Immunity, hormones, and the brain
Authors: H. S. Haas, K. Schauenstein
Journal: Allergy (2001)

Observations that the emotions affect somatic health and vice versa are as old as human medicine. Nevertheless, until recently, our Western, biologically oriented medicine largely denied "psychosomatics" as a significant pathogenic principle. Hence, the concept that the functions of the immune defense are regulated by signals of the neuroendocrine system and the central nervous system (CNS), as first suggested in the early 1970s by the experimental data of a handful of researchers, was met with great skepticism. At that time, immunologists were preoccupied by the vision of a self-regulating immune system with "helper" and "suppressor" T cells; furthermore, the respective data from studies in experimental animal models and/or cell cultures were often controversial and confusing, a phenomenon which will be referred to later on in this paper. The discipline of "psychoneuroimmunology", or "neuroimmunomodulation", owes its rise to modern molecular biologic techniques, by which it could be unequivocally proven that the communicative organs, i.e., the brain, endocrine system, and immune system, are speaking a common language by sharing common signal mediators and receptors. Thus, molecular analysis has led to a scientifically based reorientation of modern medicine toward holistic views, and it has shown that the slogan mens sana in corpore sano is valid also the other way round (corpus sanum per mentem sanam). In the present paper, we will review molecular mechanisms of the brain–immune system axis, comment on the emerging clinical relevance of these results, and propose future directions of research. One of the starting points of neuroendocrinoimmunology was the well-known immunoregulatory effect of glucocorticoids, which exert their effects via various mechanisms, such as the modification of cytokine synthesis (1, 2) and regulation of lymphocyte apoptosis (3), to name just two. The immunosuppressive effects of chronic stress were initially exclusively related to glucocorticoids as classical stress hormones. Later, however, lymphocytes were found to express functional receptors for virtually all of the endocrine components of the somatic stress reaction, such as catecholamines and the hormones of the anterior pituitary gland (4), with either stimulatory or suppressive effects on immune functions. Different stressors activate these components in different patterns, a fact which may explain how, depending on the quantity and/or quality of a stressor, stress can lead to either enhanced or suppressed immune functions (5). Another milestone was the finding of Besedovsky et al. that the the activated immune system "talks back" via cytokine signals to the CNS, with measurable effects on the activity of the hypothalamo-pituitary-adrenal (HPA) axis, as evidenced by increased plasma glucocorticoids after an antigenic challenge (6-8). Later it was realized that well-known phenomena associated with inflammatory reactions, such as fever and sickness behavior, are likewise the result of the central effects of cytokines released from activated leukocytes (9). Furthermore, it became obvious that the dialog with the immune system involves virtually the whole brain, including the cortex and, notably, structures of the "limbic system", i.e., the hippocampus and parts of the amygdala (10). In these areas, high densities of receptors for various cytokines have been detected, and it was shown that many of these mediators are locally produced by glial and/or neuronal cells, and have neurotransmitter-like functions. Taken together, these results suggest immediate mutual relationships between emotions and immune functions, relationships which may underlie the clinical observations that mood disorders are associated with increased susceptibility to infectious diseases or malignant tumors. In turn, diseases with massive activation of the immune system (trauma, sepsis, autoimmune disorders) can entail psychopathologic manifestations. The last 15 years has brought an explosion of molecular data supporting brain–immune system interrelationships. Immune cells have been shown to express hormone-, neuropeptide-, and neurotransmitter-receptors at mRNA and protein levels (11, 12). Besides steroid receptors (13, 14), functional binding sites for substance P (15) and neuropeptide Y (16), corticotropin-releasing hormone (17), prolactin (18), products of the proopiomelanocortin (POMC) gene (19-21), catecholamines (22-24), acetylcholine (19-28), and serotonin (29-31) were detected. Some data also suggest binding sites for excitatory amino acids on immune cells (32-34). Furthermore, it turned out that lymphocytes and macrophages produce not only immune mediators, such as interleukins, but also neuropeptides and neurotransmitters, which may have paracrine, autocrine, and/or endocrine effects on both the immune and the nervous systems (27, 35-37). On the other hand, neuronal and glial cells in different brain areas, depending on the state of activation, were found to express differentially a wide variety of cytokine receptors (38) and major histo-compatibility complex (MHC) molecules (39-45). Steroid receptors are present within the CNS (46, 47), and brain cells themselves synthesize steroid hormones (neurosteroids), which regulate diverse brain functions (48-51). Furthermore, as mentioned above, microglia, astrocytes, and neurons are capable of secreting central cytokines (38, 52), which influence not only immune and neuroendocrine responses, but also CNS activities, such as synaptic transmission (53-56). An important matter still awaiting definitive clarification is the route by which the peripheral immune and endocrine systems communicate with the brain, and vice versa. The most thoroughly examined afferent pathway with particular reference to the activation of hypothalamo-pituitary axes is the humoral route; i.e., circulating cytokines released from activated peripheral leukocytes bind to central cytokine receptors (57, 58). Several mechanisms for bypassing the blood–brain barrier (BBB) have been proposed in this context (59-61). However, besides this, neural pathways also play obviously important roles. This is shown in a number of studies implicating the vagus nerve in immune system–brain communications (62). As far as efferent (descending) routes are concerned, neuro-endocrine hormonal pathways are solidly established (63-65). In addition, it has been shown that the sympathetic nervous system, via catecholamines, conveys information from the CNS to the peripheral immune system (66-69), and several other neuro-transmitters, such as acetylcholine, serotonin, and excitatory/inhibitory amino acids and opioids, are involved in neuroimmune communications (70-77). Our own studies aimed to elucidate the roles of the sympathetic and parasympathetic autonomic nervous systems within the brain–immune system axis. As for adrenergic effects on the immune system, most data suggest that adrenergic immunosuppression occurs via β-adrenergic stimulation. Our in vivo data in the rat model, however, suggest more complex mechanisms involving predominantly α-receptors (76). Mechan-isms by which catecholamines control immune reactions appear to be modulation of cytokine expression, changes in leukocyte distribution, and the induction of apoptosis in lymphocytes (28). Several data strongly suggest that cholinergic signals also exert pronounced immunoregulatory effects. Immune cells express both muscarinic and nicotinergic receptors for acetylcholine (25-28), and an increased cholinergic tone was shown to lead to significant immuno-enhancement (77). Furthermore, we found that in vivo treatment of rats with physostigmine leads to a disruption of the already mentioned immune-brain feedback, confirming that the cholinergic system is critically involved in the "talking back" of the immune system to the brain (77). The close relationships between the immune system and the adrenergic/cholinergic nervous system appear to be underlined by the findings that lymphocytes can synthesize and release catecholamines (36) and acetylcholine (27, 37), and there are initial indications that these nonneuronal transmitters may have paracrine and autocrine regulatory roles in the differentiation and functions of lymphocytes within the different compartments of the immune system (78). All these data together demonstrate a complete feedback circuit between the brain and immune system that is secured by several mechanisms: the development and functions of the immune system are regulated by endocrine and neuroendocrine mediators, and cytokines released from activated immune cells in turn modulate functions of the CNS. Defects at any point of this network are expected to affect all the systems involved (Fig. 1). Psychoneuroimmunology – the network of bidirectional pathways between the immune, endocrine, and central/peripheral nervous systems. The results reviewed above strongly suggest that, besides glucocorticoids, a large array of hormones and transmitters exert pronounced immunoregulatory effects, and that the optimal functioning of the immune defense is critically dependent on the homeostasis of the neuroendocrine and/or central nervous systems. Loss of this homeostasis can lead to immune defects, as has been shown for chronic stress or depressive disorders, or it can significantly contribute to the occurrence of pathogenic immune reactions, such as allergy or autoimmune disease. The pathogenesis of allergic diseases in general is known to have a strong psychosomatic component. Concerning type I hypersensitivity reactions within the respiratory tract, this is, on the one hand, due to the pronounced autonomic regulation of the small airways. On the other hand, there exist convincing data that the functions of mast cells and the T-cell-mediated regulation of the IgE response (79) are both under the control of neurohormones and -transmitters. β-Adrenergic agonists are among the established therapeutic tools to suppress mast-cell activation. More recently, it has been shown that the pleiotropic cytokine leukemia inhibitory factor (LIF), known as a modulator of HPA activity (80, 81), is synthesized and released by human eosinophils and has proinflammatory roles in allergic airway disorders (82). Classical neurotransmitters, including acetylcholine and serotonin, as well as neurotrophins such as nerve growth factor (NGF), have been revealed as important neuroimmune regulators in allergic inflammation and anaphylaxis (83-85). Receptors for the major central excitatory neurotransmitter glutamate have also been described in the periphery, e.g., the larynx and esophagus (86), and recent data suggest that activation of the N-methyl-d-aspartate (NMDA) subgroup of glutamate receptors is critically involved in the modulation of airway smooth-muscle responsiveness (87). These authors also discuss links between glutamate-mediated neurotransmission and the pathogenic mechanisms of bronchial asthma. Furthermore, the magnesium salt of N-acetyl-aspartyl-glutamate (Naaga), which is used in ophthalmic allergies, has been found to inhibit macrophage eicosanoid secretion (88). Finally, Espey & Basile (74) have reported that excitatory neural pathways are also involved in the regulation of Th1/Th2 shifts, as observed in the LP-BM5 model of retrovirus-induced immunodeficiency. Type IV reactions, such as contact hypersensitivity, have also been shown to be under the control of neurohormones, such as the POMC-derived peptide alpha-melanocyte stimulating hormone (α-MSH) (89), which was shown to induce hapten-specific tolerance in mice (90). A mechanism contributing to these effects may be the inhibition of NF-κ B activation by α-MSH, as shown in experimental brain inflammation (91). Autoimmune diseases originate from "forbidden" immune responses to autoantigens as a result of the loss of autotolerance of the patient's immune system. Autotolerance is supposedly secured by selection processes during lymphocyte maturation in the thymus, and is permanently maintained in the periphery by intrinsic and extrinsic mechanisms of immunoregulation. In this context, the feedback between brain and immune system via activation of the HPA axis appears to be of critical importance, as the elevation of peripheral glucocorticoids during an immune reaction may suppress the activation of low-affinity "forbidden" lymphocyte clones (7). This concept was supported by the results from several groups in animal models of spontaneous or experimentally induced autoimmune diseases, showing that a blunted glucocorticoid response after antigenic challenge is associated with an enhanced propensity to develop autoimmune disease (92-94). Our data in the rat model showing that an enhanced cholinergic tone in the periphery leads to a loss of the corticosterone peak in response to antigenic challenge (77) would suggest that the adrenergic/cholinergic homeostasis is relevant to the maintenance of autotolerance. Besides immunopathologic conditions, neuroimmunoendocrine interactions have been found to play important roles in pain states, such as hyperalgesia and allodynia (95); in neurologic and psychiatric diseases, such as Alzheimer's disease, multiple sclerosis, depression, and schizophrenia (96-98); in bowel disorders, such as irritable bowel syndrome und ulcer disease (99-104); in skin diseases (105-107); and in cancer (108, 109). The broad clinical application of psychoneuroimmunology and its discoveries is still in the initial stage and requires intensive basic research. One obvious problem lies in the high complexity of the organ systems involved, such as the brain, the endocrine system, and the immune system, a problem which may account for the fact that the results of the mutual interactions show high individual variabilities and are not always predictable for a given patient. A good example is the sensitivity of the immune system to stress, which, according to the nature of the respective stressor as well as the individual stress-specific experience, can lead to either immunoenhancement or -suppression. Besides, it is evident that the immunoregulating effects of hormones and transmitters are critically dependent on the activation state of lymphocytes, as was shown long ago for glucucorticoids, where the initial phase of an immune response is much more sensitive to the suppressive effects than the established immune reaction (1). The inverse seems to be true for immuno-regulation by catecholamines, as lymphocytes from patients with rheumatoid arthritis showed a significantly increased sensitivity to β2-adrenergic activation (110). Only when we better understand the complex relationships between signal generation, signal effects, and activation states within the communicative systems will we be able to make use of the potent immuno-regulatory properties of neurohormones and -transmitters in clinical therapy. One means to tackle this problem will be increasingly to complement conventional experimental strategies of single-point observations by modern multiparameter analysis techniques, in order to recognize changes in expression patterns of multiple components within the immune system or the CNS. The results so far of psychoneuroimmunology provide convincing and scientifically sound arguments for the consideration and integration of psychologic aspects in the therapy of somatic diseases – they are an important first step toward an increased understanding of health, disease, and a "mindful" medicine. This study was supported by the Austrian Science Foundation (projects 9925, 11130, 10422, 11921, 12579, and 12679) and the Jubiläumsfonds der Österreichischen Nationalbank (projects 5692 and 6730).