Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains.

Abstract

DA rats are highly susceptible to experimental models of rheumatoid arthritis (RA). Linkage analyses in different models have identified several quantitative trait loci (QTLs) within a 70-cM region of DA rat chromosome 4 (C4). We produced congenic strains for these QTLs in order to map and characterize their impact on arthritis development. Selective breeding was used to transfer C4 intervals from arthritis-resistant PVG.1AV1 rats onto DA rats. These congenic strains were evaluated for susceptibility to arthritis induced by intradermal injection of rat type II collagen, pristane (a well-defined synthetic adjuvant oil), mycobacteria, or squalene (an endogenous adjuvant oil used in human vaccine). Rats congenic for PVG.1AV1 genes in the 70-cM region were less susceptible than DA rats to collagen-induced arthritis (CIA), pristane-induced arthritis, adjuvant-induced arthritis, and squalene-induced arthritis (SIA). Experiments in subcongenic strains indicated a gene regulating arthritis in males located in a 20-cM interval overlapping the QTL Pia5. A second gene, located in a 10-cM interval harboring the QTL Oia2, attenuated SIA and CIA. The latter caused a change in anticollagen antibody isotype levels toward a pattern similar to that seen in PVG.1AV1 rats. The QTL Oia2 regulates arthritis induced both by the nonimmunogenic immunostimulant squalene and by cartilage collagen. In CIA, it also skews anticollagen isotype profiles, suggesting qualitative regulation of autoimmunity. Interestingly, the homologous human chromosome region 12p12-p13 has also been linked to RA, suggesting that genetic and functional dissection of this locus will provide clues to disease pathways that lead to joint inflammation.