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The immune system and integrated homeostasis.

The immune system is usually viewed as an effector mechanism reacting to environmental antigenic challenge with defensive responses designed to eliminate 'foreign' substances and return to standby or surveillance mode. However, there is now substantial evidence to suggest that immunity is not effector-biased but is also a sensory organ and forms part of an integrated homeostatic network. Evidence that communication pathways exist between the immune and central nervous systems which support bi-directional information flow, and that the output of the immune system influences other physiological adjustments to environmental change, is discussed in this paper. The proposition that an endocrine-immune gradient determines the homeostatic response to combined microbial and other ambient stressors is established and the potential for management of this gradient is explored.

Animals↗

Depression, adrenal steroids, and the immune system.

During the past decade, over 30 studies have examined the immune system in depression. While a number of investigators have reported depression-related alterations in peripheral blood immune cell number and function, many researchers have been unable to replicate these findings. The relationship between depression and the immune system has turned out to be much more complex than was initially anticipated. Factors which have complicated the interpretation of the research include the heterogeneity of depressed patients, the variability of immune assays, and the clinical relevance of these assays. In this review we conclude that alterations in the immune system do not appear to be a specific or reproducible biological correlate of depression but may occur in association with other variables which characterize depressed patients including age, sex and severity of depression. Conceptual frameworks for future research on the immune system and depression are discussed and include: (i) depression as a cofactor in the development, course and outcome of diseases involving the immune system; (ii) depression as a neuroimmunological disease; and (iii) depression as a model for studying neuroendocrine-immune interactions in humans. In terms of this third line of research, patients with depression consistently have been shown to display abnormalities in the secretion of adrenal steroids, and new data is presented which indicates that adrenal steroids may play a much more complex role in the modulation of the immune response than has been previously appreciated.

Adrenal Cortex Hormones↗

[Aging and the cutaneous immune system].

The changes in the immune system during the ageing process have been described in numerous publications, which are sometimes contradictory. The study of cell mediated immunity and of hormonal immunity provide only a partial reflection of the smooth working of the cutaneous immune system, which is dependent on fragile cell interactions between T lymphocytes, cells of Langerhans and keratinocytes, which involves numerous soluble mediators. Three possible mechanisms leading to or contributing to the decline in immune function with age should be considered: a modification of the distribution of lymphocyte subpopulations (the T helper lymphocytes and T-suppressing lymphocytes are affected by age in particular), changes in the mechanisms of suppression and changes in the maturation of B and T lymphocytes.

Antibody Formation↗

Interactions between the brain and the immune system.

The observations and research described in this communication derive from a nontraditional view of the immune system. It has become abundantly clear that there are probably no organ systems or homeostatic defense mechanisms that are not, in vivo, subject to the influence of interactions between behavioral and physiological events. The complex mechanisms underlying these interactions and their relationship to health and illness, however, are imperfectly understood. The most imperfectly understood, perhaps, are the interrelationships among brain, behavior, and immune processes. Without attempting to cover all the literature, we have used stress effects and conditioning phenomena as illustrations to point out that behavior can influence immune function. We have also described data indicating that the immune system can receive and respond to neural and endocrine signals. Conversely, behavioral, neural, and endocrine responses seem to be influenced by an activated immune system. Thus, a traditional view of immune function that is confined to cellular interactions occurring within lymphoid tissues is insufficient to account for changes in immunity observed in subhuman animals and man under real world conditions. These data question seriously the notion of an autonomous immune system. Most of the research on the regulation of immune responses has been predicated on the assumption that such regulation is accomplished by the interacting components of the immune system itself, e.g. interactions among helper and suppressor T-lymphocytes, B-cells, and accessory cells that can result in the production of antibody and effector T cells. The immune system is, indeed, capable of considerable self-regulation, and immune responses can be made to take place in vitro. The functions of that component of adaptive processes known as the immune system that are of ultimate concern, however, are those that take place in vivo. There are now compelling reasons to believe that in vivo immunoregularity processes influence and are influenced by the neuroendocrine environment in which such processes actually take place--an environment that, on the one hand, can generate signals that resting and/or activated leukocytes can receive, and, on the other hand, is exquisitely sensitive to the individual's perception of and capacity to adapt to the demands of the environment. The immune system appears to be modulated, not only by feedback mechanisms mediated through neural and endocrine processes, but by feedforward mechanisms as well. The immunologic effects of learning, an essential feedforward mechanism, suggest that, like direct neural and endocrine processes, behavior can, under appropriate circumstances, serve an immunoregulatory function in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

The anamnestic response of the secretory immune system: A review.

Following topical immunization of the respiratory mucosa in man, persistence of antibody in the respiratory secretions can be demonstrated in some individuals for more than one year. The secretory response to replicating agents is generally more prolonged than the response to less persistent antigens. Repeat topical antigenic stimulation provokes a response which differs very little from the primary response in magnitude, duration or latency. Nevertheless, if more than 1 year following adequate primary intranasal immunization, at a time when secretory antibodies are no longer detectable, men are again vaccinated intranasally with a dose of formalin-inactivated rhinovirus vaccine which will not provoke a primary secretory immune response, some vaccinees will produce nasal antibody. Similarly in mice, a second topical immunization of the respiratory tract with a dose of tetanus toxoid which does not produce a detectable primary secretory immune response will cause 11S IgA antibodies to appear in bronchial and nasal washings. Thus, it is possible that the secretory immune system may possess certain attributes of immunologic memory as classifically defined by the responses of the internal immune system to repeated antigenic stimulation.

Animals↗

[The effect of moderate surgical aggression on the immune system. The usefulness of the Multitest as a method for studying immune activity].

With the aim of studying the effect of moderate surgical aggression on the immunity system, a group of 22 patients was selected, who were not affected by immuno-depressive factors apart from the surgery itself. Changes in the nutritional state of these patients were analyzed using anthropometric, biochemical and immunity procedures, with regard to levels of immunoglobulin, complement and lymphocytic populations at different times during the first 30 postoperative days. Alterations were observed both in humoral and cellular immunity in the sense of temporary immunodepression. These changes were not reflected in the skin reaction tests to antigens in the Multitest (R). The origin and significance of postsurgical immunodepression was discussed, as well as the need for developing investigation models, both clinical and in the laboratory, in order to shed some light on the dilemma of the physiopathology of the immunity system in surgical patients.

Adolescent↗

What do the paralogous regions in the genome tell us about the origin of the adaptive immune system?

During the last decade, our understanding of the immune system of ectothermic vertebrates has advanced significantly. It is now clear that all jawed vertebrates are equipped with the adaptive immune system characterized by the MHC molecules and the rearranging receptors. In contrast, there is no molecular evidence that suggests the existence of adaptive immunity in jawless vertebrates. How did the adaptive immune system emerge? Our recent work suggests that one of the driving forces that enabled the emergence of the adaptive immune system was one or more genome-wide or large-scale chromosomal duplications presumed to have taken place in a common ancestor of jawed vertebrates.

Adaptation, Physiological↗

[Molecular basis of the communication of the nervous, endocrine and immune systems].

The nervous, endocrine and immune systems integrate one another to preserve homeostasis in the stress response. The molecular bases of this network are reviewed. The neuroendocrine actions of cytokines, the immune activities of pituitary hormones, opioids, glucocorticoids as well as the immune system production of opioid peptides are examined in detail.

Adrenocorticotropic Hormone↗

Influence of adjuvant hormone therapy and chemotherapy on the immune system analysed in the bone marrow of patients with breast cancer.

PURPOSE: Bone marrow is a special compartment for antitumor immunological memory in patients with breastcancer. Until now, the influence of adjuvant systemic therapy on the immune system has only been investigated in peripheral blood and not in bone marrow. In this study, we analyzed the effect of hormone therapy and chemotherapy on the immune activation status in bone marrow. EXPERIMENTAL DESIGN: In 34 patients with breast cancer, bone marrow was aspirated 24 months after primary surgery and adjuvant systemic therapy. The immune system of these patients was compared with that of patients at the time of primary surgery (n = 90). Three-color flow cytometry was used to identify the number and activation state of T cells, natural killer (NK) cells, monocytes/macrophages, and subsets by means of a panel of monoclonal antibodies. RESULTS: The proportion of all T cells was significantly lower in patients after adjuvant systemic therapy than in patients with primary breast cancer or normal healthy donors. Chemotherapy apparently had a particularly suppressive effect on naïve CD4 T cells and, to a lesser extent, on memory CD4 T cells. Hormone therapy apparently had a significant suppressive effect on both naïve and memory CD8 T cells. The numbers of NK cells (CD56) and of monocytes/macrophages (CD14) recovered rapidly after adjuvant chemotherapy. However, subpopulations with potential antitumor reactivity, such as activated NK and NK T cells, were reduced per long term after chemotherapy. CONCLUSIONS: These findings suggest profound and long-lasting negative effects on the bone marrow immune system by present day adjuvant therapy in breast cancer.

Bone Marrow Cells↗

The immune system.

OBJECTIVE: To explain the role of the immune system in cancer control and its response to environmental and perceived stressors. DATA SOURCES: Review articles, research studies, and book chapters related to immunology and the immune system. CONCLUSIONS: The immune system responds to foreign pathogens and cancer cells by activating specific and nonspecific immune responses. The goal of immunotherapy is to enhance these responses to control the growth of cancer cells. Knowledge of the influence of stress on immune and cytokine response is evolving. IMPLICATIONS FOR NURSING PRACTICE: Knowledge of the principles of immunology, the immune response to cancer, the role of cytokines in mediating immune response, and the influence of stress on immune and cytokine response will help nurses provide quality care to patients receiving biological agents.

Antibody Formation↗

Osteoimmunology: interplay between the immune system and bone metabolism.

Studies of bone and the immune system have converged in recent years under the banner of osteoimmunology. The immune system is spawned in the bone marrow reservoir, and investigators now recognize that important niches also exist there for memory lymphocytes. At the same time, various factors produced during immune responses are capable of profoundly affecting regulation of bone. Mechanisms have evolved to prevent excessive interference by the immune system with bone homeostasis, yet pathologic bone loss is a common sequela associated with autoimmunity and cancer. There are also developmental links, or parallels, between bone and the immune system. Cells that regulate bone turnover share a common precursor with inflammatory immune cells and may restrict themselves anatomically, in part by utilizing a signaling network analogous to lymphocyte costimulation. Efforts are currently under way to further characterize how these two organ systems overlap and to develop therapeutic strategies that benefit from this understanding.

Animals↗

Symposium summary: children's health risk--what's so special about the developing immune system?

In recent years, there has been increasing regulatory pressure to protect the health of children, with the basic tenet being that children differ significantly from adults in their biological or physiological responses to chemical exposures. In a regulatory context, this has been translated to mean a requirement for an additional 10-fold safety factor for environmental contaminants, specialized tests, or both. Much of the initial focus has been on the developing endocrine and nervous systems; but increasingly, the developing immune system has been identified as a potential target organ for chemically mediated toxicity. More recently, the question has been raised regarding whether the current state of science supports the creation of developmental immunotoxicology (DIT) test guidelines. What is needed is a risk-based evaluation of the biology associated with the proposed differential sensitivity between children and adults and the impact of that assessment on additional regulatory measures to protect children in risk assessment analyses. Additionally, an understanding of whether the developing immune system shows greater susceptibility, either qualitatively or quantitatively, to chemical perturbation is critical. To address the question "What's so special about the developing immune system?" a symposium was organized for the 2003 Society of Toxicology annual meeting that brought together risk assessors, clinicians, immunologists, and toxicologists.

Adolescent↗

Central but not the peripheral action of cholinergic compounds suppresses the immune system.

Cholinergic compounds modulate the immune system; however, the mechanism of cholinergic immunotoxicity is largely unknown. Lewis rats were exposed chronically to cholinergic compounds via subcutaneous or intracerebroventricular routes. Compounds that crossed the blood-brain barrier (BBB) inhibited the antibody response when given by either route, however, poorly permeable compounds, unless given in high doses, inhibited the antibody response only by intracerebroventricular administration. Intracerebroventricular administration of cholinergic agents also reduced serum corticosterone levels, which along with the antibody response was attenuated by pretreatment with the ganglionic blocker chlorisondamine. Thus, cholinergic agents affect the neuroimmune communication and inhibit glucocorticoid production; the latter may be a biomarker for cholinergic toxicity.

Animals↗

Evidence for a direct action of melatonin on the immune system.

Pineal melatonin modulates the mammalian immune system. In vivo studies showed that melatonin enhanced the natural and acquired immunity while in vitro studies demonstrated its inhibitory influence. The mechanism of melatonin action on the immune system remains unknown. Actions through lymphokines or opioid release or via other endocrine changes have been proposed. In this paper, a direct action of melatonin on the lymphoid tissue is hypothesized. 2-[125I]Iodomelatonin binding sites have been identified in the membrane homogenates of thymus, bursa of Fabricius and spleens of a number of birds and mammals. The bindings were stable, saturable, reversible, specific and of high affinity. The Bmax ranged from 0.6 to 3.9 fmol/mg protein. The Kd was in the physiological range of circulating melatonin levels, about 30-70 pmol/l. The binding sites in the primary lymphoid organs demonstrated diurnal variation in density, with higher levels found at the middle of the light period. However, those in the spleen did not vary with the time of the day. An age-dependent decrease in the density was also found in the chicken bursa of Fabricius. In addition, when the nocturnal melatonin secretion was suppressed by constant light exposure, the density of the binding sites increased in the guinea pig spleen. Immunosuppression with cortisol injection in young ducks decreased the density of the melatonin binding sites in the thymus. The regulation of the binding characteristics by physiological variation in melatonin levels and/or immunological status of the animals provide evidence that these 2-[125I]iodomelatonin binding sites in the lymphoid tissues may be physiologically significant and represent true melatonin receptors. The melatonin receptors in the lymphoid organs may be coupled to a G protein as Guanosine 5'-0-(3-thiotriphosphate inhibited 2-[125I]iodomelatonin binding in the spleen by increasing the Kd and decreasing the Bmax.

Animals↗

Fos/AP-1 proteins in bone and the immune system.

The skeleton and the immune system share a variety of different cytokines and transcription factors, thereby mutually influencing each other. These interactions are not confined to the bone marrow cavity where bone cells and hematopoietic cells exist in proximity but also occur at locations that are target sites for inflammatory bone diseases. The newly established research area termed 'osteoimmunology' attempts to unravel these skeletal/immunological relationships. Studies towards a molecular understanding of inflammatory bone diseases from an immunological as well as a bone-centered perspective have been very successful and led to the identification of several signaling pathways that are causally involved in inflammatory bone loss. Induction of receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) signals by activated T cells and subsequent activation of the key transcription factors Fos/activator protein-1 (AP-1), NF-kappaB, and NF for activation of T cells c1 (NFATc1) are in the center of the signaling networks leading to osteoclast-mediated bone loss. Conversely, nature has employed the interferon system to antagonize excessive osteoclast differentiation, although this counteracting activity appears to be overruled under pathological conditions. Here, we focus on Fos/AP-1 functions in osteoimmunology, because this osteoclastogenic transcription factor plays a central role in inflammatory bone loss by regulating genes like NFATc1 as well as the interferon system. We also attempt to put potential therapeutic strategies for inflammatory bone diseases in perspective.

Adaptor Proteins, Signal Transducing↗

Nerve growth factor and the immune system: old and new concepts in the cross-talk between immune and resident cells during pathophysiological conditions.

PURPOSE OF REVIEW: This review provides an overview of nerve growth factor and its involvement in the immune system. Furthermore, recent data are provided revealing new important insights into the mechanisms of action of nerve growth factor in allergic reaction. RECENT FINDINGS: Recent studies on the effects of nerve growth factor on the immune cells involved allergic reaction, and on the potential role of nerve growth factor in tissue remodelling are presented. SUMMARY: Nerve growth factor has an extended function from the nervous system to a wide range of activities in the immune system. Several papers have highlighted the role of the factor in allergic inflammation. This review describes old and new concepts of nerve growth factor in the immune system: the relation between nerve growth factor and the main cells taking part in allergic inflammatory disorders, structural cells, mediators and cytokines/chemokines, as well as the mechanisms leading to nerve growth factor increase. Understanding these complex mechanisms will introduce new therapeutic approaches for nerve growth factor in the immune system, in addition to those already established in the nervous system.

Cell Communication↗

[Status of the antioxidant, monooxygenase and humoral immune system of the body in d-galactosamine hepatitis].

Galactosamine model of toxic hepatitis in rats which, as to its morphobiochemical picture, is considered adequate to human hepatitis was used to study the role of disturbances of the functional state of antioxidant and monooxygenase systems as well as humoral area of the systems of immune protection in pathogenesis of the given disease. It is shown that most components of enzymatic and nonenzymatic antioxidant system (superoxide dismutase, catalase, glutathione peroxidase, restored glutathione, phospholipids) are considerably inhibited by the toxin effect. At the same time content of ceruloplasmin is increased in the blood plasma. Considerable disturbances are also observed in the humoral chain of the immune system (content of immunoglobulins and circulating immune complexes varies) and in the processes of microsomal oxidation.

Animals↗

Chromatin structure and gene regulation in the immune system.

The development of the immune system and the host response to microbial infection rely on the activation and silencing of numerous, differentially expressed genes. Since the mid-1980s, a primary goal has been to identify transcription factors that regulate specific genes and specific immunological processes. More recently, there has been a growing appreciation of the role of chromatin structure in gene regulation. Before most activators of a gene access their binding sites, a transition from a condensed to a decondensed chromatin structure appears to take place. The activation of transcription is then accompanied by the remodeling of specific nucleosomes. Conversely, the acquisition of a more condensed chromatin structure is often associated with gene silencing. Chromatin structure is a particularly significant contributor to gene regulation because it is likely to be a major determinant of cell identity and cell memory. That is, the propagation of decondensed chromatin at specific loci through DNA replication and cell division helps a cell remember which genes are expressed constitutively in that cell type or are poised for expression upon exposure to a stimulus. Here we review recent progress toward understanding the role of chromatin in the immune system. The interleukin-4 gene serves as a primary model for exploring the events involved in the acquisition and heritable maintenance of a decondensed chromatin structure. Studies of the interleukin-12 p40 and interferon-beta genes are then reviewed for insight into the mechanisms by which the remodeling of specific nucleosomes in the vicinity of a promoter can contribute to rapid activation following cell stimulation. Finally, basic principles of gene silencing are discussed.

Alleles↗