Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease of the joints with a complex aetiology affected by largely unknown genetic and environmental factors. Since ~60% of susceptibility to RA is genetically inherited, one way to progress towards understanding of the disease is to identify the disease regulating genes.
Collagen-induced arthritis (CIA) is the most commonly used model of RA in mice. After immunisation by a subcutaneous injection of collagen emulsified in adjuvant, mice develop a T and B-cell dependent inflammation of the peripheral joints that mimics many characteristics of RA, including production of autoantibodies. Genetic inheritance of CIA has been extensively studied and by now 44 quantitative trait loci (QTL) controlling CIA have been identified. The RA susceptibility genes identified so far point to a central role of T-cell activation along with B cell activation. The central role of the TCR in these processes makes it an appealing candidate and interestingly the previously described Cia6 locus on mouse chromosome 6 is linked to the region encoding the TCR-β chain.
We have mapped seven new CIA loci on chromosome 6 and 14 using congenic strains made between the relatively resistant B10.Q and the highly susceptible DBA/1 strain. The congenics were intercrossed in a partial advanced intercross (PAI) strategy and analysed by linkage analysis, followed by confirmation of found loci in a collection of heterozygous congenic strains with partly overlapping fragments. Using this strategy, we identified seven new arthritis regulating loci including two loci corresponding to the two TCR-chains. Among these loci we found evidence of both epistatic effects and sex- specificity.
Also, we demonstrated the usefulness of the recent advancement in mapping such as genetically heterogeneous stock cross (HS) in the fine mapping of the known Cia36 locus using different lymphocyte sub-phenotypes, that were all associated with the markers within the Slc38a1 gene, as was previously shown for arthritis.
In conclusion, this thesis illustrates the capacity and importance of different mapping strategies in order to identify underlying complex set of loci in an animal model.
