Psychoneuroimmunology--cross-talk between the immune and nervous systems

Psychoneuroimmunology is a relatively new field of study that investigates interactions between behaviour and the immune system, mediated by the endocrine and nervous systems. The immune and central nervous system (CNS) maintain extensive communication. On the one hand, the brain modulates the immune system by hardwiring sympathetic and parasympathetic nerves (autonomic nervous system) to lymphoid organs. On the other hand, neuroendocrine hormones such as corticotrophin-releasing hormone or substance P regulate cytokine balance. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and immune system-mediated disease.     

Impact of the neuroendocrine system on thymus and bone marrow function

The nervous, endocrine, and immune systems interact to adapt to infection, inflammation, and tissue injury. Neural control is mediated in several ways, one of them being through the neuroendocrine regulation of the secretion of hypothalamic and pituitary hormones. The hormonal effects on the immune system range from the impact of steroidal hormones, which exhibit inhibitory effects over immune functions, to growth hormone, prolactin and neurohypophyseal hormones, known to stimulate and modulate humoral and cellular aspects of the immune system. This review will discuss the mechanisms behind the immunomodulatory role of the neuroendocrine system, including the critically important feedback loops required to maintain balance for these bidirectional interactions and alterations that occur with age.     

Conditioned immunomodulation: research needs and directions

Considering the brief time that psychoneuroimmunology has existed as a bona fide field of research, a great deal of data has been collected in support of the proposition that homeostatic mechanisms are the product of an integrated system of defenses of which the immune system is a critical component. It is now clear that immune function is influenced by autonomic nervous systems activity and by the release of neuroendocrine substances from the pituitary. Conversely, cytokines and hormones released by an activated immune system influence neural and endocrine processes. Regulatory peptides and receptors, once confined to the brain, are expressed by both the nervous and immune systems enabling each system to monitor and modulate the activities of the other. It is hardly surprising, then, that immunologic reactivity can be influenced by stressful life experiences or by Pavlovian conditioning.     

Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis

There exists a bidirectional regulatory circuit between the nervous and immune systems. This regulation has been shown to be mediated in part through neuroendocrine hormones and cytokines. Both systems have receptors for both types of signal molecules. The nervous system has receptors for cytokines and it also synthesizes cytokines. The immune system synthesizes and responds to cytokines. So, it is not too far-fetched to believe that neuroendocrine peptide hormones could bind to leukocytes and modulate immune functions. However, it is not widely known that the immune system also synthesizes functional, neuropeptide hormones. This will be discussed in this paper citing a plethora of evidence. The aim of this paper is to summarize this evidence by using three neuropeptides that are synthesized by leukocytes and modulate immune functions as examples; corticotropin (ACTH), endorphin (END), and corticotropin releasing factor (CRF). The production and action of these three neuropeptides in the immune system will be explained. Finally, the potential physiological role of leukocyte-derived ACTH, END, and CRF in inflammation as a localized hypothalamic-pituitary-like axis is discussed.     

The importance of being receptive

Neuroendocrine system and immune system can communicate via the use of soluble mediators like hormones, neurotransmitters and cytokines. The level of mediators secreted by either of these systems creates the milieu in which immune and neuroendocrine responses take place. For adequate communication between the systems, receptors for hormones, neurotransmitters and cytokines are required. This review describes the role of regulated expression and function of receptors for hormones and neurotransmitters within the immune system in neuroendocrine-immune communication.     

IL-10 as a mediator in the HPA axis and brain

Certain functional interactions between the nervous, endocrine, and immune systems are mediated by cytokines. The pro-inflammatory cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF) were among the first to be recognized in this regard. A modulator of these cytokines, IL-10, has been shown to have a wide range of activities in the immune system; in this review, we describe its production and actions in the hypothalamic–pituitary–adrenal (HPA) axis. IL-10 is produced in pituitary, hypothalamic, and neural tissues in addition to lymphocytes. IL-10 enhances corticotropin releasing factor (CRF) and corticotropin (ACTH) production in hypothalamic and pituitary tissues, respectively. Further downstream in the HPA axis endogenous IL-10 has the potential to contribute to regulation of glucocorticosteroid production both tonically and following stressors. Our studies and those of others reviewed here indicate that IL-10 may be an important endogenous regulator in HPA axis activity and in CNS pathologies such as multiple sclerosis. Thus, in addition to its more widely recognized role in immunity, IL-10's neuroendocrine activities described here point to its role as an important regulator in communication between the immune and neuroendocrine systems.     

Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems

This review briefly summarizes a part of the relevant knowledge base of neuroimmunology, with particular emphasis on bidirectional neural-immune interactions. These complex systems interact at multiple levels. Both neuroendocrine (the primary hormonal pathway is hypothalamic-pituitary-adrenal axis) and neuronal (direct sympathetic innervation of the lymphoid organs) pathways are involved in the control of the humoral and cellular immune responses. Although, the recent evidence has been made on immunosuppressive effect of acetylcholine-secreting neurons of the parasympathetic nervous system. The immune system, in turn, influences the central nervous system primarily through cytokines. At the molecular level, neuro- and immune signal molecules (hormones, neurotransmitters, neuropeptides, cytokines) or their receptors are member of the same superfamily which enable the mutual neuroimmune communication. Most extensively studied are cytokine-neuropeptide/neurotransmitter interactions and the subcellular and molecular mechanisms of these interactions. At the system (neuroanatomical) level, advances in neural-immune communication have been made in the role of discrete brain areas related to emotionality. The immunoenhancement, including the antiviral and antitumor cytotoxic activity, related to the "brain reward system", limbic structures and neocortex, offers a new directions for therapy in immune disorders.     

Immune-neuroendocrine circuits: integrative role of cytokines.

Several efficient autoregulatory mechanisms confer a certain degree of autonomy to the immune system. However, increasing evidence shows that immune processes operate in a coordinated fashion with other body systems. In this article, we discuss concepts and facts concerning interactions between immune and neuroendocrine mechanisms. There are clear examples that immune cells can be influenced by hormones, neurotransmitters, and neuropeptides and also by alterations in brain functions. Conversely, immune-derived products such as lymphokines and monokines can affect endocrine, autonomic, and central mechanisms. Neuroendocrine responses occur during the activation of the immune system. These responses can be elicited by innocuous antigens; they can also be detected during pathological conditions involving immune activation, and in many cases are dissociable from the effects of the disease itself and from the stress of being sick. On this basis, we emphasize the multidirectional nature of the communication processes between the immune, endocrine, and nervous systems. The role of lymphokines and monokines as messengers able to convey information to neuro and endocrine structures about the present state of activity of the immune system is stressed. The relevance of immune-neuroendocrine interactions for immunoregulation and host defenses is discussed as well as the active role of the immune system in mediating metabolic and homeostatic adjustments or derangements during the course of certain infectious, inflammatory, and neoplastic processes. The evidence available suggests that complex immune-neuroendocrine networks operate under both physiological and pathological conditions.     

Neural modulation of immunity: conditioning phenomena and the adaptability of lymphoid cells.

The behavioral conditioning of alterations in the immune response is one pillar supporting the growing edifice of central nervous system (CNS) modulation of immunity. The mechanisms underlying such conditioning phenomena are not understood. In this communication, we attempt to develop a theoretical position based on the concept of phenotypic and functional adaptability of lymphoid cells. We propose that these cells can learn to associate responsiveness to antigens and to other "immunoactive" agents, with responsiveness to signals originating in the CNS delivered via neuroendocrine or autonomic nervous channels. Neural/endocrine signals act on the immune system in conjunction with immunological stimuli, in a way that leads to "storage" of the association (memory) of these two kinds of stimuli in the immune system rather than in the brain.     

Neuroendocrine–immune interactions in homeostasis and autoimmunity

Recent experimental evidence confirms the interrelationships between the central nervous, neuroendocrine and immune systems. Indeed, extensive duality exists in the use of neurotransmitters, hormones and receptors each system displays. In the present annotation, the effect of cytokines, soluble mediators of immune function, on the CNS and neuroendocrine systems is addressed and conversely, we discuss the modification of the immune compartment by the sympathetic nervous and neuroendocrine systems, with particular reference to the role of noradrenaline and corticosterone. Dysfunction between the systems is considered in the context of autoimmune conditions, with emphasis on experimental allergic encephalomyelitis and the contribution of corticosterone–driven T–cell apoptosis to recovery from the disease. Finally, we speculate on the relevance of neuroimmune interactions in the pathogenesis of multiple sclerosis.     

A molecular basis for interactions between the immune and neuroendocrine systems

Homeostatic and psychologic alterations associated with infections and tumors are very interesting yet poorly understood pathophysiologic responses. Numerous anecdotal and indirect examples suggest that these responses occur through a link between the central nervous and immune systems (for review see Blalock, Bost, & Smith, 1985; Spector & Korneva, 1981; Maestroni & Pierpaoli, 1981; Felton et al., 1985; Jankovic, 1985). Interactions between the two systems are just now being described. One possible mechanism is direct modulation of the immune system by the sympathetic nervous system. This could occur in innervated immune organs such as spleen, thymus, and bone marrow (Felton et al., 1985). The evidence for this is that sympathectomy and lesioning of specific regions of the brain can be shown to both enhance and/or suppress immune responses (Miles et al., 1985; Roszman et al., 1985). Also, the firing rate of hypothalamic neurons is altered during an immune response (Besedovsky et al., 1977). Alternatively, hormonal involvement in immune reactions has been known for some time, in particular the immunosuppressive effects of glucocorticoids (for review see Cupps & Fauci, 1982). Recently, we and others found that neuroendocrine peptide hormones will modulate T and B lymphocytes plus other immunocyte responses (Besedovsky et al., 1977; Cupps & Fauci, 1982; Johnson et al., 1982; Wybran et al., 1979; Hazum, Chang & Cuatrecasas, 1979; O'Dorisio et al., 1981; Gilman et al., 1982; McCain et al., 1982; Mathews et al., 1983; Plotnikoff et al., 1985; Johnson et al., 1984). Furthermore, lymphocytes themselves can synthesize biologically active neuroendocrine hormones (Blalock & Smith, 1980; O'Dorisio et al., 1980; Smith & Blalock, 1981; Smith et al., 1983; Lolait et al., 1984; Ruff & Pert, 1984), as well as possess specific hormone receptors (Blalock et al., 1985; Johnson et al., 1982; Wybran et al., 1979; Hazum et al., 1979; O'Dorisio et al., 1981; Lopker et al., 1980; Payan, Brewster & Goetzl, 1984; Pert et al., 1985). Immune responses (Besedovsky, del Rey & Sorkin, 1981), thymic hormones (Healy et al., 1983), and lymphokines (Lotze et al., 1985; Woloski et al., 1985) have all been shown to exert hormonal effects. Thus, another method for communication between the immune and neuroendocrine systems seems to be through soluble factors such as neuroendocrine hormones. This review will concentrate on the latter topic, in particular on work this laboratory has done over the past few years to show the lymphocyte production and immunoregulatory actions of neuroendocrine hormones.     

Glucocorticoids, cytokines and brain abnormalities in depression

Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan-kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is co-morbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.     

From hormones to immunity: the physiology of immunology

Discoveries in the physiology of immunology have increased at an increasing rate during the past two decades. It is now recognized that the immune system is just another physiological system that regulates, and is regulated by, other physiological systems such as the brain. These advances make it clear that recent findings in genomic biology must be interpreted in the context of the environment in which animals and humans live. Lack of a strong genetic basis for significant human mental health disorders, such as major depression, points to the critical importance of interactions. Several examples of environmental x genetic x disease interactions are presented. Regulation of cells of the hematopoietic lineage by two genes that control over 80% of postnatal growth, growth hormone and IGF-I, are then highlighted. The reciprocal relationship of how proinflammatory cytokines from the immune system regulate the growth hormone/IGF-I axis is also summarized. Particular emphasis is placed upon TNFalpha-induced IGF-I resistance in neurons, muscle cells and epithelial cells. This cytokine regulation of hormone action may ultimately be more important for human and animal health than direct effects of growth hormone and IGF-I on hematopoietic cells. Wasting of AIDS patients is given as an important clinical example of how TNFalpha from an activated immune system reduces IGF-I sensitivity in multiple physiologic systems, including muscle, nervous and hematopoietic tissues.     

Central stimulation of hormone release and the proliferative response of lymphocytes in humans

The central nervous system (CNS) may communicate with the immune system by direct innervation of lymphoid organs and/or by neurotransmitters and changes in neuroendocrine functioning and hormone release. The consequences of selective transient changes in circulating hormones on immune functioning in humans have not yet been studied. To address this problem, the authors evaluated the lymphoproliferative responses to optimal and suboptimal concentrations of phytohemagglutinin (PHA) and pokeweed mitogen (PWM) under selective enhancement of circulating growth hormone, prolactin, or norepinephrine. The authors failed to demonstrate any effect of elevated growth hormone levels after clonidine challenge on the lymphoproliferative response to mitogens. Similarly, the results did not show any effect of elevated prolactin concentrations induced by domperidone administration on the immune test. Exposure of volunteers to cold resulted in elevation of plasma norepinephrine levels without changes in growth hormone, epinephrine, or cortisol secretion. Cold exposure induced elevation of plasma norepinephrine and reduction of the lymphoproliferative response to the suboptimal dosage of PHA. The reduction was significant 180 and 240 min after exposure. These results are indicative of a relationship between norepinephrine and immunity.     

D-Aspartic acid: an endogenous amino acid with an important neuroendocrine role

D-Aspartic acid (d-Asp), an endogenous amino acid present in vertebrates and invertebrates, plays an important role in the neuroendocrine system, as well as in the development of the nervous system. During the embryonic stage of birds and the early postnatal life of mammals, a transient high concentration of d-Asp takes place in the brain and in the retina. d-Asp also acts as a neurotransmitter/neuromodulator. Indeed, this amino acid has been detected in synaptosomes and in synaptic vesicles, where it is released after chemical (K(+) ion, ionomycin) or electric stimuli. Furthermore, d-Asp increases cAMP in neuronal cells and is transported from the synaptic clefts to presynaptic nerve cells through a specific transporter. In the endocrine system, instead, d-Asp is involved in the regulation of hormone synthesis and release. For example, in the rat hypothalamus, it enhances gonadotropin-releasing hormone (GnRH) release and induces oxytocin and vasopressin mRNA synthesis. In the pituitary gland, it stimulates the secretion of the following hormones: prolactin (PRL), luteinizing hormone (LH), and growth hormone (GH) In the testes, it is present in Leydig cells and is involved in testosterone and progesterone release. Thus, a hypothalamus-pituitary-gonads pathway, in which d-Asp is involved, has been formulated. In conclusion, the present work is a summary of previous and current research done on the role of d-Asp in the nervous and endocrine systems of invertebrates and vertebrates, including mammals.     

Psychoneuroendocrinoimmunology: the basis for a novel therapeutic approach in aging.

Along with the nervous and the endocrine systems, the immune system is one of the three major integrative systems in higher organisms. Growing evidence demonstrates an intimate relationship between the immune system and the endocrine and nervous systems: The psychoneuroendocrine system can influence the immune response and thereby the capacity of the organism to cope with illness, and the immune system can have an impact on neuroendocrine function. Such cross-talk among systems is dependent upon feedback loops working to maintain homeostatic equilibrium.     

The vitamin D neuroendocrine system as a target for novel neurotropic drugs

Vitamin D is a seco-steroid hormone with multiple functions in the nervous system. Physiological brain mechanisms of vitamin D and its receptors include neuroprotection, antiepileptic effects, immunomodulation, possible interplay with several brain neurotransmitter systems and hormones, as well as the regulation of behaviours. Here we review the important role of the vitamin D neuroendocrine system in the brain, and outline perspectives for the search for novel neurotropic drugs to treat various vitamin D-related dysfunctions.     

Neuro-immune network. Basic structural and functional correlates.

The relationship among the nervous, endocrine and immune systems can be addressed in a number of ways. In this minireview, after introducing the immune microenvironment and outlining the principal domains of neuroimmune investigations, the preference was given to the influence of lesioning and stimulation of brain structures on immunological responsiveness; the relationship between micromagnetic fields, brain and immunity; the humoral and cell-mediated immunological features of certain neurological and psychiatric diseases; and the effect of stress on immune reactions. Described phenomena support the contention that there are numerous and continuous intercommunications between the nervous system and the immune system.     

Neural-endocrine-immune complex in the central modulation of tumorigenesis: facts, assumptions, and hypotheses

For the precise coordination of systemic functions, the nervous system uses a variety of peripherally and centrally localized receptors, which transmit information from internal and external environments to the central nervous system. Tight interconnections between the immune, nervous, and endocrine systems provide a base for monitoring and consequent modulation of immune system functions by the brain and vice versa. The immune system plays an important role in tumorigenesis. On the basis of rich interconnections between the immune, nervous and endocrine systems, the possibility that the brain may be informed about tumorigenesis is discussed in this review article. Moreover, the eventual modulation of tumorigenesis by central nervous system is also considered. Prospective consequences of the interactions between tumor and brain for diagnosis and therapy of cancer are emphasized.