Institutionen för medicin / Department of Medicine
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting
peripheral joints. Persistent inflammation causes cartilage deterioration
with severe joint deformations as a consequence. The etiology is largely
unknown but complex interactions between genetic and environmental
factors contribute to the disease. The disease is also clinically
heterogeneous which further hampers etiological investigations.
Analogs of certain disease pathways can be studied in experimental models
mimicking RA. A more thorough characterization of such disease pathways
may tell us of discrete disease subsets of RA.
Numerous experimental models for RA exists, both spontaneous and induced.
The DA rat is remarkably arthritis prone, an intradermal injection of a
mineral oil is sufficient to induce arthritis. The difference in
arthritogenicity between the arthritis inducers depends on the genetic
susceptibility threshold of each rat strain.
The general aim of this thesis was to by a genome - inducer approach
identify a suitable experimental system to use for mapping arthritis
susceptibility genes in the rat, and through this approach identify genes
of equal importance in humans, ultimately to provide new insights for
pathway characterization of RA.
I characterized the arthritis susceptibility in a set of recombinant
congenic strains overlapping several arthritis regulating regions on rat
chromosome 4, in five arthritis models; collagen type H-induced
arthritis, pristane-induced arthritis, mycobacteria-induced arthritis,
squalene-induced arthritis and oil-induced arthritis. All five induced
arthritis-models were regulated by chromosome 4 genes. A 10 cM fragment
that harbor the Oia2 locus mediated arthritis down-regulation in collagen
type H induced arthritis and squalene-induced arthritis. Oil-induced
arthritis was completely prevented. Further fine mapping was continued in
oilinduced arthritis. By using 18 Oia2 intra-recombinant congenic strains
the arthritis regulating interval was fine-mapped to 1.2Mb.
The arthritis regulating interval was further mapped to 600 kb that only
harbor a Ctype lectin gene complex denoted Aplec. Comparison of gene
sequences identified a nonsense mutation in Dcar1 in the DA strain as the
most possible arthritis-regulating rat gene. The human homolog to rat
Dcir, one of the other genes in the complex, was tested in a patient 1
control material. One SNP showed significant association to RA.
Association was pronounced in RF-negative patients
The genome - inducer approach was also applied in mapping of the
arthritis regulating region, Oia3, on rat chromosome 10 in the F7
generation of an advanced intercross (AIL) between the arthritis
susceptible rat strain DA, and the arthritis resistant PM I AV I. To
chose the most appropriate arthritis model for linkage mapping in the AIL
pristane-induced arthritis, squaleneinduced arthritis and oil-induced
arthritis was induced. Pristane-induced arthritis was the most
appropriate for the population. Aplec and the newly identified arthritis
regulating gene Ncf1 was also mapped to determine the mapping resolution.
Linkage mapping of Oia3 identified two distinct quantitative trait loci
(QTL), one at D10Rat13 at 97.2Mb, and an other at D10Got158 at 105.2Mb.
The placement for the Ncf1 gene, and the Aplec were both less than 100kb,
200kb surrounding the Oia3 peak marker was considered as the confidence
interval. The proximal Oia3 QTL contains the Protein kinase C alpha gene
together with a set of calcium channel voltage-dependent gamma subunit
genes. The distal Oia3 QTL contain a cluster of dendritic cell derived
Ig-like receptors, among them the homolog to the human CMRF35 gene
previously associated to psoriasis.
In conclusion the search for appropriate experimental systems to map
arthritis susceptibility regions, subsequent congenic mapping in oil
induced arthritis, lead to the identification of Aplec, a C-type lectin
complex, that codes for genes important in a number of immunological
processes. The human homolog to rat showed association to RA in a
patient/control material