The lethal defect in acquired immune deficiency syndrome (AIDS) is the profound defect in immune function caused by initial loss of helper T lymphocytes and eventually of all immune competent cells. Little has been published about hypothalamic-pituitary-adrenal (HPA) axis function in AIDS and AIDS-related complex (ARC), but cytomegalovirus adrenalitis, occasionally causing adrenal insufficiency, is surprisingly common. In addition, there is progressive loss of adrenocortical 18-hydroxylase activity in ARC and AIDS, perhaps reflecting loss of a factor separate from ACTH that stimulates aldosterone biosynthesis. With the immune system's first line of defense crippled, the HPA axis assumes an even greater importance in responding to the stress of infection. Furthermore, JE Blalock, EM Smith, WJ Meyer 111 and their coworkers have presented a body of data which indicate that immunocompetent cells produce proopiomelanocortin (POMC) peptides in response to the same agents that induce human leukocyte interferon (hlFN alpha), that POMC production is regulated by the same hormones that regulate anterior pituitary POMC peptide secretion and that these leukocyte-derived POMC peptides may act in an autocrine or paracrine fashion to modulate the immune response and can even directly stimulate adrenocortical steroid biosynthesis in hypophysectomized animals. These findings have potentially fundamentally important implications for regulation of the immune response and interaction of the immune and endocrine systems. However, the only three groups that have attempted to reproduce the findings of Blalock, Smith and Meyer have failed completely to do so. This, the lack of supporting data from other laboratories and questions of proper methodologic rigor raise reservations about this work, although there is little doubt that some immunocompetent cells can synthesize POMC peptides under appropriate conditions. We propose to examine rigorously the essential findings of these investigators, using independent, widely-accepted methods, and extend them by (1) detecting, quantifying and characterizing leukocyte POMC mRNA, (2) determining the concentrations of leukocyte POMC mRNA and peptides in the immune cells and POMC peptides in the medium after stimulation by various agents, (3) determining if there is a leukocyte-derived peptide that specifically stimulates aldosterone biosynthesis, (4) defining which subset(s) of immune cells produce POMC peptides in response to specific stimuli, (5) determining if leukocyte POMC peptide synthesis is impaired in ARC and AIDS and (6) assessing whether leukocyte POMC peptide production is impaired in response to febrile illnesses in AIDS patients. If the findings of Blalock et al are correct, they will be confirmed by the most rigorous examination and will be extended to define possible fundamental defects in immune regulation and immune-endocrine interactions in ARC and AIDS patients.
| Olsen, N J; Nicholson, W E; DeBold, C R et al. (1992) Lymphocyte-derived adrenocorticotropin is insufficient to stimulate adrenal steroidogenesis in hypophysectomized rats. Endocrinology 130:2113-9 |
