EXPERIMENTAL AUTOIMMUNE ARTHRITIS AND RELATED DISEASES

Arthritis, Musculoskeletal, Skin Dis

Investigators

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Abstract

BACKGROUND: 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, 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 and -gonadal axes. 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 experimentaly arthritis-prone DA and LEW and relatively resistant F344 and BN rats. RESULTS: We have demonstrated that both autoimmune disease-prone LEW and 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, DA and 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 made substantial progress this past year in developing and characterizing QTL-congenic rat strains. We have successfully introgressed 5 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, or vice versa. We have generated data confirming that QTLs on chromosomes 4, 10 and 20 exert substantial influence on CIA severity, and interesting these regulatory effects are subject to gender influences. We have also demonstrated that these QTLs exert potent regulatory influences on OIA and PIA. These observations clearly support the concept that various autoimmune diseases share many regulatory genes in common. Further characterization of the phenotypic responses in the newly developed QTL-congenic rat strains 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 gender may also contribute to some of the neuroendocrine influences to susceptibility. Moreover, the effects of gender are intimately linked to the genetic factors. Our data may provide potential insights to human autoimmune diseases such as rheumatoid arthritis and may facilitate the development of novel therapies.