Institutionen för klinisk neurovetenskap / Department of Clinical Neuroscience
Abstract
Many central nervous system (CNS) diseases are characterized by
inflammation and nerve cell loss, but the exact relationship between
these phenomena is not known. The complex etiology of CNS disorders
includes a genetic component. MHC class II molecules are key mediators of
immune activation and variations in MHC class II genes are the main
genetic determinant of several complex autoimmune disorders. Gene regions
regulating complex phenotypes can be mapped in experimental animal
crosses. In this thesis, the genetic regulation of the response to
mechanical nerve injury and experimental autoimmune encephalomyelitis
(EAE) was investigated in populations of intercrossed mice and rats.
The effect of a previously identified gene region, Vra4, on MHC class II
expression was characterized in DA.PVG1av1-Vra4 and PVG1av1DA-Vra4
congenic rat strains after ventral root avulsion (VRA). Vra4 contains the
class II transactivator gene, Mhc2ta, which is a transcription factor for
MHC class II. The influence of the same region was tested in EAE. The
results show that Vra4 regulates MHC class II on microglia after VRA, as
well as risk and severity of EAE. In addition, IFN-g inducible class II
expression on antigen presenting cells (APCs) is dependent on the Vra4
region. Similar results were obtained in a study of inbred mouse strains,
where differential MHC class II expression was observed in the facial
nucleus after axotomy of the facial nerve. Congenic strain experiments
and sequencing of C2ta strongly indicate that polymorphisms in the
regulatory region of the pI promoter are regulating this trait. Vra4/C2ta
had no effect on expression of microglial markers, co-stimulatory
molecules or MHC class I, nor T cell infiltration. Additional genetic
influence on MHC class II expression was mapped to chromosomes 1 and 7 in
a F2 cross between BN and LEW.1N rats, two strains which share Mhc2ta
haplotype but display differential MHC class II expression after VRA.
Analysis of other inflammatory markers in this cross revealed common
regulation of several immune related molecules by the same gene region,
which may suggest upstream effects.
Finally, the genetic impact on nerve cell death following VRA by two gene
regions previously detected in a F2(DAxPVGc) cross, Vra1 and Vra2, was
fine mapped in 2 generations of an advanced intercross line (AIL) between
DA and PVG1av1 rats, as well as in a panel of Vra1 congenic strains. The
effect of Vra1 on neurodegeneration was reproduced in both AIL
populations. Increased support was given by the congenic strains, where
PVG alleles in the Vra1 region on DA background resulted in significantly
reduced neuronal loss. These studies also narrowed down the Vra1 region
from 54 to 9 Mb. Vra2 displayed suggestive linkage to neurodegeneration
only in one AIL cohort, but showed an additive effect on the phenotype
together with Vra1.
To conclude, these results show that neuroinflammation and
neurodegeneration are influenced by genetic factors. Identification of
genes and pathways will increase our understanding of the molecular
pathways of human complex disease