Abstract
Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development. The Abl2 gene, encoding the non-receptor tyrosine kinase Arg, is located in the 4,1 megabase pair long Eae27 region. The Arg protein plays an important role in cellular regulation and is, in addition, involved in signaling through the B- and T-cell receptors, important for the autoimmune response. The presence of a single nucleotide polymorphism causing an amino acid change in a near actin-interacting domain of Arg, in addition to altered lymphocyte activation in the congenic mice upon immunization with myelin antigen, makes Abl2/Arg a candidate gene for EAE. Here we demonstrate that the non-synonymous SNP does not change Arg’s binding affinity for F-actin but suggest a role for Abl kinases in CNS inflammation pathogenesis by showing that pharmacological inhibition of Abl kinases ameliorates EAE, but not experimental arthritis.
Highlights
The complexity of autoimmune diseases, involving both genetic and environmental factors, makes it difficult to reveal mechanisms responsible for initiating an immune response against self-structures
In order to study the effect of this locus for EAE development, a congenic mouse strain was bred (BR.RIIIS/J-Eae27)
Our results demonstrate a role for the murine locus Eae27 in EAE development and lymphocyte activation
Summary
The complexity of autoimmune diseases, involving both genetic and environmental factors, makes it difficult to reveal mechanisms responsible for initiating an immune response against self-structures. One strategy to study genetic factors linked to disease susceptibility is breeding of congenic mouse strains followed by studies of disease development in models resembling human inflammatory disease. This strategy enables studies of specific genetic loci, and the impact of therein located genes, and natural allelic variation, on disease development (Rogner and Avner, 2003). The RIIIS/J mouse strain is, in contrast to the B10.RIII strain, resistant to experimental autoimmune encephalomyelitis (EAE), the animal model for MS, when immunized with myelin basic protein peptide 89–101 (MBP89–101) (Jansson et al, 1991). The B10.RIII and RIIIS/J mouse strains both express the murine H-2r MHC haplotype, concluding that non-MHC genes are responsible for the difference in disease phenotype observed in the two strains (Sundvall et al, 1995; Karlsson et al, 2003; Lindvall et al, 2011)
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