2 region across autoimmune conditions, it was hypothesised that this complexity reflects shared but also distinct pathogenic mechanisms, with the consequences of disease-associated SNPs being unlikely to all be restricted to genotype-dependent effects influencing TYK2. Therefore, the main aim of the work presented in this thesis has been to address this hypothesis by investigating the functional consequences of the disease-associated SNPs in the TYK2 gene region. Using an in vitro cell line system and primary human immune cells, obtained from a genotype-selectable donor cohort, protection at the MS-associated nsSNP was found to correlate with reduced TYK2-mediated signalling downstream of the type I interferon receptor. However, other cytokine signalling pathways were not affected, indicating a greater specificity to the function of TYK2 than has previously been appreciated. For the other SNPs in the region, substantial effects on TYK2 were not observed but immune cell subset-specific correlations with RNA-level expression of other genes in the region were identified. Thus, this is the first study to support the concept that a careful cross-comparative analysis of SNP association patterns in a single genomic region across multiple autoimmune diseases can have significant implications for enabling the delineation of pathways common or specific to different conditions, and this is of particular importance for drug repositioning strategies.

<p>Macrophages are an important key effector cell in the immune system which can practically be found in every tissue. Macrophages have for a long time been considered a population of cells only responsible for pro-inflammatory responses and anti-microbial activities. But over the past decade, many have come to realize the amazing plasticity of macrophages in response to different stimulations. The anti-microbial and pro-inflammatory macrophage is known as classically activated macrophages but newly discovered phenotypes have been revealed named wound-healing macrophages and regulatory macrophages. Through systematic screening we have identified an inducible macrophage activation state which has both wound-healing and regulatory capabilities activated by the novel cytokine combination IL-4/IL-10 with or without TGF-β.</p>

Macrophages are an important key effector cell in the immune system which can practically be found in every tissue. Macrophages have for a long time been considered a population of cells only responsible for pro-inflammatory responses and anti-microbial activities. But over the past decade, many have come to realize the amazing plasticity of macrophages in response to different stimulations. The anti-microbial and pro-inflammatory macrophage is known as classically activated macrophages but newly discovered phenotypes have been revealed named wound-healing macrophages and regulatory macrophages. Through systematic screening we have identified an inducible macrophage activation state which has both wound-healing and regulatory capabilities activated by the novel cytokine combination IL-4/IL-10 with or without TGF-β.

No description available.