Susceptibility to experimentally-induced inflammatory diseases, including various forms of experimental arthritis resembling rheumatoid arthritis, varies substantially among inbred rat strains. For example LEW and DA are generally highly susceptible to streptococcal cell wall, adjuvant and collagen-induced arthritis, whereas F344, BN and other strains are relatively resistant. These differences are under multigenic control. OBJECTIVE: We are interested in defining the mechanisms that functionally underlie these divergent patterns of susceptibility and resistance because this information may provide insights in human autoimmune inflammatory diseases. We have been evaluating the hypothesis that differences in susceptibility may, in part, reflect biased type 1 versus type 2 cytokine expression in these rat strains. In addition, we are attempting to generate a variety of quantitative trait loci (QTL)-congenic inbred rat strains to analyze in more depth the regulatory mechanisms. RESULTS: We have observed that autoimmune disease-prone LEW rats, in collaboration with Dr. Rachel Caspi, NEI, readily produce large numbers of gamma interferon-producing Th1 cells in response to uveitic autoantigen challenge in vivo, whereas F344 rats generate a more balanced type 1/type 2 cytokine profile. A manuscript on this topic was published (Caspi R et al., Eye 11:209, 1997). We extended this cytokine analysis into autoimmune eye disease-prone mice and found similar results, although we could not characterize all susceptible and resistant mouse strains simply as type 1 or type 2 cytokine dominant responders (Sun B et al., J. Immunol. 159:1004, 1997). These data indicate that cytokine profiles are related to susceptibility, but many other factors are likely to be involved. We have also made substantial progress in achieving our goal of producing QTL-congenic rat strains. We have successfully introgressed 4 genomic regions from F344 rats, which putatively contain resistance genes, onto the DA background. We plan to begin characterizing the phenotypes of the QTL-congenic inbred rats over the next year. 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. These data provide potential insights to human autoimmune diseases such as rheumatoid arthritis and various forms of immune-mediated eye diseases. The data may facilitate the development of novel therapies.
