A Molecular Basis for Bidirectional Communication Between the Immune and Neuroendocrine Systems
J. EDWIN BLALOCK
Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama
A SENSORY FUNCTION FOR THE IMMUNE SYSTEM
Perhaps the most interesting conceptu: al advance that follows from many of these studies is the idea that a principal new function of the immune system may be to serve as a sensory organ. It has been proposed that the immune system may sense stimuli that are not recognized by the central and peripheral nervous systems (15). These stimuli have been termed noncogni-tive and include those things (i.e., bacteria, tumors, viruses, antigens, etc.) that would go unnoticed were it not for their recognition by the immune system. The recognition of such noncognitive stimuli by immunocytes is then converted into information, in the form of peptide hormones, lymphokines, and monokines, that is conveyed to the neuroendocrine system, and a physiological change occurs. Contrariwise, central and peripheral nervous system recognition of cognitive stimuli results in similar hormonal information being conveyed to and recognized by hormone receptors on immunocytes and an immunologic change results. It seems that the sensory function of the immune system mimics the neuroendocrine system in terms of a given stimulus evoking a particular set of hormones and hence physiological responses. If
J. EDWIN BLALOCK
this proves to be the case, then the pathophysiology that is associated with a particular infectious agent, antigen, or tumor could be related in part to the particular hormone or set of hormones that are produced by the immune system. For instance, lymphocyte-derived ACTH or IL 2 or macrophage-de-rived IL 1 or HSF acting alone or in concert may be responsible for the well-known increase in circulating corticosteroid levels observed during viral and bacterial infections. It would be most gratifying if in the future, for example, successful embryo implantation might be associated with lymphocyte CG or alterations of thyroid function might be associated with lymphocyte-derived TSH.
Certain experimental models and clinical observations would seem to support the above view. The finding that cells of the immune system are a source of secreted ACTH suggested that stimuli that elicit the leukocyte-derived hormone should not require a pituitary gland for an ACTH-mediated increase in corticosteroids. This seemed to be the case, since Newcastle disease virus (NDV, an in vitro inducer of leukocyte ACTH) infection of hypo-physectomized mice caused a time-dependent increase in corticosterone production that was inhibitable by dexamethasone. Unless such mice were pre-treated with dexamethasone, their spleens were positive for ACTH by immunofluorescence (129). It should be noted that the possibility of an ex-trapituitary ACTH response in mice is currently an unsettled problem in that Dunn et al. (45) were unable to completely reproduce this finding. In this study, only a small proportion of verified hypophysectomized mice (4 of 47) showed a virus-induced increase in corticosterone. One important difference between the studies that could account for the discrepancy is the omission of a crucial control/Although the first study showed that the spleens of NDV-infected animals actually produced ACTH, the second did not verify spleno-cyte production of ACTH. In the more recent study, perhaps the small number of verified hypophysectomized mice that showed corticosterone increases were the only ones that produced splenocyte ACTH. This is a particularly important control, since Dunn et al. (45) used a different and more virulent strain of NDV.
Another study that supports the concept of an extrapituitary ACTH response was performed in children with hypopituitarism. Children who were pituitary ACTH deficient were pyrogen tested (typhoid vaccine, another in vitro inducer of leukocyte ACTH) and were shown to have an increase in the percentage of ACTH-positive mononuclear leukocytes (99). Both the response in hypophysectomized mice and hypopituitary children peaked at ~6-8 h after administration of virus and typhoid vaccine, respectively. These findings might also explain the earlier observation of bacterial polysaccha-ride (piromen)-induced cortisol responses in seven of eight patients who underwent pituitary stalk sectioning (142). More recently, a patient presented with the clinical and laboratory features of the ectopic ACTH syndrome. Whereas the absence of a gradient in ACTH concentration between the inferior petrosal sinuses and the periphery argued against pituitary overproduction, no ACTH-producing tumor was found, and bilateral adrenal-
January 1989 IMMUNE-NEUROENDOCRINE INTERACTIONS
ectomy was performed to correct the hypercortisolism. Six months later, a pseudotumor containing only normal fat and inflammatory tissue was observed in the patient. On removal of this inflammatory tissue, basal plasma ACTH levels immediately returned to normal and leukocytes within the inflammatory tissue stained positively for ACTH by an immunoperoxidase procedure (46).
A possible in vivo corollary of the aforementioned ability of CRF and AVP to elicit in vitro ACTH was also observed (130). We found an increase in the percentage of circulating immunoreactive ACTH-positive leukocytes in normal short children who were undergoing assessment of pituitary function by insulin tolerance testing (99). In contrast to the previously described peak in the percentage of ACTH-positive leukocytes that occurred at 6-8 h post-typhoid vaccination, the peak was observed at 45-60 min after the administration of insulin. If both the in vivo and in vitro data are considered, it is tempting to speculate that in stressful situations leukocytes may produce ACTH in response to an encounter with CRF, which perhaps occurs as these cells pass through the portal circulation between the hypothalamus and pituitary gland. More recently it has been shown that CRF administration to pituitary ACTH-deficient individuals results in both an ACTH and cortisol response (50), and their leukocytes are positive for ACTH (H. L. Fehm, personal communication).
Gram-negative bacterial infections and endotoxin shock may represent yet another situation in which leukocyte production of hormones play a pivotal role. For instance, endorphins have been implicated in the pathophys-iology associated with these maladies since the opiate antagonist, naloxone, improved survival rates and blocked a number of cardiopulmonary changes associated with these conditions (115). Furthermore, two separate pools of endorphins have been observed after endotoxin administration, and it was suggested that one pool might originate in the immune system (33). If the potent immunologic effects of endotoxin are considered, as well as its ability to induce in vitro leukocyte production of endorphins, cells of the immune system seem the most likely source of endogenous opiates that are observed during Gram-negative sepsis and endotoxin shock. Consistent with this idea is the observation that lymphocyte depletion, like naloxone treatment, blocked a number of endotoxin-induced cardiopulmonary changes (23). Our interpretation of these results is that lymphocyte depletion removes the source of the endorphins, whereas naloxone blocks their effector function. Thus this may represent a situation in which leukocyte-derived endorphins are involved in a disease state as a manifestation of the sensory function of the immune system.
XI. CONCLUSIONS AND PREDICTIONS
The recent observations of neuroendocrine peptide hormones and their receptors in and on leukocytes seem to now provide a molecular basis for the numerous interactions between the immune and neuroendocrine systems
J. EDWIN BLALOCK
(21). With such findings, it appears a new scientific discipline has emerged, i.e., neuroimmunoendocrinology. New functions for these two systems, as well as novel conceptions of how each system perceives itself and one another, seem evident. Further knowledge of the interactions of these two systems at a molecular level should provide many new insights into neuroen-docrine and psychological disorders as well as the pathophysiology of infectious diseases and tumors. For instance, leukocyte ACTH, IL 1, IL 2, and HSF may be responsible for the well-known increases in corticosteroid levels observed during infections, and leukocyte ACTH certainly explains at least one instance of “ectopic” ACTH syndrome. Novel treatments for human diseases are also suggested, and the efficacy of naloxone in Gram-negative sepsis may represent the first example.
It is our feeling that perhaps one of the first major applications of this knowledge will be in the area of psychiatry. For instance, if brain receptors are important in behavior and are expressed with fidelity on white blood cells, then there is an easily accessible peripheral source to study more centrally located receptors. Correlations of aberrant leukocyte receptor numbers or functions may ultimately be diagnostic for psychological diseases. Thus this may lead to more objective type evaluations of psychiatric disorders. Future possibilities might also include correction of pituitary hormone deficiencies by an action of hypothalamic-releasing factors on leukocytes or the correction of immunodeficiencies by treatment with neuroendocrine hormones. Regardless of the specific outcome, it seems clear that neuroimmunoendocrinology will have a major impact on our understanding of physiology and consequent diagnosis, therapeusis, and prophylaxis of human diseases.
I am indebted to my former and present graduate students, postdoctoral fellows, and faculty colleagues for advancing the study of neuroimmunoendocrinology. I also thank Diane Weigent for typing this manuscript and for excellent editorial assistance.
These studies were supported in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-38024, Office of Naval Research Grant N00014-84-K-0486, Cancer Center Core Grant CA-13148, Triton Biosciences, and the James W. McLaughlin Foundation.
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