We and others have shown that Lewis (Lew) rats are highly susceptible to a wide spectrum of autoimmune diseases such as bacterial cell wall arthritis. We have also demonstrated that they develop severe inflammation in response to nonspecific proinflammatory agents such as carrageenin. In contrast, Fischer (F344) rats develop minimal or no inflammation in response to the same stimuli. We have previously provided data suggesting that these differences are related to a global deficiency in hypothalamic-pituitary-adrenal axis (HPA) responsiveness in Lewis rats. We have continued to characterize the functional basis of the HPA axis defect and have now shown that Lewis and Fischer rats respond similarly to corticosteroids. These data render unlikely the hypothesis that the HPA axis defect in Lewis rats is a consequence of primary abnormalities in type 1 corticosteroid receptors or tissue sensitivity to corticosteroids. We have also continued to characterize cytokine responses of Lewis and Fischer rats following LPS injection and have noted several prominent differences in these strains. These responses parallel the HPA differences. As an extension of these studies, we have also begun to clone genes that are differentially expressed in these strains in response to LPS. To date, we have cloned 2 novel transcripts (LF-1 and LF-2) and are sequencing these mRNAs. These data may provide important insights into the mechanisms regulating susceptibility and resistance to autoimmune inflammatory diseases.