Neuroimmunomodulation of homeostasis and host defense.
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Allergy and Immunology↗
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The neuro-immune network. Some recent developments.
Neuroimmunomodulation encompasses, by definition, numerous components and activities primarily derived from the immune system, and treats the immunoneuroendocrine interconnections at different levels of the integrated whole functioning organism. The arbitrary unit of the immunoneuroendocrine network is the immune microenvironment composed of lymphocytes, neurons, endocrine cells, nonlymphoid accessory cells, humoral factors from immune, nervous, endocrine and other tissues, receptors for endogenous and exogenous ligands, pathways for transduction of biological signals, physiological ions, various magnetic and electromagnetic compartments, and impulses from the higher nervous activity (the mind, the psyche). The neuroimmunomodulation is a marvelous mechanism from which arises an amazing quantity of variables and intercommunications in the living organism. Being a multidisciplinary science par excellence, neuroimmunomodulation is strongly antidogmatic and favors multidirectional organization of research. That means that actions of the immune, nervous and endocrine systems should be studied together in terms of intercommunications among identifiable structures and processes. Therefore, research endeavors in neuroimmunomodulation have different directions with seminal discoveries much too numerous to list here. This mini-review is confined to some recent findings dealing with the immunomodulatory activity of micromagnetic fields when applied to the brain, the humoral and cell-mediated components of certain neurological and psychiatric diseases, the autoimmune features in heroin addicts in relation to dementia and HIV infection, the neuroimmunobiology of lithium cation, and the in vivo immune function of enkephalins, and methionine-enkephalin in particular.
Animals↗
Brain neuromediator systems in the immune response control: pharmacological analysis of pre- and postsynaptic mechanisms.
The involvement of the dopaminergic (DAergic), GABAergic and serotoninergic (5-HTergic) synaptic mechanisms in neuroimmunomodulation are considered. It is shown that the central DA- and GABAergic systems exert a stimulatory influence on the immune reactivity. Activation of postsynaptic DA receptors with apomorphine and (+)(3-hydroxyphenyl)-N-n-propylpiperidine [(+)-3-PPP] at high doses, D2 receptor activation with quinpirole, as well as DA reuptake blockade with amantadine and bupropion, resulted in an increase in the immune response. The intensity of the immune response was also increased during activation of the GABAergic system with the GABA agonist muscimol or the benzodiazepine agonists diazepam and tazepam. On the other hand, decreases in the activity of either system by different drugs inhibiting DAergic and GABAergic neurotransmission (antagonists of DA postsynaptic receptors haloperidol at 1.0 mg/kg and (-)-3-PPP at 6.8 mg/kg, agonists of DA autoreceptors apomorphine at 0.02 mg/kg, (-)- and (+)-3-PPP at 1.7 and 3.4 mg/kg, antagonist of GABA receptors bicuculline, blocker of chloride channels picrotoxin, blockers of benzodiazepine receptors Ro 15-1788 and Ro 15-3505) produce suppression of the immune response. The 5-HTergic system is involved in the inhibitory mechanism of neuroimmunomodulation. 5-HT reuptake blockade with 4-(5,6-dimethyl-R-benzophuranil)-piperidine (CGP-6085A) and sertraline led to immunosuppression.
Animals↗
Cerebellar interposed nucleus lesions suppress lymphocyte function in rats.
We previously reported that the cerebellar fastigial nucleus, output nucleus of the spinocerebellum, modulates lymphocyte function. To further explore the role of the cerebellum in neuroimmunomodulation, we here lesioned bilaterally the cerebellar interposed nuclei (IN) of rats with kainic acid (KA) injections. On days 8, 16 and 32 after IN lesions, lymphocyte percentage in peripheral white blood cells was examined. Furthermore, proliferation of lymphocytes from mesenteric lymph nodes induced by concanavalin A, sheep red blood cell-specific IgM antibody in the serum and cytotoxicity of natural killer cells from spleen against YAC-1 cells were measured by methyl-thiazole-tetrazolium assay, enzyme-linked immunosorbent assay and flow cytometric assay, respectively. On days 8, 16 and 32 after KA injection in the IN, the lymphocyte percentage in the peripheral white blood cells was notably diminished with respect to control rats injected with saline in the IN. Concanavalin A-induced lymphocyte proliferation, serum sheep red blood cell-specific IgM antibody and natural killer cell toxicity of the IN-lesioned rats were significantly attenuated with respect to IN-saline control rats at all the post-lesion time points. The findings reveal that KA-induced neuronal loss in the IN of both sides exerts an inhibitory effect on number and functions of T, B and natural killer lymphocytes, and indicate that the cerebellar IN participates in regulating immune function. Thus, the data suggest that the cerebellum may be an important brain area for neuroimmunomodulation, besides its well-known role in motor control.
Animals↗
Cell-mediated immune hypersensitivity is stronger in the left side of the body than the right in healthy young subjects.
More frequent appearance of herpes zoster infection on the left side of the body has been noted. In women, breast cancer occurs more frequently on the left side. It has been suggested that the left neocortex is involved in neuroimmunomodulation via the dopaminergic system. In this study, our purpose was to investigate the possible difference in cell-mediated hypersensitivity between right and left body sides using the tuberculin test with 22 male and 36 female healthy high school students. In the present study, the cell-mediated hypersensitivity was higher in the left side of the body than the right. This difference was slightly more apparent in the girls and may be related to brain asymmetry in neuroimmunomodulation.
Adolescent↗
Neuroendocrinology of infection and the innate immune system.
This chapter deals with two topics: the evolutionary and functional implications of the effects of bacterial endotoxin on the neuroendocrine system in higher vertebrates and a newly recognized neuroendocrine mechanism of immune regulation by the direct secretion of immunoregulatory cytokines from the brain. Endotoxin is a highly specific stimulus to hypothalamic-hypophysial activity; neuroendocrine responses are integrated with behavioral, body temperature, and innate immune responses. All depend upon the genetically programmed capacity of several classes of cells to distinguish molecular patterns foreign to self that are characteristic of pathogenic microorganisms. One component of the response to endotoxin and inflammation in the brain is the direct secretion into the blood (by bulk flow) of appreciable amounts of immunoregulatory cytokines that can modify peripheral levels of IL-6 and TNF-alpha. These can arise from activated glia, endothelia, choroid plexus, and possibly specific neuronal groups. Despite its being an "immune-privileged" organ, brain-presented antigens provoke a greater humoral immune response than by other routes. The capacities of the brain to regulate peripheral cytokine levels by their direct secretion into the blood and to induce antibody response are potential pathways of peripheral neuroimmunomodulation. This mechanism is integrated with the better-established modes of neuroimmunomodulation, sympathetic nervous system, and hypothalamic-pituitary axis.
Animals↗
Neuroimmune interactions: experimental and clinical strategies.
This historical mini-review is devoted to the 30th Anniversary of the research activities of the Neuroimmunomodulation Group at the Immunology Research Center of Belgrade. During the past 30 years, these scientists have contributed to: (a) the definition of the structural and functional complexity and the lymphoneuroendocrine web of the immune microenvironment; (b) the structural and functional dissection of the neuron, brain and mind by means of anti-neural antibodies; (c) the antigenic relationship among the multiple components of the nervous and lymphoid tissues; (d) the methodological and conceptual aspects of the influence of lesioning and stimulation of various brain structures on immune responsiveness; (e) the lymphoneuroendocrine relationships during embryonic development; (f) the definition of immunopsychiatric diseases, i.e., neural tissue immunologic hypersensitivity in psychiatric diseases; (g) the immunomodulating and regulating activity of methionine-enkephalin and leucine-enkephalin; (h) the correlations between associative learning and immunity (behavioral immunology). The theoretical, experimental and clinical devices created, and observations collected from 1957 to 1987 by the Belgrade group of neuroimmunologists proved to be useful for elucidation of the complex interactions between the immune system and the nervous system, and provided a broad perspective for research in neuroimmunomodulation.
Allergy and Immunology↗
Immunomodulatory effects of IL-12 in relation to the pineal endocrine function in metastatic cancer patients.
In addition to IL-2, IL-12 would constitute one of the most promising cytokines in the treatment of human neoplasms. IL-2 has been proven to induce in vitro and in vivo several evident changes in the secretion of cytokines and various other immunoinflammatory substances. In contrast, very little data are available about the immune effects of IL-12 in humans. The present study was carried out to investigate the in vivo immunoinflammatory effects of IL-12 by analyzing the secretions of neopterin, soluble IL-2 receptor (SIL-2R), tumor necrosis factor alpha (TNF), IL-2 and IL-6 in relation to the neuroendocrine function of the pineal gland, which is one of the most important organs involved in neuroimmunomodulation. Pineal endocrine function was investigated by evaluating the whole daily urinary excretion of the main catabolite of its hormone melatonin, 6-sulfatoxymelatonin (6-MTS). The study was performed on metastatic renal cell cancer patients. Each course of IL-12 consisted of 1.25 microg/ kg b.w. subcutaneously in the morning once a week for 3 consecutive weeks. The study evaluated 10 IL-12 courses. Mean serum levels of neopterin, SIL-2R and TNF significantly increased in response to IL-12, whereas no significant change occurred in IL-6 and IL-2 mean concentrations. Finally, 6-MTS urinary excretion was significantly reduced by IL-12 injection, particularly during the dark phase of the day. This preliminary study would suggest that IL-12 may induce important changes in the in vivo immunoinflammatory response. Moreover, IL-12 administration would suppress pineal endocrine activity, thus confirming its previously suggested involvement in the neuroimmunomodulatory processes. Because of the fundamental role of the pineal gland in neuroimmunomodulation, IL-12-induced immune variations could depend at least in part on its action at central neuroendocrine sites.
Adjuvants, Immunologic↗
Receptor biology of the melanocortins, a family of neuroimmunomodulatory peptides.
Melanocortins, melanocyte-stimulating hormones (MSH) and adrenocorticotropic hormone (ACTH) are homologous natural peptides derived from pro-opiomelanocortin (POMC). Recent breakthroughs in melanocortin receptor (MCR) biology are relevant to neuroimmunomodulation because melanocortins are known to modulate fever, inflammation and immunity, by acting both on peripheral targets and within the brain. During fever, endogenous melanocortins exert antipyretic effects by acting on MCR located within the brain, suggesting a protective counterregulatory role of the central melanocortin system. MCR are also found in melanocytic cells and adrenal cortical cells, the classical targets for alpha-MSH and ACTH, respectively, in myelogenous and lymphoid tissues, and in various endocrine and exocrine glands, adipocytes, and in autonomic ganglia. In the CNS, MCR are prominently distributed in close proximity to the terminal fields of melanocortinergic neurons that innervate neuroendocrine and autonomic motor nuclei as well as other subcortical brain regions important in neuroendocrine and autonomic regulation, sensory processing and various aspects of behavior. Furthermore, the presence of MCR in circumventricular organs of the brain provides direct access of systemic melanocortin hormones to central MCR. Together, these attributes provide an anatomical basis for bidirectional MCR-mediated communication between brain and periphery. A group of five G-protein-associated MCR subtypes, each of which is positively coupled to adenylate cyclase, has been identified. Among these, the adrenal ACTH receptor (MC2-R) is selectively activated by ACTH. In contrast, the other MCR subtypes (MC1-R, MC3-R, MC4-R, MC5-R) recognize a common group of ligands that includes various forms of MSH as well as ACTH; nevertheless they do exhibit important differences in ligand selectivity. MCR concentrations and MCR mRNA levels are influenced by availability of cognate ligands, by drugs, and by pathological stimuli. Two types of endogenous MCR antagonist proteins have been discovered: agouti protein and the corticostatins. Agouti protein dramatically alters coat color in mammals by antagonizing melanocytic MC1-R. Moreover, spontaneous dominant mutations of the agouti gene in several strains of mice lead to its ubiquitous overexpression and produces not only yellow coat color, but also obesity and insulin resistance, perhaps as a result of its antagonism of other MCR subtypes. The recent emergence of synthetic MCR antagonists, and the feasibility of molecular approaches for targeted inactivation of individual MCR subtypes, should facilitate elucidation of the roles and mechanisms of neuroimmunomodulation by endogenous melanocortins, and the determination of whether selective pharmacological targeting of MCR may ultimately have therapeutic utility.
Adjuvants, Immunologic↗
[Expression of c-fos protein in brain and lung in ovalbumin sensitized rats].
OBJECTIVE: c-fos expression and its distribution in brain and lung of ovalbumin sensitized and challenged rats were investigated. METHODS: Asthma rat model sensitized and challenged by ovalbumin was established. c-fos expression was detected with immunohistochemical ABC and image analysis methods. RESULTS: c-fos positive staining increased significantly in both brain and lung in asthmatic group as compared with normal control. (P < 0.01). c-fos positive products were mainly concentrated in frontal and parietal cortex, forebrain limbic system (cingulated cortex, piriform cortex and central amygdaloid nucleus), paraventricular thalamic nucleus, hypothalamic paraventricular nucleus, supraoptic nucleus, lateral hypothalamic area, periventricular hypothalamic nucleus, nucleus of solitary tract, area postrema and ventrolateral medulla. No distinct gathering area of c-fos protein was found in the cerebellum. CONCLUSION: It is suggested that neuroimmunomodulation may play a role in the pathogenesis of asthma and c-fos protein might be involved in the neuroimmunomodulation.
Animals↗
Brain IL-1beta increases neutrophil and decreases lymphocyte counts through stimulation of neuroimmune pathways.
Leukocytosis after cerebral injury is well described and may participate in the generation of cerebral damage. However, the mechanisms of brain-induced leukocytosis are still speculative. Since it is known that proinflammatory cytokines are involved in neuroimmunomodulation and since others and we have demonstrated high cytokine levels in the cerebrospinal fluid following injury, we supposed that brain cytokines may also influence leukocyte counts. In order to evaluate this hypothesis, we established an animal model using continuous intracerebroventricular (i.c.v.), intrahypothalamic (i.h.), or intravenous infusion of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta. Controls received vehicle solution. With this experimental paradigm we could show that i.c.v. and i.h. infusion of IL-1beta but not TNF-alpha dramatically increased neutrophil counts, whereas lymphocytes dropped. Blocking the hypothalamic-pituitary-adrenal (HPA) axis by hypophysectomy abolished the neutrophilia, whereas the lymphopenia remained unchanged. Furthermore, application of the beta2-adrenoreceptor antagonist propranolol prevented the decrease of lymphocytes and diminished the neutrophilia. All parameters normalized within 48 h after termination of infusion. So, our results demonstrate that brain IL-1beta can modify blood leukocyte counts through stimulation of both the sympathetic nervous system (SNS) and the HPA axis.
Adrenergic beta-2 Receptor Antagonists↗
Aging decreases beta-endorphin enhancement of T-cell mitogenesis in mice.
Numerous studies have demonstrated the role of the central nervous system in immunomodulation. beta-Endorphin, a neuropeptide that is released along with adrenocorticotropin by the pituitary in response to stress, has been shown to have various effects on immune function, although these effects are dependent on dose, animal model, and immune cell tested. Since the increased risk for infection and tumor that is observed in the elderly is thought to be in part secondary to waning cell-mediated immunity, we investigated the effect of age on beta-endorphin immunomodulation of T-cell proliferation in a murine model. Spleen cells obtained from young and old BALB/c mice were cultured in vitro with various mitogens with and without beta-endorphin. beta-Endorphin at 10(-8) M on day 3 of culture significantly enhanced concanavalin A (2.0 micrograms/10(6) cells per ml) mitogenesis but not phytohemagglutinin or lipopolysaccharide mitogenesis. Moreover, this enhancement was shown only in spleen cells from young mice and was not blocked by the opiate receptor antagonist naloxone, which suggests that enhancement of mitogenesis by beta-endorphin was mediated by a non-opiate receptor. Finally, our results support an altered response to neuroimmunomodulation with age.
Aging↗
Effects of stress on the immune system.
Stress, distress and a variety of psychiatric illnesses, notably the affective disorders, are increasingly reported to be associated with immunosuppression. The concept that psychic distress may predispose to medical illness is centuries old but has only recently attracted the attention of the scientific community at large. Interdisciplinary collaboration has established psychoneuroimmunology, or neuroimmunomodulation, as a new field of investigation with the goal of rigorous scientific research into the elusive mind-body connection. This has resulted in the rapid accumulation of information which falls across the boundary lines of psychiatry, immunology, neurosciences and endocrinology. Here David Khansari, Anthony Murgo and Robert Faith review the effects of stress on the endocrine and central nervous systems and the interactions between these systems and the immune response after exposure to stress signals.
Animals↗
Stress/strain/life revisited. Quantification by blood pressure chronomics: benetensive, transtensive or maletensive chrono-vasculo-neuro-immuno-modulation.
We propose to initiate the automatic self-assessment of wear and tear as "stress and strain" by the time structures of blood pressure (BP) and heart rate (HR), in order to arrive eventually at an individualized timely and timed routine of life and to early preventive intervention as soon as needed. The routine may involve physiological scheduling of physical and mental activities and meals, and if need be of non-drug or drug treatment for stress amplification, e.g., by exercise, and/or strain (not stress) relief by relaxation. In so doing, we recognize the circulation as a pillar and marker of preventive and active neuroimmunomodulation (NIM), suggesting that some concerns of a vasculo- and broader NIM can be quantified by transdisciplinary chronobiology using its cartography--chronomics--of time structures, i.e., chronomes, from chronos = time and nomos = rule. Thus, we are introducing the chronomics of BP, HR and of other variables in the historical context of pioneers who were indispensable to experimental medicine. We build upon their contributions, but we must point out when, in the past, by necessity rather than choice, the giants provided rationalizing truisms that are no substitute for systematic serial data collection and appropriate computer analysis. A time-unspecified spotcheck as a baseline is much better than no measurement, but very often it is not enough, and it is always insufficient when an estimate of variability constitutes the information needed. For dynamic cycles, there are only reference cycles as a routine, although when maps are available, single timed spotchecks can be invaluable. With reference to their historical context, here we rely only upon data which necessity, rather than philosophy, compels us to collect.
Activities of Daily Living↗
Modulation of the immune response by changing neuromediator systems activity under stress.
The possible correction of the immune response affecting the mechanisms of neuroimmunomodulation in the animal model of immobilization stress is considered. Immobilization (3 h on the back) of CBA mice caused a suppression of the immune response. The number of plaque-forming cell (PFC) on the 4th day as well as rosette-forming cell (RFC) number on the 5th day of the immune reaction to sheep red blood cells (SRBC) were found to be reduced as compared to the control. Immunoinhibition in the stressed mice was reversed by the depletion of the cerebral serotonin (5-HT) with p-chlorophenylalanine (PCPA) 2 days before immobilization at a dose of 500 mg/kg. Activation of postsynaptic D-1 and D-2 dopamine (DA) receptors with apomorphine administered 30 min before stress attenuated stress-induced immunosuppression as well. Thus, the immunosuppression elicited by a stressor can be modified by drugs influencing the 5-HT and DAergic systems. It is suggested that the stress-provoked alterations of the immune response can be a consequence of changing neurochemical pattern of the brain and the disturbances of the mechanisms of psychoneuroimunomodulation.
Animals↗
Serum cytokine levels are altered in patients with West syndrome.
The objective of this study is to explore the neuroimmunomodulator effect of interleukin (IL)-2, tumor necrosis factor (TNF)-alpha and interferon (IFN)-alpha in West syndrome (WS). Twenty-three cases of WS (13 males and 10 females, aged 4-14 months old) who first visited and consisted from 10 cryptogenic and 13 symptomatic, were enrolled in this study. Double-antibody sandwich enzyme-linked immunosorbent assay was used to measure serum IL-2, TNF-alpha and IFN-alpha levels in 23 patients with WS and the data were compared to those of 15 healthy infants who were matched with regard to age and sex. Levels of all three cytokines were significantly higher in both cryptogenic and symptomatic WS groups than the control group. Serum IL-2 levels in symptomatic WS were significantly higher than that in cryptogenic WS. There was a positive correlation between IL-2 and TNF-alpha in both cryptogenic and symptomatic WS groups. The immune systems of patients with WS are in an activated state. An imbalance in cytokine levels may be involved in the immunopathology of WS.
Cytokines↗
Melatonin inhibits PHA-stimulated chicken lymphocyte proliferation in vitro.
Many studies have shown that melatonin plays a fundamental role in neuroimmunomodulation. There are known differences between mammals and birds in immunomodulatory function of melatonin exerted in vivo. In present study the effect of exogenous melatonin on chicken lymphoid cell proliferation in vitro was examined. Melatonin alone (10(-10)M-10(-5)M) did not exert any effect on the proliferation of the chicken thymocytes, splenocytes and lymphocytes from the bursa of Fabricius. On the other hand, melatonin addition strongly inhibited the proliferation of PHA-activated thymocytes and splenocytes from young chickens. The effect of melatonin was hormone- and mitogen-(PHA) dose-dependent; the most pronounced effect was obtained at low PHA and melatonin concentrations i.e., 1.6-3.125 microg/100 microl of PHA and 10(-10) M-10(-7) M melatonin, respectively. Prior immunization of chickens with sheep red blood cells (SRBC) inhibited the proliferative response of splenocytes to the same dose of PHA and, consequently, the effect of melatonin addition was not observed. The results reported demonstrate a direct inhibitory effect of melatonin on in vitro activated chicken lymphocytes.
Animals↗
Hypothalamic mechanisms of immunity.
The present article considers a synthetical analysis of the results reported by our laboratory in the last twenty years in the field of neuroimmunomodulation. The studies we discuss here continue a previous research activity, a synthesis of which has also been published in this journal (Baciu, 1988). In that paper, we reported data concerning the role of the hypothalamic tubero-mammillary area in triggering of the phagocytic and of the secondary immune specific response. Here, we present an analysis of experimental facts gathered after 1988, and also of some prior to that date, which were not included in the above-mentioned review. They regard localizations, attained with stereotactical methods, of hypothalamic areas involved in maintenance of basal phagocytosis and of its circadian rhythm, of the phagocytic and of the primary and secondary specific response. We attempted to re-analyze these data in an integrative view, and accomplish a coherent image of the hypothalamic mechanisms of the nonspecific and specific immune response. The conclusion we draw is that the nervous system may exert its modulatory action upon the immune response in several ways: i) subsequent to a direct hypothalamic stimulation (electrical or through bacteria or bacterial products) or to a cortico-hypothalamic stimulation; ii) depending on the nature, intensity, duration, and frequency of the appropriate stimulus, it may either enhance the immune response, via neural and humoral pathways, or depress it; iii) via the hypothalamus-pituitary-adrenal axis. Nervous triggering and enhancement of the immune response are essential, their occurrence in the initial stages ensuring its favorable course. The finding that repeated electroconvulsant shocks, employed for hypothalamus stimulation in dogs of different breed, age, weight, and individual history, are followed by extremely variable changes of the phagocytic activity raises the question on the individuality of the immune response.
Animals↗