Autoimmune disorders start to develop when the body’s immune system recognizes organs
and tissues as foreign and initiates uncontrolled immune reactions against them. Most of
these disorders are regarded as complex with both environmental and genetic factors
contributing to disease development. Current treatment of autoimmune disorders such as
Rheumatoid arthritis (RA) is associated with lack of efficacy, development of resistance and
serious side-effects and accentuates the need for development of new therapeutics.
Improved understanding of the underlying genetic pathways that convey pathogenicity in
arthritis is key to discover more efficient and safe therapies. The heterogenetic nature of
autoimmune diseases and the interaction with environmental factors delays the discovery
of susceptibility genes in humans, which suggests the use of animal models where both
genetic background and environment can be controlled. In this thesis we have used rat
models to identify genes that regulate the induction of autoimmune arthritis. In study one,
we identify the gene encoding Endophilin A2 as a major determinant in regulating the
induction of autoimmunity and show that the Endophilin A2 mediated protection is
regulated via T cell responsiveness. In study two, we investigate the role of the Vav1 gene,
previously associated to multiple sclerosis, for its role in arthritis in rats and humans and
show that natural variants in the Vav1 gene regulate T cell dependent arthritis. In study
three, we determine by functional studies that the increase in reactive oxygen species
conveyed by the Ncf1 gene, is responsible for reduced arthritis severity seen in Ncf1
congenic rats. In study IV, we use high resolution mapping in a rat heterogeneous stock to
identify genes regulating expression of cell surface molecules and frequency of different
leukocytes in blood. By combining animal studies and human data we have in this thesis
identified new genes involved in the pathogenesis of arthritis, which further illustrates the
heterogenic nature of RA and the shared peripheral tolerance pathways regulating different
autoimmune disorders. Furthermore, the results in this thesis have demonstrated the value
of using animal studies to identify genes and pathways relevant to human disorders
