Susceptibility to experimentally induced inflammatory diseases, including various forms of experimental arthritis resembling rheumatoid arthritis, varies substantially among inbred rat strains. For example, DA rats are highly susceptible to collagen-induced arthritis (CIA), adjuvant-induced arthritis (AIA), pristane-induced arthritis (PIA), and oil-induced arthritis (OIA). LEW rats are highly susceptible to CIA, AIA, PIA, and streptococcal cell wall arthritis (SCWA). By contrast, F344, BN and other strains are relatively resistant to these experimental models. These differences in susceptibility are under both MHC and non-MHC multigenic control. OBJECTIVE: We have been investigating the mechanisms that functionally underlie these divergent patterns of susceptibility and resistance because this information may facilitate the identification of the regulatory genes, and may also provide insights into human autoimmune inflammatory diseases. To understand the differences among the various rat strains more deeply, we are developing and characterizing a variety of quantitative trait loci (QTL)-congenic inbred rat strains. They are being compared with experimentally arthritis-prone DA and LEW and relatively resistant F344 and BN rats. RESULTS: We have continued to make substantial progress this past year in developing and characterizing experimental arthritis QTL-congenic rat lines and sub-lines. These lines confirmed that QTLs on chromosomes 4, 10 and 20 exert substantial influence on CIA severity. We also demonstrated that these QTLs exert potent regulatory influences on OIA and PIA. Interestingly, the chromosome 4 CIA QTL resistance alleles were specific for female congenic rats. Data from QTL-congenic sub-lines implicated the presence of multiple CIA regulatory loci with different sex effects within the chromosome 10 QTL region. Although F344 alleles at QTL regions on chromosomes 7 and 8 failed to independently influence CIA, they significantly reduced OIA severity in males, but not females. These observations, as well as results from new mapping studies, clearly support the concept that sex effects are intimately linked to individual genetic factors regulating experimental arthritis. Only modest AIA modifying effects were found in AIA QTL-congenic lines with a single AIA resistance locus transferred to the susceptible strain background. A line we constructed with resistant strain alleles at three AIA loci also had a relatively modest arthritis modulating effect compared with the arthritis-resistant line. This observation suggested the existence of additional arthritis regulatory regions that were not detected in the original AIA genome scan. We tested the CIA-QTL congenic lines and found that the chromosome 10 CIA QTL region also conferred resistance to AIA. Further characterization of the phenotypic responses in these QTL-congenic rat lines and newly developed sub-lines is in progress. CONCLUSIONS: Susceptibility to autoimmune diseases in rats and mice is regulated by a variety of genetic factors, some of which involve the unbalanced production of proinflammatory versus anti-inflammatory cytokines or differences in neuroendocrine control mechanisms. Our data strongly suggest that factors related to sex may also contribute to some of the neuroendocrine influences to susceptibility. Moreover, the research is providing strong support for the concept that sex influences are exerted on genes located on multiple autosomal chromosomes, and are not limited to effects of the X and Y chromosomes. These new data provide insights into the interactions of age, gender, reproductive status and genetics in regulating the expression of autoimmune diseases. Our data may provide potential insights to human autoimmune diseases such as rheumatoid arthritis and may facilitate the development of novel therapies.
