Rheumatoid arthritis is a complex disease that involves participation of both genetic and environmental factors, a complexity that current mouse models do not always mirror. New approaches are urgently needed to elucidate the mechanisms underlying susceptibility to this disease, as well as factors influencing both the initiation and perpetuation of systemic inflammation in distal joints. Using a new genetic tool, a set of C57BL/6J-ChrNPWD chromosomal substitution (consomic) strains in which a single chromosome from the wild derived PWD/PhJ mouse strain is transferred onto a C57BL/6J genetic background, I have shown that 1) a 2.2-Mb region on PWD/PhJ Chromosome 6 (Chr 6), containing seven genes, confers resistance to serum induced arthritis, and 2) modifier genes on other chromosomes interact with the Chr 6 region to change its dominance status. None of these seven genes has to date been implicated in rheumatoid arthritis. The goal of this study is to determine which of the candidate genes is responsible for the arthritis resistance and map the additional genes that confer arthritis resistance either independently or by interaction with the gene(s) on Chr 6. Narrowing the list of seven genes will be accomplished by investigating the primary structure and expression of the candidate genes in the C57BL/6J and PWD/PhJ strains. Microarray, flow cytometric, cytokine/chemokine, and histopathological analyses of peripheral blood and joint tissues will be used to gain understanding of the genetic factors and mechanisms that induce and sustain the joint-specific inflammation in C57BL/6J mice, but not in the PWD/PhJ and C57BL/6J-Chr6PWD consomic strains. Mapping the additional genes on other chromosomes participating in arthritis resistance will be done using two approaches. The first will test for genes that confer the resistance phenotype independently or semiindependently of Chr 6. To achieve this, the entire set of C57BL/6J-ChrNPWD strains will be analyzed for susceptibility to serum-induced arthritis. If some strain(s) prove resistant to inflammatory arthritis, the underlying genes will be mapped in a backcross or F2 cross between the corresponding strain and C57BL/6J. In the second approach, modifier genes on other chromosomes that interact with the gene(s) on Chr 6 to confer arthritis resistance will be mapped in another cross, in which the progeny will be heterozygous PWD/PhJ-C57BL/6J for Chr 6 and recombinant for the remaining chromosomes. These studies will provide the opportunity to find new gene(s) that inhibit arthritis initiation and/or progression and dissect molecular pathways involved in arthritis pathogenesis. The novelty of the proposal is that it allows the mapping of genes modifying the response to arthritogenic stimulus, a task that is extremely difficult if not impossible in humans.
The proposed mouse model provides a unique opportunity to determine susceptibility genes and dissect molecular pathways that could be similar or common in human rheumatoid arthritis. This will not only improve our understanding of the molecular events that underlie the pathology of arthritis, but also have the potential for development of new therapeutic approaches.
