The Immune-Neuroendocrine Circuitry: History and Progress: v. 3 (NeuroImmune Biology)

TGF-beta is produced as an inactive protein and it is bound to cell surfaces or to matrix components before it is activated enzymatically. TGF-beta is a powerful immunosuppressor and has a systemic anti-inflammatory effect. It promotes the induction of oral immunological tolerance, promotes tissue repair and wound healing and regulates cell proliferation and differentiation. Migration inhibitory factor MIF - MIF is a pleiotropic cytokine that is produced within the immune and neuroendocrine systems, including the pituitary gland. MIF is secreted by the pituitary gland during infection and injury and regulates glucocorticoid action systemically and locally and it is a major regulator of immune function.

Steroid hormones Glucocorticoids, aldosterone, estrogens, androgens and vitamin D play major roles in the neuroimmune regulatory network. The receptors for these hormones are nuclear transcription factors that directly regulate gene expression. Glucocorticoids are produced in the adrenal gland and in the thymus and are fundamental to immune function. Physiological levels are required for the normal development and functioning of the immune system.

Under pathophysiological conditions the serum level of glucocorticoids is elevated, which plays an important role in the suppression of the adoptive immune response, which is T cell-dependent. Glucocorticoids exert a powerful anti-inflammatory effect. Elevated glucocorticoids during acute phase reactions augment the production of natural antibodies and of acute phase proteins by the liver.

Luteinizing hormone releasing hormone and gonadotropins exert a direct regulatory influence on the immune system, in addition to the regulation of sex steroid hormones. In turn immune-derived cytokines regulate the production of gonadotropins. These mechanisms insure the coordination of reproduction with health status and prevent inopportune conception.

Estrogens regulate thymus function and suppress cell-mediated immune reactions. The antibody response and natural immunity NK cytotoxicity, phagocytosis are augmented by estradiol. Testosterone is immunosuppressive during trauma and shock. Many of the immunological effects of testosterone are due to its conversion to estradiol by aromatase in the thymus and in other lymphoid organs. The adrenal androgen, dehydroepyandrosterone DHEA , stimulates immune reactions in experimental animals and in man and antagonizes the immunosuppressive effect of glucocorticoids.

The age-related decline of DHEA may contribute to the immunodeficiency that develops in elderly individuals. Progesterone is a powerful immunosupressive hormone and plays a major role in the protection of the fetus during mammalian reproduction. Progesterone also contributes to the generation of self tolerance and protects against the excessive activation of the immune system. Deficiency of VD3 plays an important role in the development of autoimmune disease. It is also required for normal immune function and for proper defense against infectious disease and cancer.

Enzymes Members of the serine protease family induce a wide range of biological effects by activating several hormones and growth factors. They also participate in enzyme cascades for inflammation, blood coagulation, complement activation, and other reactions. The action of these proteases is regulated by the endocrine system and by several inhibitors, which are also under endocrine control. Many inhibitors of these enzymes belong to a single family of proteins called serine protease inhibitors or serpins. Immunocompetence Immune reactions, which are based on lymphocyte proliferation, are regulated by mechanisms that are involved in the growth control of all cells in higher animals.

Growth and lactogenic hormones GLH are required for the development and function of the immune system. GLH deliver the first signal to cells, including lymphocytes, that prepares them for proliferation, differentiation and function. This signal is designated as the competence signal, which is required for lymphocyte growth and is obligatory for the maintenance of immunocompetence. The second group of signals, that control cell growth, is delivered by cell-to-cell and cell-to-matrix signaling and are designated as stromal or adherence signals.

Adhesion molecules, tissue bound hormones, cytokines and matrix components deliver these signals. Within the immune system antigen presentation represents a dominant signal for which cell-to-cell interaction is obligatory. Adhesion molecules are fundamental to the organization of multi-cellular organisms and the signals delivered by them serve the basis of species, organ and tissue specific growth and development. The adhesion molecule system has been perfected during evolution from self-recognition to individually specific antigen recognition.

Adhesion molecules also play a role in the elimination of degenerated and neoplastic cells. Cell-to-cell signaling has a dominant power over other signals to commit the cell to proliferation. The cell cycle is then completed after the delivery of cytokine signals. The nature and combination of these three groups of signals will determine the fate of each cell, which may be survival, proliferation, differentiation and function or alternately apoptosis.

Hormones and neurotransmitters, that alter signal delivery, modulate further this basic pattern of animal cell growth. Current evidence that GLH maintain immunocompetence, which enables the immune system to respond to specific antigenic and mitogenic stimuli. Antigen presentation Antigen presentation takes place by cell-to-cell interaction whereby a complex signaling process via cell surface adhesion molecules initiates the adaptive antigen specific immune responses. External antigens are engulfed by phagocytic mononuclear cells and are digested in endosomes. The peptide fragments are then joined with MHC-II molecules in endocytic vesicles endocytic pathway of processing prior to expression on the cell surface.

The APC of this pathway are resposible for the induction of the antibody response and of delayed type hypersensitivity reactions. Endogenous antigens are processed in the cytoplasm, in enzyme-containing proteosomes cytosolic pathway and the peptides generated are associated with MHC-I in the endoplsmic reticulum, which in turn is expressed on the surface of all nucleated cells in the body. Cytotoxic T lymphocytes recognize MHC-I-peptide complexes on the cell surface and destroy infected and cancer cells. Because the antigen presenting system requires the digestion of the antigen after phagocytosis, it protects against extracellular and intracellular pathogens, it also exposes hidden antigenic determinents, decreases the impact of mutations by employing short peptides and allows for self-non-self discrimination.

Non-classical MHC antigens are also involved in antigen presentation. Specialized surface molecules CD1 mediate carbohydrate and lipid presentation. Heat shock proteins normally serve to eliminate dead cells from tissues but also form complexes with antigen, which are taken up by APC through a specific receptor CD Such complexes are taken up by macrophages and dendritic cells, digested and are presented by MHC-I.

The dominant role of antigen presentation in the adaptive immune system illustrates the fundamental regulatory function of adherence signals in multi-cellular organisms. Immune reactions Under physiological conditions the immune system provides continuous defence against infectious agents and cancer, and is part of the homeostatic neuroimmune regulatory circuit that co-ordinates the normal function of the entire organism.

The immune system provides local and mobile defence and regulation and it has enormous capacity to deliver defense and regulatory molecules to sites that are in need. Every organ and tissue possesses stromal lymphoid elements that intervene locally to control autoimmune reactions, inflammation, and in general, participate in the physiological processes.

Adaptive cell mediated and humoral immunity and immunological memory are reactions exerted by T and B lymphocytes in concert with members of the leukocyte series. The complement system and of T and B lymphocytes activated by alternate pathways are also part of the natural immune system. The natural immune system relies on germ-line coded receptors that recognizes evolutionarily highly preserved homologous epitopes homotopes on microbes and also on self components. Cell-to-cell interactions by the antigen receptor and of MHC molecules and by other adhesion molecules are fundamental to immune activation as well as to stromal regulation.

Cytokines are an essential part of this regulatory system. Immunoregulation by the HPA axis. Glucocorticoid hormones exert a multitude of functions that affect virtually every cell in the body. The physiological significance of glucocorticoids is most remarkable at times of stress, when the hypothalamic-pituitary-adrenal axis HPA is fully mobilized. The same hypothalamic hormone that stimulates the HPA axis, CRF also mediates behavioral, autonomic and neuroendocrine responses to stress in rodents and primates.

Hyperfunction of CRF neurons, therefore, appears to underlie a variety of psychiatric, gastrointestinal, cardiovascular, metabolic and reproductive illnesses attributable to stress. Nonpeptide CRF type-1 receptor antagonists are novel tools to moderate CRH activity in the brain after systemic administration [14] Neurogenic inflammation The release of neuropeptides, including tachykinins and calcitonin gene-related peptide, from sensory nerves via an axon or local reflex may have inflammatory effects in the airways.

This neurogenic inflammation may be initiated by the activation of sensory nerves by inflammatory mediators and irritants. The phenomenon of neurogenic inflammation is well developed in rodents and may contribute to the inflammatory response to allergens, infections and irritants in animal models. However, the role of neurogenic inflammation in airway inflammatory diseases, such as asthma and chronic obstructive pulmonary disease is still uncertain.

There is still little direct evidence for the involvement of sensory neuropeptides in human airways. Initial clinical studies using strategies to block neurogenic inflammation have not been encouraging. In order to clarify the situation, it is necessary to perform prolonged studies of more severe forms of airway disease in the future to explore the role of neurogenic inflammation [15]. Defensins DEF Defensins are antimicrobial cationic peptides with a cysteine-stabilized amphipathic structure. Some DEF are released into the blood during the course of infection, inflammation or stress.

DEF function not only as endogenous animal antibiotic molecules, killing microbial cells and enveloped viruses, but also as physiological regulators. Defensins are implicated in the regulation of endocytosis, chemotaxis, mast cell degranulation and inflammation. Moreover, these molecules are modulators of hemostasis and neuroendocrine-immune interaction. Defensins lower the stress-induced elevation of corticosteroid levels in the blood, and abolish the stress-induced inhibition of the humoral immune response.

These facts support the hypothesis that DEF are antibacterial peptides with a broad spectrum of biological activity [16]. The acute phase response Mild infection or sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum, which are proinflammatory and immunostimulatory. In severe trauma, sepsis and shock, GH and PRL are suppressed, whereas glucocorticoids and catecholamines are elevated.

These cytokines elicit a profound neuroendocrine and metabolic response. Fever and catabolism prevails, whereas the synthesis of acute phase proteins APP in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes is elevated. This is an emergency reaction to save the organism after the adaptive immune sytem has failed to protect the host.

During sepsis and endotoxin shock the systemic activation of the complement system and of leukocyte-derived enzymes, tissue-derived bare-down products and highly toxic cytokines seriously threaten survival. The hypothalamus-pituitary-adrenal axis is activated. Glucocorticoids play a major role in the regulation of proinflammatory cytokine production and potentiate the secretion of acute phase proteins. Some APP, such as C reactive protein, LPS binding protein and mannose binding protein in the serum are designed to combine with microorganisms and trigger their destruction by the activation of complement system and of phagocytes.

The increased production of some complement components also helps host resistance. The rise in serum fibrinogen promotes blood clotting which can serve to isolate the invading agent by triggering thrombosis in infected tissues. A number of enzyme inhibitors are produced as APP, which are likely to serve to curb the nonspecific damage inflicted by enzymes. Catecholamines are also elevated, which serve to inhibit inflammatory responses and to promote, even initiate, the acute phase response.

Serum leptin is also increased, which governs energy metabolism as well as it has an immunostimulatory effect. If the acute phase reaction fails to protect the host, shock will develop. Patients with subclinical adrenal insufficiency succumb to septic shock almost invariably if glucocorticoid therapy is not given. However, glucocorticoid treatment of septic patients with normal adrenal function has not been helpful. During the acute phase response the T-cell regulated adaptive immune response is switched off and natural immune mechanisms are amplified several hundred to a thousand times within hours.

This phenomenon has been designated as immunoconversion, which is initiated by immune derived cytokines, and involves profound neuroendocrine and metabolic changes, all in the interest of host defense. Therefore, natural immunity is essential for a first and last line of defense and the neuroendocrine system is an important promoter and regulator of this fundamental form of immune defence.

Autoimmunity Auto-reactive lymphocytes and natural antibodies do exist physiologically and participate in the homeostatic regulation of bodily functions. Under normal conditions mature T lymphocytes with autoimmune effector potential are in equlibrium with suppressor cells and with other inhibitory elements, the end result of which is self-tolerance. Immune homeostasis does not rely exclusively on internal suppressive mechanisms of the immune system.

Immunocompetence is dependent on growth and lactogenic hormones. Adaptive and natural immune responses and inflammation are controlled by neuroendocrine regulatory mechanisms. By definition autoimmune disease develops upon the loss of self-tolerance. An autoimmune reactions are due to de-regulated lymphocyte proliferation and maturation into effector cells directed towards self antigens.

There is evidence to indicate that the de-regulation of multiple genes are required for the development of autoimmune disease. It appears that that de-regulation at the cellular level as well as an altered neuroendocrine milieu are necessary for autoimmmune disease to develop. Autoimmune reactions may be specific for self-molecules, cells, organs or tissues.

These specific reactions are due to de-regulated cells of the adaptive immune system. Rheumatoid diseases are characterized by polyclonal lymphocyte activation, inflammation and acute phase reactants, which are indicative of a disorder of the innate immune system. Abnormalities of the hypothalamus - growth and lactogenic hormone - insulin like growth factor axis, of the hypothalamus - pituitary - adrenal axis and of the hypothalamus - pituitary - gonadal axis are freequently observed in autoimmune disease.

An imbalance of these major immunoregulatory axes of the pituitary gland is very likely to play an etiological role in the pathogenesis of autoimmune disease. It is also becoming apparent that defective regulation by neurotransmitters and neuropeptides contribute significantly to the pathogenesis of autoimmune and inflammatory conditions. Animal experiments and some observations in man clearly indicate that abnormalities of neuroendocrine sytem are also able to cause immunodeficiency.

In hypohysectomized Hypox rats immune function is inhibited. If the residual serum PRL present in such animals is neutralized, the thymus, spleen, adrenals and gonads become atrophic, severe combined immunodeficiency, anemia, wasting and death will occur in weeks. The spontaneous occurrence of joint and complete deficiency of pituitary GH and PRL has never been demonstrateed in man or in animals.

This suggests that this condition must be lethal. Memory cells survive hypophysectomy and resist glucocorticoids.

Pituitary PRL and GH support the adaptive T cell dependent immune system and are suppressed during febrile illness acute phase response , where natural immune mechanisms are amplified. Animals lacking adrenal function may be killed by excess cytokine production after simple immunization or after minute amounts of endotoxin, which are harmless to normal animals. The HPA axis is also the prime neuroendocrine mediator of APR, which is fundamental for survival in emergency situations e. This axis contributes to the conversion of the immune system from the adaptive mode of reactivity to boosting of natural immune mechanisms and to metabolic alterations catabolism in most tissues.

Growth hormone treatment of patients with severe acute illness worsened their survival. One possible reason for this is that GH interfered with boosting natural immune defence by inhibiting the HPA axis and catabolism, which are fundamental to APR. Androgens and progesterone are immunosuppressive steroids. Sex hormones are fundamental for reproductive function, where the immune system is an active participant. Disturbances of sex hormone function due to ageing or to other factors contribute to deficient immune function and to the development of disease.

Whenever the adaptive immune system becomes deficient e. APR develops at major metabolic costs to the host, and may lead to malnutrition, wasting and eventually to death. Proper nutrition and hormone supplements e. Some of the key issues are addressed below both from the theoretical and practical points o view. Hierarchy It is clear that the hypothalamus is the highest regulatory organ of immune and inflammatory reactions.

Indeed, there is ample evidence to support the proposal that the Nervous-, Endocrine- and Immune systems form a regulatory network that involves the entire organism and governs all functions from conception till death. Network communication is achieved by innervation, by hormones and cytokines distributed through the blood, and by re-circulating cells of the immune system Figure 1.

Innervation is bi-directional, as the CNS sends signals to each organ and tissue in the body and receives feedback signals through sensory nerves and by the vagus nerve. Communication by hormones and cytokines is of multi-directional network type. Immune- and tissue-derived cytokines provide feedback towards the hypothalamus. Shared mediators assure efficient communication between members of the regulatory triad as well as with the tissues and organs of the entire organism [18]. Competence It is known for over a century that GH is capable of promoting the proportional growth of all tissues and organs in the body.

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Naturally, this includes the immune organs, such as the spleen, thymus and lymph nodes. Receptors for GLH are expressed on every tissue and organ in the body. Current indications are that all cells require some members of this hormone family for normal growth and function. GLH in conjunction with IGF-I exert a growth stimulatory and an anti-apoptotic effect on all cells and thus assure maintenance in a functional state, i.

On this basis GLH may be defined as competence hormones. The competence signal is the first in the signaling hierarchy of cell activation No. There is evidence to indicate that the immune system is dependent on GLH for the maintenance of immunocompetence. This is related to the general function of these hormones to promote growth and development, as lymphocyte growth is a prerequisite of adaptive immune reactions [19]. Tissue specific growth factors, cytokines and adhesion molecules play important roles in cell to cell signaling and the regulation of growth and differentiation of various cells in the body.

GH in conjunction with IGF-I promote the survival and growth of all cells in the body and maintain them in a state of competence. Prolactin, which may be regarded as a modified growth hormone, is also capable of providing competence to most tissues and organs, with the possible exception of the skeleton where its growth promoting effect is limited. The IGF-I signal may be regarded as the ubiquitous cytokine signal that is needed for the survival of competent cells. On this basis one may suggest that competence hormones maintain their target cells by a direct stimulatory effect on the genome and by the stimulation of IGF-I or equivalent cytokine.

Prolactin synthesis is detectable in numerous tissues, including lymphoid tissue. Within the immune system, small lymphocytes are in a quiescent state and do not synthesize significant amounts of mediators. They need to be activated in order to do so. Moreover, pituitary PRL and GH maintain vital bodily functions and thus must act as survival hormones for the entire organism [].

Redundancy Failure of the neuroimmune regulatory system invariably leads to the death of the organism. In order to avoid frequent failures, the system must have multiple and overlapping regulatory pathways with a high degree of flexibility and plasticity. This is achieved by isologous forms of regulatory molecules, multiple forms of receptors, and by the existence of functionally overlapping or interchangeable regulatory pathways. It is quite common in immunology that unsuspected redundancy is revealed in the system by knocking out a particular gene.

Similarly, the disabling of prolactin or growth hormone, or even IGF-I, would not paralyze immune function. Elaborate physiological and pathophysiological mechanisms assure that this systemic regulatory network remains functional under the most adverse conditions. Under physiological, or homeostatic conditions two basic forms of immune reactivity can be observed, e.

These function hand-in-hand, providing efficient host defense quietly in total harmony with the organism. Emotional and physical stress activates the HPA axis, which has a suppressive effect on the adaptive immune system by the inhibition of the thymus and of T lymphocytes. Severe trauma or infection will induce febrile illness, which is now termed the acute phase response APR. During APR the innate immune system is amplified and the adaptive, T-cell-dependent system is suppressed. This immunoconversion is a very intensive and highly co-ordinated process, that requires the catabolic breakdown of body constituents in order to fuel the neuroendocrine and immune systems bone marrow, leukocytes and the intensive production of liver-derived acute phase defense molecules [24].

Because the immune-, neuroendocrine- and metabolic alterations are strictly regulated, the use of the term allostasis [25,26], in comparison with homeostasis, is justified. The allostatic milieu assures the promotion of host defense at the expense of other tissues and organs.

NeuroImmune Biology: Vol.3/ The Immune Neuroendocrine Circuitry: History and Progress-Chapter V

Immunodeficient individuals rely more and more frequently on APR for host defence, which may create a negative energy balance leading to cachexia and eventually to death. Invariably the stroma of all tissues and organs contain immune derived elements such as lymphocytes, macrophages or more specialized cells that include the glia cells in the nervous system, Kuppfer cells in the liver, the Langerhans cells in the skin, etc. These lympoid cells play important functional roles both in health and disease. Cell to cell regulation in tissues is mediated by adhesion molecules that have complimentary binding sites.

These molecules are capable of delivering activation or inhibitory signals []. Upon lymphocyte activation adhesion molecules and other cell membrane receptors have the capacity to co-aggregate within the semi-fluid cell membrane capping. These motifs promote activation by phosphorylation, or inhibit activation by dephosphorylation of signal transuding molecules, respectively.

The relevance of this phenomenon to cell function is especially well established for NK cells and lymphocytes. Adhesion signals have a dominant power to regulate cell activation, proliferation, differentiation and function, or alternately inhibition or commit cells to the suicide pathway. Adhesion signals are in second place in the hierarchy of cell signaling Figure 1. The immune system consists of mobile cells that are able to home readily to specific target tissues and also to sites of infection, injury, regeneration and healing. Stromal lymphoid cells play important physiological roles and are fundamental to host defense, regeneration and repair.

Adhesion molecules mediate immunocyte homing and lymphocyte re-circulation. Blood vessels also provide important barrier function in some tissues and organs that are known as immunologically privileged sites. The blood brain barrier is very important from the point of view of neuroimmune interaction. Ultimately, adhesion molecules, that are capable of delivering non-diffusible cell-to-cell or cell-to-matrix signals, determine the proliferation and functional activation of all cells in the body.

Adherence signals are capable of regulating cell function specifically on an individual basis. For example the antigen presenting cell delivers regulatory signals to the antigen specific T lymphocyte [18]. Innervation All the immune organs are innervated and functional neurotransmitter receptors are present on immune cells. These facts create the foundation of the research field of neuroimmunology, which examines the homeostatic interactions between the nervous and immune systems in the process of host resistance.

Much evidence is available which shows the effects of neurotransmitters on various in vitro measures of immune cells. However, the complex interactions created by neural-immune interactions at sites of antigen challenge and within immune organs cannot be accurately modeled in tissue culture systems. This fact created a need for focusing attention on in vivo model systems, which maintain the local microenvironment created when antigen is encountered in skin or mucosal membranes. The central nervous system has the capacity to deliver neurotransmitters and neuropeptides to all tissues and cells in the body.

Interestingly the spleen contains only sympathetic efferent nerve fibers. Tissue mast cells are form synapses with nerve fibers. Neurogenic inflammation is the direct result of the discharge of inflammatory mediators from mast cells after stimulation by neurotransmitters primarily by substance P released from sensory nerve terminals. Neurotransmitters and neuropeptides, e. Catecholamines are important regulators in the acute phase response, which is an emergency defense reaction.

Sensory nerves provide feedback signals towards the CNS from sites of injury, inflammation, and infections. The vagus nerve carries feedback signals to the CNS from visceral organs. One may also include here immunoglobulins, which originate from B lymphocytes. Immunoglobulins have evolved from adhesion molecules. In addition, virtually every cell membrane bound molecule is present in the serum, which includes MHC molecules and receptor-like-binding proteins. Moreover, cytokines, which have been originally discovered within the immune system, are now known to be synthesized in other tissues and organs, including the neuroendocrine system.

Therefore, the historical definition of hormones neurotransmitters and neuropeptides no longer applies. Rather, systemic and locally produced mediators complement each other, so that optimal function is assured both under physiological and pathophysiological conditions. Cytokine signals are third in the hierarchy of signals required for cell activation Figure 1. In the mitotic cycle, third signals are delivered during the late G1 phase. Insulin-like growth factor 1 and insulin are the classical hormones that act at this stage and initiate the synthetic S phase, which will then progress to mitosis [35].

It is clear, however, that at least some of the cytokines produced locally in the bone marrow, e. Therefore, these cytokines should be considered as competence hormones, delivering signal 1 and not signal 3. It has been also observed on B-cell hybridomas in culture that PRL potentiated the effect of interleukins for the stimulation of proliferation and antibody formation [37].

In cell biology epidermal growth factor, platelet-derived growth factor and fibroblast growth factor have been designated as competence hormones [35]. In addition estradiol is capable of inducing IGF-I in mammary tissue [38]. These observations indicate that competence may be inducible by hormones and cytokines other than GLH. However, in vivo observation in GLH deficient animals strongly indicate that the total lack of GLH leads to wasting disease and death.

Therefore, GLH is fundamental to the maintenance of vital bodily functions, including immune function. A simple explanation for this could be that the production of all the other factors that are capable of delivering signal 1 in the mitotic cycle requires competent cells to begin with and the production of such cells rests with the availability of GLH. Indeed, we have observed that PRL disappeared from lymphoid tissue of rats after hypophysectomy [17]. Clearly, GH, PRL, IGF-I and insulin are readily available in significant quatities in the serum at all times, and thus provide competence to all cells in the body whether they are active or in a quiescent state.

Further studies are required to elucidate these questions in more detail. Numerous receptors in immunology and several hormone receptors need to be cross-linked by the ligand in order to deliver an activation signal to the target cell. When more than one receptor isotype is available, the homo- and hetero-diamers formed by the specific ligand may have different biological functions.

This is the case with steroid hormones. In addition, cross-linking may be one of the important mechanisms that promote capping of the receptors prior to activation. These organisms rely continuously on their central nervous system for the regulation of all bodily functions. Some time ago it was realized that the Endocrine system is an essential part of this systemic regulatory circuitry. Now a case can be made for the Immune system, which also belongs to this systemic regulatory network of higher organisms that play a fundamental coordinating role form conception till death.

Some important aspects of this regulation are discussed below [17]. Placental hormones play a major role in the development of the fetus. Indeed, now there is decisive evidence to indicate that placental GLH gradually overrule the maternal pituitary gland and regulate metabolism and the level of developmental hormones even in the maternal organism in the interest of normal fetal development. Virtually all other hormones required for fetal development are produced in the placenta in a self sufficient and autonomous manner [39,40].

These hormones govern fetal development, which include the development of the immune system. In this context it is interesting to note, that fetuses with the congenital lack of the pituitary gland develop normally in utero, but are not viable after parturition [41]. This indicates that placental and perhaps maternal hormones fully support fetal development and that the pituitary gland takes over the regulatory role of the placenta after parturition.

Mice are born with an immature immune system and probably also, with an immature pituitary gland. It is likely that during the transition period of immune and pituitary maturation the newborn pups rely for survival on PRL received via placental transfer and in the colostrum. If this PRL is neutralized, there is no other competence hormone to take over, which could result in wasting and death. This situation is analogous to the case of hypophysectomized rats, where there is residual PRL in the serum of long-term survivors.

If this PRL is neutralized by antibodies, immune and bone marrow function ceases, the thymus, spleen, adrenals and gonads become very athrophic and a rapid wasting disease and death occurs within 6 weeks [19]. Pit-1 deficient mice and human beings, which have been claimed to be free of pituitary GLH, do in fact have detectable serum hormone levels []. This explains their survival. It is known that old people may be deficient in GH. However, PRL deficiency is virtually unknown. Again, it is possible that those individuals that become deficient in both hormones pass away before their condition would be recognized.

Preliminary clinical evidence indicates that the treatment of immunodeficiency-related wasting disease with GH and with anabolic steroids is beneficial. These crucial observations, along with much additional evidence presented in this volume, indicate that GLH maintain vital bodily functions, including immune function, in the entire organism from conception till death. These hormones provide all cells in the body with competence to develop and function.

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The fundamental importance of these hormones in the biology of higher organisms cannot be over-emphasized. In contrast with GLH, which have an overall stimulatory effect on the organism, the hormones of hypothalamus - pituitary - adrenal HPA axis act both synergistically with GLH under physiological conditions and antagonistically during pathophysiological events by inhibiting growth, metabolism, immune responses and inflammation.

Glucocorticoid and other steroid hormone receptors are nuclear transcription factors and are necessary for normal signal transcription by membrane bound receptors. Thus they are integrated into the signal transduction sequence under physiological conditions. The immune system and other tissues have the capacity to generate bioactive steroid hormones from the adrenal steroid precursor-hormone, dehydroepyandrosterone-sulphate DHEA-S.

There is evidence to indicate that the HPA axis begins to function already within the fetus, prior to the activation of pituitary GLH secretion [41]. This suggests that it is of vital importance to have the nuclear control of signaling in place for normal development and function of the organism, including immune function.

Animals that lack HPA function respond with exaggerated cytokine production after immunization or if given minute doses of LPS. Such animals die easily, due to cytokine toxicity. The HPA axis plays a fundamental regulatory role also during the acute phase response by promoting the production of acute phase proteins and keeping cytokine production and immune activation at a level, which is compatible with survival. In rheumatoid arthritis and in other chronic inflammatory conditions the HPA axis responds at a subnormal level to inflammatory cytokines, which is likely to play an etiological role in the prolongation of the disease process.

DHEA declines with ageing and also during chronic illness, which contributes to the deficiency of adaptive immunity under these circumstances. The immunomodulatory role of estradiol and progesterone is fundamental to the success of mammalian reproduction. Thymus function is regulated by estradiol, some of which is testosterone derived in males. Estrogens suppress cellular immunity and enhance the humoral response and the activity of phagocytes.

Testosterone has an overall suppressive effect, which appears to be significant for protection against autoimmune reactions, but it is a definite disadvantage in trauma-relatd immunosuppression. Because castration does not create life threatening immune disturbances, these hormones my be designated as facultative immunomodulators that help to fine tune immune reactions to accommodate some physiological events such as the reproductive cycle in females.

By now it is clear that the immune system is integrated with the neuroendocrine systems to form a systemic regulatory network in higher organisms. Immune function is required for reproductive success. All tissues and organs contain immune derived stromal cells, which participate in normal development and function as well as provide protection under pathophysiological conditions. They play major roles as cytokine producing regulatory cells that are also capable of phagocytosis and antigen presentation. Parenchymal cells, such as keratinocytes in the skin, neurons in the brain, enterocytes in the gut and liver cells form important local regulatory circuits with immune-derived stromal cells [].

According to recent evidence MHC-specific suppressor and effector T lymphcytes are present in all tissues, balancing against each other during homeostasis. The effector T cells rapidly mount immunity against foreign invaders and against cancer, and also participate in the elimination of degenerated cells.

The immune system is fundamental also to regeneration and healing [52]. Immunological studies in ageing animals revealed a correlation between longevity and the preservation of immune function. In healthy 90 and year old individuals the level of NK cell-mediated cytotoxicity was similar to that of young subjects. Thyroid hormone and vitamin D levels were maintained and lean body mass was preserved [53].

These observations point again to the fundamental importance of the neuroimmune regulatory triad in the maintenance of long and healthy lifespan. Clearly, this systemic regulatory network is fundamental to the development and normal function of higher organisms throughout the entire life cycle. The power of these approaches is unprecedented and is expected to produce major advances to our understanding at the cellular level. The need for the integration of the accumulated knowledge has also been realized and is promoted by several groups world-wide.

There is no doubt that these efforts will lead to major advances in our understanding of higher organisms in their entire complexity, as well as yield abundant practical information for more rational approaches to the prevention and management of diseases. The Neuroimmune Regulatory Network This figure shows the interaction of major systemic neuroimmune regulatory pathways with local paracrine-autocrine regulatory circuits.

Some key organs are also shown with their major regulatory input. Mobile elements of the immune system home to all organs and tissues and participate in physiological and pathophysiological processes. Neuroimmune regulation is fundamental to the development and function of all cells in the body from conception till death. Immunoregulation is used as an example for detailed explanation. It is proposed that the development and maintenance of lymphocytes and other cells in the body in a functional state is dependent on competence hormones.

Additional signals are required for fine tuned functional regulation that includes hormones, adhesion molecules, neurotransmitters, neuropeptides and cytokines. There is a hierarchy for the 3 major groups of signals as given below: Many tissues also produce competence hormones ectopically, including the immune system. This local regulatory circuit makes rapid lymphocyte proliferation possible, which is a prerequisite of immune reactions. This remains to be clarified.

Antigen presentation by specialized cells is an adherence signal and a dominant lymphocyte activator. This is accompanied by additional co-stimulatory adherence signals, eventually leading to lymphocyte activation. Adherence signals also play a role in the induction of immunological tolerance, in lymphocyte survival, and in the induction of programmed cell death PCD. These signals fulfil tissue-, site- and cell-specific regulation in the body, i.

Lymphocyte activation is completed by cytokine signals, which lead to cell proliferation, differentiation, and functional activation. Cytokines may also perform inhibitory function e. Glucocorticoids, sex and other steroid hormones SH , tri-iodothyronin T3 and vitamin D3 control lymphocyte signalling by the regulation of nuclear transcription factors.

These steroid hormones and T3 play a regulatory role also in cell differentiation and in the elimination of unwanted cells via the induction of PCD. Bioactive thyroid and steroid hormones are locally generated from inactive precursors by immunocytes e. T3, E2, androstenediol, androstenetriol, and vitamin D3 while the primary function of others corticosteroids, estradiol, progesterone, aldosterone is systemic immunoregulation.

The thymus itself is also a steroidogenic organ. Quiescent lymphocytes do not synthesize DNA and exert minimum metabolic activity. Neurotransmitters and neuropeptides are locally acting functional regulators, basically acting as signal modulators and cytokines. Some neuropeptides may be able to deliver competence signals.

The primary and secondary lymphoid organs, the mucosal and cutaneous lymphoid systems contribute leukocytes to the circulation that mediate systemic immunity. These sessile lymphoid elements fulfil important local regulatory function. The adrenal, thyroid and gonads produce important immunoregulatory hormones. The liver contributes to immune function by producing serum IGF-I, by promoting the induction of oral immunological tolerance and it plays a major role in the acute phase response.

The pancreas produces insulin and the submndibular gland nerve growth factor, which are major immunoregulators. These glands also produce glandular kallikrein, which have a major immunoregulatory function. All other tissues and organs have an input into the neuroimmune regulatory network via nerve impulses and by cytokine production. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol ; 6: Anaphylaxis and nervous system. Acta Med Hung ; 2: Szentivanyi A, Filipp G.

Anaphylaxis and the nervous system. Ann Allergy ; Filipp G, Szentivanyi A. Role of the nerve terminals in the mechanism of inflammatory reactions. Cambridge University Press, Bretscher P, Cohn M: A theory of self-nonself discrimination. Ann Rev Med ;8: Szentivanyi A, Fishel CW. Die Amin-mediatorstoffe der allergischen Reaktion und die reaktionfahiegheit ihrer Erfolgeszellen. In Pathogese und Therapie allergisher Reaktionen. Neurohumoral concepts of bronchial asthma. Acta Allergologica ; 29 Suppl. The beta adrenergic theory of the atopic abnormality in bronchial asthma.

Neurogenic inflammation in the airway in this volume. Berczi I, Gorczynski R. The role of the growth and lactogenic hormone family in immune function. Pituitary dependence of bone marrow function. Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue. Nagy E, Berczi I. Hypophysectomized rats depend on residual prolactin for survival. The neuroimmune biology of growth and lactogenic hormones.

Lecons sur le phenomenes de la vie communs aux animaux et au vegetaux. Natural immunity and neuroimmune host defence. Ann NY Acad Sci ; Allostasis, allostatic load, and the aging nervous system: Neurochem Res ; Oct; 25 Berczi I, Nagy E. Neurohormonal control of cytokines during injury. Integrin activation by chemokines: Histol Histopathol ; Oct; 15 4: Transduction of cytotoxic signals in natural killer cells: However, we predict on the basis of our own observations that the disabling of GLH genes in the same animal would have lethal consequences [23].

There is evidence to suggest that lymphocyte-derived GLH is capable of paracrine and autocrine growth stimulation [52,53]. It is suggested that during immune reactions, such locally generated GLH is required to support the rapid proliferation of lymphocytes in the interest of promotion of an effective immune response. This situation has parallels with the development of the mammalian embryo, which gradually grows independent of the pituitary hormones and relies mostly if not exclusively on placental lactogenic hormones.

Moreover, placental GLH actually have a major influence on maternal metabolism, which serves the interest of the fetus [54]. It is suggested that these cells are dependent on pituitary GLH and on IGF-I for survival in lymphoid organs and rapidly undergo apoptosis in Hypox animals. On the other hand memory cells are metabolically active and remain functional in Hypox animals.

Memory T lymphocytes are glucocrticoid resistant and produce cytokines readily after stimulation with the spcific anigen. The lymphocyte derived PRL gene was shown to have placental promoting sequences [56 ]. If such a gene becomes activated in memory cells they would be able to syntehesize PRL for autocrine stimulation in a pituitary independent manner and to assure survival even in hypohysectomized animals. The glucocrticoid resistance of memory cells would also be explained as PRL is an antagonis of glucocorticoids.

This possibility remains to be established. Self recognition has been thought for a long time to be the exsclusive feature of the immune system.

However, self recognition is easily demostrable in the most primitive multi-cellular animals, sponges. Sponges also control cell proliferation and differentiation. They are capable of rejection of grafts from another species of sponges, and show self defence against infection, which is mediated by phagocytic cells. One may easily disintegrate sponges by passing them through a screen. When brought together, the cells are capable of re-aggregation and regeneration to form a functional sponge unit.

These facts demonstrate the ability of these seemingly loosely aggregated cells to behave in a highly coordinated fashion. Sponge cells will grow and differentiate into functional cells according to their topographical localisation [57]. Similar observations were made in higher animals. For instance, if cells from different anlages of the amphibian embryo are mixed, they will sort out in a pattern that resembles the initial organization of embryonic tissue.

Such aggregation experiments may be performed also with embryonic cells from birds or mammals. Cell adhesion molecules present in embryonic tissue mediate re-aggregation and cell motility and play a key role in morphogenesis [58,59]. Embryonic morphogenesis is governed by cell-to-cell contact and by diffusible mediators. Adhesion molecules are non-diffusible and for this reason are capable of signalling single cells very specifically. It is very clear from embryonic development and from antigen-induced lymphocyte proliferation that adhesion signals are dominant over growth factor signalling.

At the cellular level, this means that only certain cells will divide at any given time while others go into differentiation and take up the appropriate function according to their location in the body, or be on standby stem cells, as well as differentiated cells or may even be eliminated. Thus, the general growth stimulus is modified according to local needs so that the morphological and functional integrity of the organism is maintained at all times.

GH is well recognized as a hormone capable of stimulating the proportional growth of all tissues and organs. This dominance of local regulatory mechanisms, that also include tissue bound hormones and cytokines, over the systemic GLH signals assures the development of a fully functional animal or human being. Injured nerve cells in the CNS can be reinduced to grow axons and establish functional connections if exposed to non-neural elements of the peripheral nervous system [61].

This illustrates very well that even in adult tissues that lost their capacity to grow stromal adherence signals are capable of inducing growth and regeneration. Plants show a remarkable morphological and functional differentiation. Some proteins extracted from plants and collectively named lectins [62] have the capacity to activate animal cells, especially lymphoid cells for proliferation and function, including immunoglobulin secretion, cytotoxicity, helper or suppressor activity [38]. Therefore, plant lectins function as regulatory molecules on animal cells and probably fulfil similar functions in the plants as well.

Animal tissues also contain lectin-like molecules [62]. Adherence signals mediate positional regulation, which is species-, organ- or tissue-specific, and in the case of MHC and antigen receptor molecules, individually specific. The antigen receptor also shows epitope specificity. The antigen receptors of B and T lymphocytes, MHC antigens, CD4 and CD8, some receptors of natural killer cells and numerous other cell bound molecules belong to the immunoglobulin family of adhesion molecules.

Both activating and inhibitory receptors are found in this group that carry ITAM immunorecptor tyrosine-based activation motif and ITIM inhibitiory motifs respectively Figure 10, Receptors with ITIM promote tyrosine phosphorylation and are stimulatory. Receptors with ITIM dephosphorylate tyrosine residues and are inhibitory. The restrictive power of cell-to-cell signaling is also fundamental to the immune response.

Clearly, an antigen specific lymphocyte clone must not proliferate unless it is triggered by the specific antigenic epitope in the context of self-MHC molecules. Without this restriction antigen-specific immune reactions would not be possible. Further, MHC recognition by suppressor T lymphocytes and killer inhibitory receptors in natural killer cells serves as safeguards against the killing of normal non-infected and non-cancerous cells [38].

The schematic structures shown are representative but not a genuine reflection of the individual molecular structures After Bluestone et al. Capping of stimulatory and inhibitory receptors prior to T and NK cell activation. The co-aggregation of activating and inhibitory receptors by capping facilitates the interaction of enzymes that stimulate cell activation by phosphorylation and inhibit activation by dephosphorylation After Renard et al.

Cell-to-cell interaction between stromal cells and B cell precursors and IL-7 play an essential role in B lymphocyte development in the bone marrow. The thymic microenvironment is essential for normal T cell development. Here MHC-T cell receptor interactions and a special cytokine and neuroendocrine milieu regulate T cell maturation [38, ]. Therefore, cytokines do not only complete the signalling process for cell proliferation, but also appear to play a role in the determination of the type of effector cells that are generated during the proliferative response.

Cytokine signals are usually, but not always, delivered by locally generated mediators. These signals antagonize apoptosis and complete the positional signalling cycle for growth, differentiaton, functional activation, etc. Insulin-like growth factors are both systemic and locally generated and insulin is a systemic hormone. As systemic mediators, these hormones deliver third signals to all cells in the body. The cells affected may be in an inactive quiescent state incapable of synthesis and circulating IGF and INS enable such quiescent cells to metabolise and survive.

Moreover, GH itself can also exert an insulin-like action. However, given the heterogeneity of GLH and of their receptors, these hormones may be capable of delivering a number of signals other than the competence signal [3, 4, 45, 72, 73]. A detailed discussion of these questions is beyond the scope of this chapter. These steroid hormones may mediate activation, inhibition and apoptosis within the immune system.

This regulation is fundamental for normal immune function and for the adaptability of immune system to reproduction and for protection against stressful insults and of various other pathological processes. These hormones may be designated as nuclear signal regulators [71,73,74]. A number of other mediators, including opioid peptides, act through G-proptein linked adenylate cyclase receptors as well.

In primitve multi-cellular animals, like the sponge, cell-to-cell recognition and communication is the basis of organization, and little is known about the role of soluble mediators. However, in embryos of higher animals soluble mediators are clearly important, which are necessary for cell growth and differentiation, which must fulfil the functional requirements posed by the position of a given cell in the body. During evolution and during embryonic development growth control is gradually taken over by the pituitary gland.

In mammals this happens abruptly at paturition, when pituitary GH assumes the regulation of body growth and PRL joins in as a similar regulator, but with a very limited ability to promote body growth. The adaptive immune response is based on the recognition of MHC antigens presenting either self-related or foreign epitopes to T lymphocytes. Both the MHC molecules and antigen receptors are adhesion molecules, that belong to the immunoglobulin family. Therefore, the fundamental mechanism of self recognition has been modified to recognize non-self in the context of self.

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According to recent consensus, suppressor T lymphocytes actively recognize self antigens and exert a local suppression in the various organs and tissues against the development of effector autoimmune cells. When the self-MHC presents a foreign epitope, no suppressor cells would be present against such modified self antigen and consequently effector T lymphocytes can freely develop against them [38].

Therefore, the immune system is an essential part of growth control in higher organisms, that exercises quality control, allowing the growth of normal cells and destroying cells which display an altered phenotype e. This way the homeostasis of the immune system, which is based on the equilibrium of effector and suppressor mechanisms is closely linked to the homeostasis and growth control of the entire organism.

The growth promoting effect of GH and PRL is no different on lymphocytes from the effect of other cells in the body. This control is based on cell activation, which in practical terms must mean to shift the signalling balance by adhesion molecules towards activation. This is followed up by the production of IGF-I, which completes the mitogenic signal. Once differentiation is initiated, new adhesion molecules are induced e. Some cells that show resistance to hypophysectomy, such as memory cells, are likely to have their GLH genes under the control of the placental promoter.

Cytokines, such as interleukin-2, IL-3 and GM-CSF may actually be able to boost the competence signal in lymphocytes and in the bone marrow, respectively. Thus during the evolution of an immune response the immune system may gradually escape pituitary control by the production of competence hormones locally, which are capable of maintaining immune function in an autonomous fashion.

A stable output of leukocytes of the bone marrow is also required for the maintenance of immune function and health. These remain pituitary dependent. However, the bone marrow is actually activated. Under these conditions IL-6 and insulin are elevated. Because bone marrow function is glucocorticoid resistant, these systemic growth promoting mediators are free to act and, combined with locally produced growth factors, could explain the intensive bone marrow activation. This remains to be validated. Steroid, thyroid hormones and vitamin D regulate nuclear signalling proteins and for this reason are required for normal immune function.

These hormones are the ultimate regulators of signling in all cells in the body, including the immune system. Other hormones, cytokines and neuropeptides e. It may be concluded on the basis of available evidence that immunocompetence depends on pituitary and lymphocyte-derived GLH. Without these hormones the immune system looses cellularity and the ability to respond to antigenic and mitogenic stimuli.

Moreover, the entire organism ceases to function if no GLH is available and death will ensue within a short period of time. This hypothesis is supported by observations in animals and man. Therefore, it is postulated that GLH provide vitality not only to the immune system, but to the entire organism. The Immune Neuroendocrine Circuitry: Advances in Neuroimmune Biology: Advances in Neuroimmune Biology. New Insights to Neuroimmune Biology. Insights to Neuroimmune Biology Second Edition. History and Progress Volume Editors: Istvan Berczi and Andor Szentivanyi. A comprehensive presentation of neuroimmune biology.

Introduces the subject matter to the uninformed reader. Contains basic information, theoretical considerations and up-to-date clinical chapters. The clinical chapters will be helpful to practising physicians. Gabry, George Chrousos, Philip W. Gold Immunoregulation by innervation. The treatment schedule of the various groups is explained in the legends of Figure 4. The animals were killed on day 20 and bone marrow cells from the femurs were tested for nucleic acid synthesis in vitro.

After Nagi and Berczi,[20].

Insulin like growth factor-I mRNA expression in the thymus of hypohysectomised rats after treatment with ovine growth hormone or prolactin. The animals were killed at 15, 60 and minutes after hormone injection. One and two signal theories of the immune response. Today it is clear that the adherence interaction of an antigen presenting cell APC with antigen specific T lymphocytes is required for the initiation of an immune response. Initially the APC interacts with helper T cells and later on the helper T cell with B cells antibody response or immature antigen sensitive T cells cell mediated immunity.

This adherence interaction stimulates the secretion of cytokines from helper T lympocytes, which function as growth factors. The cytokine signal completes the mitogenic stimulus and enables the immature cell to proliferate clonal expansion. Multiple cytokines are available to deliver this signal, which varies according to the type and stage of the immune response [31, 37,38]. This basic signaling process is modulated further by hormones, neurotransmitters and neuropeptides, as discussed later If one carefully examines the theories for cell growth and for the initiation of an immune response, in fact they define three groups of signals: The function of the pituitary body.

Amer J Med Sci ; Uber die Funktion der Hypophyse. Matera L, Rapaort R. Growth and lactogenic hormones. Berczi I, Szentivanyi A, Series editors. Neuroimmune Biology, Volume 2. Berczi I, Szetivanyi A. Berczi I, Szentivanyi A,series editors. Neuroimmune Biology, Volume 3. N Engl J Med ; Increased somatomedin receptor sites in newborn circulating mononuclear cells. J Clin Endocrinol Metab ; Insulin-induced loss of insulin-like growth factor-I receptors on IM-9 lymphocytes. Prolactin directly stimulates the liver in vitro to secrete a factor synlactin which acts synergistically with the hormone.

Lactogenic hormones stimulate the liver to secrete a factor that acts synergistically with prolactin to promote growth of the pigeon crop-sac mucosal epithelium in vivo. Growth factors and cancer. Physiology of growth hormone secretion and action. Endocr Metab Clin N Amer ; Growth hormone, growth factors and hematopoiesis. Horm Res ;45 Insulin growth factor-I inhibits apoptosis in hematopoietic progenitor cells.

Implications in thymic aging. Estrogen receptor ER -alpha, but not ER-beta, mediates regulation of the insulin-like growth factor I gene by antiestrogens. J Biol Chem ; Transforming growth factor-beta1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors. Neurohormonal control of cytokines during injury. Brain Control of the Response to Injury. Cambridge University Press Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue.

Nagy E, Berczi I: Pituitary dependence of bone marrow function. Br J Haematol ; Endocrine control of the immunosuppressive activity of the submandibular gland. Brain Behav Immun ;6: Effect on growth of prolactin deficiency induced in infant mice. Hypophysectomized rats depend on residual prolactin for survival.

What is the role of growth hormone and related peptides in implantation and the development of the embryo and fetus. Pathology of the fetus and the infant. Chicago, Year Book, Pituitary control of growth in the neonatal rat: Berczi I, Nagy E: The effect of prolactin and growth hormone on hemolymphopoietic tissue and immune function, in: Berczi I, Kovacs K eds: The role of the growth and lactogenic hormone family in immune function.

Ann Rev Med ;8: