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Download ABSTRACT The etiology of multiple sclerosis involves a
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ABSTRACT The Role of a Non-Receptor Tyrosine Kinase in Experimental Autoimmune Encephalomyelitis By Freja Aksel Jacobsen The etiology of multiple sclerosis involves a combination of genetic predisposition and environmental factors, and results in an autoimmune response against myelin peptides. Human and mouse genomes share a high degree of similarities, and the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), provides an important tool for studying genetics and cellular mechanisms leading to increased disease susceptibility. Tyrosine kinases connect extracellular stimuli to intracellular activation of signaling molecules through phosphorylation cascades. The tyrosine kinase Arg takes part in lymphocyte’s signalling cascades, and is furthermore a key actor in cytoskeletal reorganization. A specific genetic locus, Eae27, located on mouse chromosome 1, has previously been linked to disease in EAE studies. The Arg gene, which encodes the tyrosine kinase Arg, is located within Eae27. A single nucleotide polymorphism (SNP) causes an amino acid shift in one of Arg’s protein-binding domains, and together with the role of Arg in lymphocyte signaling, this led to the hypothesis that Arg was an EAE candidate gene within Eae27. In vitro studies aimed to elucidate whether genetic variations within Eae27 caused differences in lymphocyte phenotype. Furthermore, studies of the ameliorating effect of an Abl kinase inhibitor aimed to strengthen the hypothesis that Arg could be an EAE candidate gene. In addition, binding studies with actin should clarify the influence of an SNP-related amino acid shift on Arg function. Finally, studies in Arg knockout mice aimed to investigate whether lack of Arg would result in altered EAE susceptibility and different lymphocyte phenotype. Our results demonstrate that genetic variations within Eae27 cause altered EAE susceptibility and lymphocyte activation. Furthermore, inhibition of Abl kinases was found to ameliorate EAE. Together with data, which indicate that a known polymorphism within Arg results in changed ability of Arg to bind actin, we conclude that Arg is an EAE candidate gene. In addition, we show that Arg-/- mice develop EAE with similar severity as Arg+/+ mice, but reveal a significant reduction in relative B-cell number in spleens from immunized Arg-/- mice. Together this PhD thesis elucidates a role for Abl kinases in signaling mechanisms leading to autoimmune neuroinflammation.