Download ABSTRACT The etiology of multiple sclerosis involves a

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.