2001): First is the presence of host immune response genes which carry the potential for autoimmunity. Second is exposure to a proinflammatory or antigenic challenge (which may include infection) that initiates the cascade of immune reactions that ultimately result in autoimmunity. Third is a dysregulation of the immune response to which a deficiency in the HPA axis responsivity is thought to contribute.

Studies have shown that hyporeactive stress responsivity can contribute to increased susceptibility to autoimmune and proinflammatory disorders (Mason et al., 1990; Sternberg et al., 1992a; Harbuz et al., 1997; Tonelli et al., 2001; Sternberg, 2001; Webster et al., 2002; Harbuz et al., 2003). In a series of seminal studies, Sternberg et al. (1989) showed that decreased HPA axis reactivity to inflammatory stimuli results in increased susceptibility to experimental arthritis (Sternberg et al., 1989a; Sternberg et al., 1989b; Sternberg et al., 1992b). These investigators studied the development of streptococcal cell wall (SCW)-induced arthritis in female rats belonging to the genetically related Lewis/N (LEW/N) and Fischer 344/N (F344/N) strains (Sternberg and Wilder, 1989; Sternberg et al., 1989a; Sternberg et al., 1989b; Webster et al., 2002). The F344/N strain is resistant to the development of SCW-induced arthritis, while the LEW/N strain is susceptible. Interestingly, the F344/N strain mounts a significantly greater corticosterone and adrenocorticotropin response than does the LEW/N strain when challenged with a variety of stressors or with inflammatory mediators such as SCW peptidoglycan polysaccharide or interleukin-1α (IL-1α) (Sternberg et al., 1989a; Sternberg et al., 1989b; Dhabhar et al., 1995a).

Compared to the F344 strain, the Lewis strain shows a significantly greater habituation or adaptation to an acute or chronic stressor (Dhabhar et al., 1997). F344/N rats treated with the glucocorticoid receptor antagonist RU486 are rendered susceptible to SCW-induced arthritis, indicating that they do carry the immune response genes with potential for triggering autoimmunity (Sternberg et al., 1989a; Sternberg et al., 1989b). Conversely, LEW rats treated with pharmacologic doses of dexamethasone become completely resistant to the development of SCW-induced arthritis (Sternberg et al., 1989a; Sternberg et al., 1989b). Furthermore, compared to Fischer 344 (F344) rats, adrenal steroid receptors in neural and immune tissues of LEW rats show a significantly lower magnitude of activation in response to stress-induced increases in plasma corticosterone (Dhabhar et al., 1993; Dhabhar et al., 1995a). Thus, strain differences in plasma corticosterone levels also are manifest as significant differences in the extent of activation of corticosterone receptors in target tissues.

Experimental allergic encephalomyelitis (EAE) is another animal model of an autoimmune disease in which a similar immunosuppressive role for the HPA axis has been proposed (for reviews see Mason et al., 1990; Mason, 1991; Whitacre et al., 1998). The Lewis strain shows a greater



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