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PubMed2002

Cutting edge: recruitment of the ancestral fyn gene during emergence of the adaptive immune system.

The adaptive immune system (AIS) is characterized by the MHC molecules and the rearranging Ag receptors, and was established in a common ancestor of jawed vertebrates. Fyn, a Src-family tyrosine kinases, is important for normal development and function of T lymphocytes and neuronal cells. Indeed, as the result of an alternative splicing of a distinct exon 7, fyn encodes for two isoforms, FynT in T lymphocytes and FynB in the brain. How this alternative splicing of fyn transcripts has emerged and evolved in relation to the setting of the AIS remains to be established. In this study, we show that exon capture in a vertebrate ancestor by the fynT-like gene has yielded a novel fyn-encoded isoform, fynB. Unexpectedly, the newly established AIS recruited the ancestral Fyn isoform, FynT, whereas the CNS expresses the most recent one, FynB. These results shed new light on the emergence of the AIS.

Adaptation, Physiological↗
PubMed1991

The immune system is a key factor in the etiology of psychosocial disease.

The immune system is proposed as the key to understanding the etiology and treatment of psychosocial disease. There is a dense communication network between the immune system and the central nervous system (CNS). Immune cell cytokines, via direct action on the CNS, induce fever, alter sleep, pain perception and pituitary hormone release and reduce appetite and activity in animals. Interleukin-2 and interferon given to humans result in global behavioral and cognitive pathology. Activation of the immune system by pathogens produces global cognitive and behavioral pathology also. Recently, controlled trials have demonstrated that diet can cause psychosocial disease, presumably by an immune mechanism. Immune system abnormalities have been identified in manic-depressive psychosis, schizophrenia and alcoholism. Lithium carbonate is not only prophylactic for all three of these diseases, but it also powerfully stimulates the immune system. This is proposed as the mechanism of lithium's therapeutic effect. The antipsychotics, haloperidol and the phenothiazines, affect the immune system also. The rapid development of AIDS dementia complex can be explained by the remarkable influence the immune system has on the CNS.

AIDS Dementia Complex↗
PubMed2000

Induction of oral tolerance in the primed immune system: influence of antigen persistence and adjuvant form.

Oral tolerance is being promoted as a therapy for autoimmune diseases and therefore will need to be functional in a primed immune system. In previous studies, we found that although primed mice could be tolerized by feeding ovalbumin (OVA), the degree of the tolerance and its effects on individual components of the systemic immune response were more limited than that found in naive animals. Here we increased the dose and frequency of antigen feeding in an attempt to extend the effects of oral tolerance in primed mice and to understand why its effects are limited under these conditions. Increasing the amounts of OVA fed, up to a single dose of 400 mg, or using multiple feeds of 5 x 5 or 5 x 25 mg OVA, did not radically alter the extent of tolerance, with DTH responses, antigen-specific proliferation, and IL5 and IFN-gamma production still being tolerized, but antibody responses remaining generally resistant. The deficient tolerance in primed mice could not be overcome by waiting for maximum clonal expansion to wane and was not influenced by persistent release of antigen from a depot adjuvant. We conclude that the resistance of primed mice to oral tolerance may be due to the fact that antigen-experienced T cells may be inherently resistant to induction of tolerance, or that the microenvironment of the primed immune system inhibits the delivery of tolerogenic signals to antigen-specific T cells.

Administration, Oral↗
PubMed2005

The mammalian innate immune system: potential targets for drug development.

The innate immune system is the oldest mammalian defence against invading micro-organisms and provides the first line of defence against them, however until recently a detailed understanding of its complexity has been lacking. This review describes recent advances that have been made in understanding the components of the innate immune system, including the pathogen sensing mechanisms, receptor and intracellular signalling pathways, linkage to the acquired immune system, and effectors of the innate immune response. These discoveries have created an opportunity for the development of novel drugs through the identification of targets for rational drug design. The opportunity for the development of novel anti-inflammatory and antimicrobial drugs through modulation of pro-inflammatory or antimicrobial signals within the innate immune system, are discussed. A more detailed understanding of the effectors of the innate immune system is providing an opportunity for the design of effector mimetics as novel antimicrobial drugs. The innate immune system is providing the basis for much-needed alternative approaches to controlling infection and inflammation in human medicine.

Animals↗
PubMed1985

Proopiomelanocortin-derived peptides in the immune system.

Cells of the immune system have recently been recognized as a source of the proopiomelanocortin (POMC)-derived peptides, ACTH and endorphins, and their receptors. In this review, the nature of the immunoregulatory and hypothalamic signals which elicit the production of these leukocyte-derived hormones is discussed. Further, comparisons are made between the various proteolytic processing patterns of POMC in leukocytes as compared with those observed in the hypothalamus and anterior or intermediate lobes of the pituitary gland. The possible functioning of leukocyte-derived ACTH and endorphins as well as their pituitary counterparts in a complete regulatory loop between the neuroendocrine and immune systems is described.

Adrenocorticotropic Hormone↗
PubMed1986

The immune system.

The components and functions of the immune system are described, and the clinical applications of agents that affect the immune system are discussed. Through both nonspecific and specific responses, the immune system recognizes and destroys or eliminates harmful foreign substances with which a host comes into contact. Nonspecific responses are usually associated with the first introduction of a foreign substance into the body and consist mainly of phagocytosis and inflammation. When the same substance, or antigen, is introduced into the body on subsequent occasions, antibodies specific for that antigen combine with the antigen and activate a complex network of specialized cells and soluble cellular secretions that eliminate the substance from the body. Certain antigens are inherited and are found on the cells and tissues of the body; these antigens play a major role in human allotransplantation, blood transfusions, and certain disease states. Recent advances in biotechnology have made it possible to alter an individual's immunologic response with such agents as azathioprine, cyclosporine, or monoclonal antibodies or to augment an individual's antitumor defenses with immunopotentiators. As the products of biotechnology are used more frequently in the hospital setting to treat or prevent disease, pharmacists will need to have a good understanding of the immune system to appreciate the functional capacity of and the problems that may exist with these agents.

Antibodies↗
PubMed1986

A neural network model based on the analogy with the immune system.

The similarities between the immune system and the central nervous system lead to the formulation of an unorthodox neural network model. The similarities between the two systems are strong at the system level, but do not seem to be so striking at the level of the components. A new model of a neuron is therefore formulated, in order that the analogy can be used. The essential feature of the hypothetical neuron is that it exhibits hysteresis at the single neuron level. A network of N such neurons is modelled by an N-dimensional system of ordinary differential equations, which exhibits almost 2N attractors. The model has a property that resembles free will. A conjecture concerning how the network might learn stimulus-response behaviour is described. According to the conjecture, learning does not involve modifications of the strengths of synaptic connections. Instead, stimuli ("questions") selectively applied to the network by a "teacher" can be used to take the system to a region of the N-dimensional phase space where the network gives the desired stimulus-response behaviour. A key role for sleep in the learning process is suggested. The model for sleep leads to prediction that the variance in the rates of firing of the neurons associated with memory should increase during waking hours, and decrease during sleep.

Artificial Intelligence↗
PubMed1999

Biologic rhythms in the immune system.

In all of its components, the immune system shows regularly recurring, rhythmic variations in numerous frequencies; the circadian (about 24 h) rhythms are the best explored. The circadian variations in immunocompetent cells circulating in the peripheral blood are of a magnitude to require attention in medical diagnostics. Both the humoral arm and the delayed (cellular) arm of the immune system function in a rhythmic manner. The response of the immune system to introduction of an antigen and to challenge of the sensitized organism varies in extent in the circadian frequency range and also in lower frequencies, for example, of about a week (circaseptan) or seasonally (circannual). The medical application of the biologic rhythms of the immune system extends to diagnostic measures, as well as treatment.

Animals↗
PubMed1994

[Evaluation of the effects of methods of suppurative-inflammatory complications prevention after cesarean section on cellular and humoral components of the immune system].

The immune status of 73 pregnant women and puerperae, administered proteolysis inhibitors or common antibacterial therapy to prevent pyoseptic complications, was assessed before cesarean section and 1 and 7 days after it. The results indicate certain shifts in the immunity status of puerperae of all groups, which were the most expressed 1 day after surgery (reduced content of CD3 lymphocytes, IgG and IgA, and a marked increase of the content of C-reactive protein) and normalized by day 7 postoperation. These changes are most likely to be caused by the surgical intervention but not the infectious inflammatory process, which is proved by the absence of pyoseptic complications after prophylactic measures taken. Hence, proteolysis inhibitors, along with the traditional methods, may be recommended for the prevention of pyoseptic complications after cesarean section.

Adult↗
PubMed1997

Aging, exercise, training, and the immune system.

Human immune function undergoes adverse changes with aging, including development of a relative immune deficiency and an immune dysregulated state. The T cells show the largest age-related differences in distribution and function. The antibody production capacity of B cells also shows an age-related decline. Acute bouts of exercise modulate many immune parameters as seen in peripheral blood. With regard to NK cell activity, a single bout of moderate exercise seems to be well tolerated by the elderly, and the resting NK cell activity of elderly subjects seems to increase with training. Cross-sectional comparisons of immune status imply that habitual physical activity may enhance NK cell activity and check certain aspects of the age-related decline in T cell function. Future studies are required to clarify whether such long-term exercise and resulting improvements of immune function give rise to any beneficial effects on infections, malignancies, and autoimmune disorders.

Adult↗
PubMed2004

Recognition strategies in the innate immune system of ancestral chordates.

Many components of the innate immune system in vertebrates can be reliably traced to urochordates and successful strategies for the detection and elimination of pathogens are present at that level of animal evolution, but the issue of where and how the adaptive immune system emerged is still obscure. There is a paucity of evidence for a gradual transition from the innate immune system of invertebrates to the recombinatorial immune system of higher vertebrates. None of the classical elements of MHC based transplantation immunity (MHC, TCR) or humoral immunity (Ig) have been found in urochordates or Agnathans. Nevertheless there is abundant evidence for adaptive immune responses in the agnathans. This remarkable paradox raises a number of questions. How do these ancestral chordates discriminate between the constituents of the external world and the constituents of "self"? Are these strategies universal within the animal kingdom and among chordates, or are different strategies used by representatives of the different taxonomic groups? The current state of our knowledge indicates that the immune system of lower chordates is very different from that of cartilaginous fishes. Pure homology hunting for vertebrate-specific immuno-relevant molecules in invertebrates is therefore of limited value. A more promising approach may involve unbiased functional screening methods. To understand better the evolution of adaptive immune systems, more comparative data from jawless vertebrates (lamprey or hagfish) and a representative of Acrania (e.g. Amphioxus) are clearly needed.

Animals↗
PubMed2005

High level of functional polymorphism indicates a unique role of natural selection at human immune system loci.

Several studies have shown that immune system proteins have on average a higher rate of amino acid evolution between different species of mammals than do most other proteins. To test whether immune-system-expressed loci show a correspondingly elevated rate of within-species nonsynonymous (amino acid altering) polymorphism, we examined gene diversity (heterozygosity) at 4,911 single nucleotide polymorphism (SNP) sites at 481 protein-coding loci. At loci with nonimmune functions, gene diversity at nonsynonymous SNP sites was typically lower than that at silent SNP sites (those not altering the amino acid sequence) in the same gene, a pattern that is an evidence of purifying selection acting to eliminate slightly deleterious variants. However, this pattern was not seen at nonsynonymous SNPs causing conservative amino acid replacements in immune system proteins, indicating that the latter are subject to a reduced level of functional constraint. Similarly, immune system genes showed higher gene diversities in their 5' noncoding regions than did other proteins. These results identified certain immune system loci that are likely to be subject to balancing selection that acts to maintain polymorphism in either coding or regulatory regions.

Chromosomes, Human↗
PubMed2005

Regenerative capacity and the developing immune system.

Many components of the vertebrate immune system have evolved with dual, interrelated functions of both protecting injured tissues from infection and providing for tissue maintenance and repair of injuries. The capacity for organ regeneration, prominent among invertebrates and certain phylogenically primitive vertebrates, is poorly developed in mammals. We have proposed that evolution of the mammalian immune system has produced inflammatory cellular interactions at sites of injury which have optimized tissue defense and facilitated tissue repair, but that these improvements included concomitant loss of regenerative capacity. This chapter briefly reviews work in two regenerating systems: scar-free repair of fetal mammalian skin and regeneration of amputated limbs in larval frogs. In both organs the potential to regenerate anatomically and functionally complete new structures is lost gradually during ontogeny and this loss coincides with development of an immune system producing an inflammatory response in injured tissues. Failure of organ regeneration has long been associated with scarring or fibrosis and this phenomenon is a direct result of inflammatory interactions of immune cells and fibroblasts at sites of injury. Several aspects of immunity related to repair are reviewed, including the importance of antigen-presenting cells and lymphocytes, relevant cytokines and growth factors released by these and other cells, immune functions of extracellular matrix components, and immunological functions of fibroblasts. Skin repair in various transgenic mouse models has been especially informative. Further study of immune mechanisms associated with the loss of regenerative capacity in the skin and amphibian limb will be useful for efforts to promote mammalian organ regeneration.

Animals↗
PubMed1999

Nutrition, exercise, and immune system function.

Many components of the immune system exhibit adverse change after prolonged, intense exertion. During this "open window" of impaired immunity (which may last 3-72 h, depending on the immune measure), viruses and bacteria may gain a foothold, increasing the risk for subclinical and clinical infection. The influence of nutritional supplements, primarily zinc, vitamin C, glutamine, and carbohydrate, on the acute immune response to prolonged exercise has been measured in endurance athletes. Vitamin C and glutamine have received much attention, but the data thus far are inconclusive. The most impressive results have been reported with carbohydrate supplementation. Carbohydrate beverage ingestion has been associated with increased plasma glucose levels, an attenuated cortisol and growth hormone response, fewer perturbations in blood immune cell counts, decreased granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro-inflammatory and anti-inflammatory cytokine response. Overall these data indicate that the physiologic stress to the immune system is reduced when endurance athletes use carbohydrate beverages before, during, and after prolonged and intense exertion. The clinical significance of these carbohydrate-induced effects on the endocrine and immune systems awaits further research.

Carbohydrate Metabolism↗
PubMed1998

[Mucosal immune system of the intestine].

Gut-associated lymphoid tissue is the major inductive site of mucosal immune system, functionally independent of the systemic immune system. Particulate antigens are mainly uptaken from M cell of Peyer's patches, inducing IgA production in the intestinal mucosa. Lymphocytes are continuously recirculating through the intestinal mucosa to facilitate intestinal immune response. Dysregulation of lymphocyte migration and cytokine imbalance in the intestinal mucosa may be largely involved in the pathogenesis of inflammatory bowel diseases including intestinal allergy and Crohn's disease. There is also a possibility that dietary components especially long chain fatty acid could influence immune cell function of the intestinal mucosa. Because dietary components are closely associated with immunological function of intestinal mucosa, the importance of dietary manipulation for the management of inflammatory bowel diseases should be concerned.

Animals↗
PubMed2006

The etiology of hypertension in the metabolic syndrome part four: the systemic perspective--the role of the neuroendocrine and immune systems, and the challenge of integration.

Insulin resistance can be regarded to be a cause, a consequence, a sustainer or a marker of the wider neuroendocrine dysfunction within which it occurs. In the final part of our series of reviews, we examine the systemic influences which operate within the metabolic syndrome: the endocrine system, the central nervous system and the immune system. We discuss strategies for integrating the array of information that is being gathered, in particular the need for computer simulation. We also advocate the need to move beyond the linear paradigm of 'cause and effect' and use causal networks to think about this system. We also discuss the need to understand the temperospatial organisation of the factors being studied. Finally, we draw together the data, concepts and hypotheses we have reviewed over the course of these four articles.

Adipose Tissue↗
PubMed2000

The immune system as a potential target for environmental estrogens (endocrine disrupters): a new emerging field.

It is now well known that natural (17beta-estradiol) and synthetic (e.g. diethylstilbestrol) estrogens not only affect the reproductive system, but also markedly influence the immune system. Recently, a new class of estrogens that is abundant in the environment (in industrial chemicals, pesticides, and surfactants) has been recognized. Some of these estrogenic chemicals (which are a large subgroup of endocrine disrupters) have also been shown to influence the immune system. This review assimilates growing evidence in wildlife, laboratory animals and to a limited extent in humans, which suggests that environmental chemicals may also affect the immune system. Further studies are needed to ascertain the immunological consequences of exposure to environmental estrogens, especially in humans. At the present time, it is not known whether the human immune system responds to a low dose of environmental estrogens or if environmental estrogens influence certain subsets of human populations, rather than the general population. Conceivably, an alteration of the immune system by environmental estrogens could affect the individuals' ability to mount well-regulated immune responses to microbial and vaccine antigens, allergens, self and tumor antigens. Possible changes in the immune system must be investigated routinely in toxicity studies. A comprehensive mechanistic understanding of potential immunomodulatory chemicals is needed. In this regard, relevant laboratory animals may be especially useful in identifying susceptible periods of life, whether both genders are equally affected, in analysis of changes in target lymphoid organs, and to determine the immunological effects of mixtures of chemicals.

Animals↗
PubMed2006

The postnatal development of the mucosal immune system and mucosal tolerance in domestic animals.

The mucosal immune system is exposed to a range of antigens associated with pathogens, to which it must mount active immune responses. However, it is also exposed to a large number of harmless antigens associated with food and with commensal microbial flora, to which expression of active, inflammatory immune responses to these antigens is undesirable. The mucosal immune system must contain machinery capable of evaluating the antigens to which it is exposed and mounting appropriate effector or regulatory responses. Since the immune system is likely to have evolved initially in mucosal tissues, the requirement to prevent damaging allergic responses must be at least as old as the adaptive immune system, and studies of the mechanisms should include a range of non-mammalian species. Despite the importance for rational design of vaccines and for control of allergic reactions, the mechanisms involved are still largely unclear. It is not clear that the classical experimental protocol of "oral tolerance" is, in fact, measuring a biologically important phenomenon, nor is it clear whether tolerance is regulated in the evolutionarily recent organised lymphoid tissue (the lymph nodes) or the more ancient, diffuse architecture in the intestine. The capacity of the immune system to discriminate between "dangerous" and "harmless" antigens appears to develop with age and exposure to microbial flora. Thus, the ability of an individual or a group of animals to correctly regulate mucosal immune responses will depend on age, genetics and on their microbial environment and history. Attempts to manipulate the mucosal immune system towards active immune responses by oral vaccines, or towards oral tolerance, are likely to be confounded by environmentally-induced variability between individuals and between groups of animals.

Aging↗