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 in human autoimmune inflammatory diseases. We have been evaluating the hypothesis that differences in susceptibility in these rat strains may, in part, be reflected in different patterns of cytokine production by macrophages and T cells. Related to this hypothesis, we are also investigating the hypothesis that the functional differences may, in part, be related to hormonal mechanisms associated with the hypothalamic-pituitary-adrenal axis. To characterize these differences among the various rat strains more extensively, we are developing and characterizing a variety of quantitative trait loci (QTL)-congenic inbred rat strains. We are beginning to use these animals to investigate our hypotheses in greater depth. RESULTS: As we have previously shown for LEW rats, we have now demonstrated that autoimmune disease-prone DA rats, in contrast to F344 and BN rats, fail to display a circadian rise in basal corticosterone levels in the late light phase and early dark phase of the 24 hour cycle. That is, they, like LEW rats, have a flattened 24-hour circadian rhythm for corticosteroids. Because both autoimmune disease-prone strains have a similar problem producing corticosteroids, we suspect that this abnormality may influence susceptibility to autoimmune disease and may relate, in part, to the pronounced overproduction production, in response to numerous stimuli, of TNF-alpha and IL-12 previously demonstrated in DA rats. We have also made substantial progress in developing QTL-congenic rat strains. We have successfully introgressed 4 genomic regions from F344 rats, which putatively contain resistance genes for AIA and/or CIA that we identified through genome scanning techniques, onto the DA background. We have begun to characterize the expression of several traits in these QTL-congenic inbred rats. Initial data suggest that several of the congenic strains show substantial changes in phenotypic expression compared to the parental DA or F344 rats. Further characterization of these changes 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 models provide an experimental system to study these hypotheses. The data may provide potential insights to human autoimmune diseases such as rheumatoid arthritis and may facilitate the development of novel therapies. - rheumatoid arthritis, autoimmunity, animal models, cytokines, rats, genetics
