The Hypothalamic‐Pituitary‐Adrenal Axis in Autoimmunity

Abstract

We have characterized the activation of the HPA axis in the chronic inflammatory stress model of adjuvant-induced arthritis. Alteration in the hypothalamic control mechanism, where CRF is no longer the major corticotrophin-releasing factor, has been noted in a number of other immune-mediated disease models, including experimental allergic encephalomyelitis, eosinophilia myalgia syndrome, systemic lupus erythematosus, and leishmaniasis. These changes occur in both the mouse and the rat, suggesting this may be a common mechanism to chronic immune activation. We have good evidence to suggest that AVP takes over as the major stimulator of the axis. The arthritic rat is unable to mount a response to acute stressors, such as restraint or ip hypertonic saline. However, these animals are able to mount a response to an acute immune challenge. These data provide further evidence for a differential activation of the HPA by acute stress or acute immune stimulation. This presumably reflects an adaptive response to the development of chronic inflammation. We have demonstrated that central neurotransmitter systems are able to influence the severity of peripheral inflammation. In particular we have shown that depletion of serotonin at the time of the development of the inflammatory episode reduces the severity of the inflammation. These findings suggest the possibility of novel therapeutic strategies targeting neurotransmitter systems to alleviate inflammation.

Review: Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis

“…It has been proposed that, depending upon whether the stressor is non-immune or immune, NO may exert either a stimulatory effect on the synthesis of CRH within the PVN or an inhibitory effect upon its release from the ME (Rivier 1998). These mutually opposing influences may explain the failure of the non-immune stressors of restraint or hypertonic saline to further stimulate the HPA axis in the chronic immunological stress of adjuvant-induced arthritis (Harbuz et al 1997).…”

“…It is instructive to examine the complex interaction of all the components, peptides and neurotransmitters, that coordinate HPA axis responses to various stressors, and to consider whether it is likely that glucocorticoids alone, acting through only two types of receptor, can provide the complex range of controls required to terminate every type of stress, of which there is a considerable range. Although the release of CRH and AVP from the hypothalamus is considered to be the final common pathway in the stress response, it has become increasingly apparent over the last decade that different types of stress are characterised by altered contributions of CRH, AVP and probably other compounds as well, depending on whether the stress is physical, psychological, immunological, acute or chronic (Harbuz et al 1997). These responses may in turn reflect differential stimulatory input to the hypothalamus.…”

“…endotoxin strongly stimulated corticosterone secretion, suggesting that central SP may be influential in mediating acute physical or psychological, but not acute immunological, stress. Based upon data from Chowdrey et al (1995) and Harbuz et al (1997).…”

Plasma Osteopontin Modulates Chronic Restraint Stress-Induced Thymus Atrophy by Regulating Stress Hormones: Inhibition by an Anti-Osteopontin Monoclonal Antibody

“…Thus, cytokine-HPA interactions represent a fundamental mechanism of the maintenance of homeostasis and the development of disease during stress or infection (29). For example, HPA axis hormones play an important role in autoimmune diseases such as multiple sclerosis, adjuvant-induced arthritis, eosinophilia myalgia syndrome, and systemic lupus erythematosus (30,31). Additionally, since OPN expression is highly perturbed in cancer, autoimmune, and inflammatory diseases, manipulating OPN levels may have a wide impact on overall health (16,32,33).…”

Site-specific overexpression of corticotropin-releasing hormone (CRH) in the mouse brain – modelling central CRH system hyperactivity

“…Some stress paradigms (e.g. adjuvant-induced arthritis) that continuously activate the HPA axis are actually associated with reductions in central CRH drive, but concomitant increases in AVP drive on the pituitary (Harbuz et al, 1997) (Shanks et al, 1998).…”