Regulation Of Natural Immunity

5.1. Leukocyte migration

Leukocyte migration is essential for reactions to inflammatory stimuli at various locations in the body. However, leukocyte movement is also crucial during non-inflammatory processes such as haematopoietic development and routine passage through secondary lymphoid organs, which is also required for effective antigen presentation. Immune defects occur in chemokine receptor deficient mice. Chemokines, their receptors and adhesion molecules play a key role in the regulation of the immune response during inflammatory and under homeostatic conditions. Leukocyte trafficking plays a role during developmental processes, for example in haematopoiesis and thymic maturation of T cells and in regulatory circuits that ensure immune surveillance and communication between the innate and adaptive components of immunity [47].

Leukocytes utilize an active process to halt chemotaxis and switch to effector activity, with the aid of the arrestin protein, which blocks chemotactic signalling from chemokine receptors and converts it to a signal for degranulation [48,49]. The discovery of chemorepulsive activity mediated by CXCR4 provides a mechanism by which mature T cells may exit the thymus [50, 51].

5.2. Neuroendocrine regulation of natural immunity

Natural killer (NK) cells, y8 T lymphocytes and CD5+ B lymphocytes are key effector cells in the natural immune system. These cells utilize germ-line coded receptors that recognize highly conserved, homologous epitopes (homotopes). Under physiological conditions the natural immune system is regulated similarly to the adaptive immune system: growth and lactogenic hormones (GLH), insulin-like growth factor-I (IGF-I), insulin, leptin, some steroid (glucocorticoid at physiological concentrations, dehydroepiandrosterone and some of its derivatives) and thyroid hormones are stimulatory. The peptides of the hypothalamus-pituitary-adrenal axis (CRF, AVP, ACTH, aMSH, (3END) exert an immunosuppressive, anti-inflammatory and anti-pyretic effect. Opioid peptides and estradiol are immunomodulators that promote some immune activities while inhibiting others. High (pathophysiological) levels of glucocorticoids, progesterone and testosterone act as immunosuppressive hormones. Beta-adrenergic agents are immunosuppressive and anti-inflammatory, whereas cholinergic agents promote immunity and inflammation. Substance P and calcitonin-gene related peptide are pro-inflammatory and promote immunity, whereas somatostatin is an antagonist of these neuropeptides [52],

Mild infection or a sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum. Severe trauma, sepsis and shock results in the elevation of TNFa, IL-1 and IL-6 in the blood stream, the GLH-IGF-I axis is suppressed, whereas the hypothalamus-pituitary-adrenal axis is activated. LH, FSH, estrogens, androgens, progesterone, and thyroid hormones all decline during infection and endotoxin shock, as a rule. Leptin, insulin, glucagon, a-MSH, endorphin, and arginine vasopressin are increased during endotoxemia. A "sympathetic outflow" leads to elevated blood levels of catecholamines. Fever and catabolism prevails, whereas acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes are increased. This is an acute emergency reaction to save the organism after the adaptive immune system has failed to contain and eliminate the pathogenic agent. During sepsis and endotoxin shock, glucocorticoids potentiate the production of acute phase proteins and regulate pro-inflammatory cytokine production. Catecholamines also inhibit inflammatory responses and promote, even initiate, the acute phase response. Leptin regulates energy metabolism and it is a major stimulator of the immune system. If the acute phase reaction fails to protect the host, shock will develop and death will follow [52].

The acute phase response leads to immunoconversion, which involves the suppression of the T-cell regulated adaptive immune system and the amplification of natural immunity. Natural antibodies, C-reactive -, endotoxin binding- and mannose binding proteins are boosted and serve as polyspecific recognition molecules for leukocytes. The natural immune system provides the first and the last line of host defence and its functional integrity and massive activation is largely dependent on the neuroendocrine system [52].

5.3. Natural immunity - Effect of exercise

Natural immunity is influenced by pharmacological agents, the environment, exercise and diet. Exercise induces increased circulating levels of a number of cytokines, especially IL-6, which is produced locally in contracting skeletal muscles and accounts for the arterial IL-6 concentration. In turn, IL-6 stimulates the production of a number of anti-inflammatory cytokines such as IL-1 ra and IL-10 and also works in a hormone-like fashion. IL-6 also stimulates Cortisol production and in the recovery phase of heavy exertion, a cortisol-induced shift in leukocyte subsets is seen. The dominant features in the post-exercise period are lymphopenia, neutrophilia and a markedly suppressed natural killer cell activity. In addition secretory IgA is inhibited [53],

Many clinical physical stressors (e.g., surgery, trauma, burn, sepsis) and environmental factors such as hyperthermia and hypoxia induce hormonal and immunological responses that have similarities to the cellular response to exercise [54], Training at an intense level over many years can result in a chronic suppression of salivary immunoglobulin levels. The degree of immune suppression and the recovery rates after exercise are associated with the intensity of exercise and the duration or volume of the training [55], The effect of acute hypoxia on lymphocytes resembles the effect of exercise [56],

The production of IL-6 from working muscles is further enhanced if muscle glycogen content is low. Carbohydrate intake during exercise attenuates the IL-6 production and consequently exercise-induced Cortisol production and fluctuations in NK cells and neutrophils. A major new finding is that exercise-induced immune changes are not a secondary phenomenon to exercise-induced hormonal changes. Rather, muscle contractions induce the release of IL-6. By producing IL-6, muscle fibres are directly involved in exercise-induced immune changes, and exercise-induced Cortisol changes can be viewed as a secondary phenomenon, which in turn leads to altered leukocyte subset composition. As IL-6 works as an energy sensor, it is also clear that dietary factors such as carbohydrate, may influence the immune response to exercise. It is noteworthy, that a cytokine, previously known as a component of the natural immune defence, should now also be considered as an important player in metabolism [53].

5.4. Enhancement of natural immunity

Endotoxin injections produce endotoxin tolerance and elevate natural resistance. However, such injections may have serious side effects, such as high fever, hypotension and abortion. For this reason LPS injections are not suitable for the enhancement of natural immune mechanisms in endotoxin-sensitive mammalian species. Various techniques have been used (physical, chemical, etc.) for the detoxification of endotoxins while the beneficial effects were maintained. One of the best detoxification techniques is treatment with ionizing radiation. The irradiation of LPS with 60Co (100-200 kGy) decreased its toxicity. Such radiodetoxified endotoxin (RD-LPS) preparations showed decreased toxicity, whereas the beneficial effects were preserved (150 kGy:TOLERIN(R)). Irradiation causes marked chemical alteration in LPS, such as the decrease of glucosamine, KDO and fatty acids. A single parenteral injection of TOLERINĀ® is capable of preventing various shock syndromes in experimental animals. Unlike endotoxin, TOLERIN has barely any hypotensive effect and pretreatment with this preparation can prevent practically all the haemodynamic changes induced by LPS. LPS plays an important role in the pathogenesis of the intestinal syndrome of radiation disease, which may be prevented by up to 70% in rats with RD-LPS pretreatment. TOLERIN retains the adjuvant activity of LPS and it is a good adjuvant for inactivated virus vaccines. TOLERIN can also evoke the regeneration of the immune system in irradiated animals. The decrease of natural immunity in immunodeficient or immunosup-pressed patients is the most important cause of opportunistic infections that may lead to sepsis, endotoxaemia, pneumonia and so on. Boosting of natural resistance and the induction of endotoxin tolerance are important in such patients. RD-LPS could produce significant proliferation of lymphoid cells in germ-free animals, which are immunodeficient. Many other beneficial effects are exerted by RD-LPS preparations, such as the activation of macrophages and of the reticuloendothelial system, antitumour activity, etc. On the basis of these favourable experimental results, TOLERIN was tested on 350 surgical patients suffering from gastrointestinal tumours, on patients suffering from AIDS and on cancer patients treated with CYSPLATINC. TOLERIN treatment prevented sepsis and activated bone marrow function in these patients [57].

6. PHYSIOLOGICAL, PATHOLOGICAL AND BEHAVIORAL SIGNIFICANCE 6.1. Physiological activities of the natural immune system

Recent research has revealed the extensive underlying physiological role of the innate immune system in the development and homeostasis of the organism. The impact on development is evident during embryogenesis and also during normal cyclical changes in reproductive tissues in the adult. Mediators of the innate immune system are essential for normal tissue renewal and healing, regeneration, air breathing, cell signalling and cancer control. Natural immunity contributes to the normal physiology of the organism in many and diverse ways arguing for an evolutionary selection centred on self-organization for survival [8],

6.2. Pathophysiological relevance

The natural immune response is a pre-programmed, poly-specific first line of defence that is primarily responsible for eliminating or containing pathogens at the site of entrance into the host. This evolutionary conserved system was described first in cells of the immune system. However, it became apparent this form of immune potential exists in various tissues, where its activation plays a significant role in host defence, autoimmunity, inflammatory disease and pathogenesis of sepsis-induced multiorgan dysfunction. It is possible that natural immunity plays a role in the aging process, and in tumour immunosurveillance [9],

6.3 Behavioural mechanisms in host defence

Behavioural strategies assist organisms to defend themselves against pathogens. Reflexive behaviours, like coughing and vomiting, can be instrumental in expelling pathogens from the body. The avoidance of excrement is an important strategy for minimizing contact with pathogens. Learned food aversions and the avoidance of stimuli previously associated with illness minimize contact with pathogens. Behavioural changes can be induced by immune activation, and it has been argued that this "sickness behaviour" may assist the organism to recover from infection. Immune activation is associated with the production of cytokines, some of which (most notably, interleukin-1, IL-1) have potent behavioural activities. IL-1 decreases several behavioural activities, such as food intake, and sexual activity in females, but not in males. Certain kinds of behavioural experiences, most notably stressful ones, may induce immune activation and cytokine production. Environmental stressors and immune activation produce some similar physiological responses: increased body temperature, and activation of the sympathetic nervous system, the adrenal medulla, and the hypothalamo-pituitary-adrenal axis, as well as brain catecholamines and indoleamines. These observations have led to the concept that pathogen invasion induces "immune stress". The physiological responses induced can assist the defence of the organism against infections, at least in part by changing behaviour. It is argued that learned and reflexive behavioural strategies, and physiological and behavioural responses to illness, are all important components of host defence against pathogens [58],


The concept of 'missing self' first was coined with respect to the failure of activating NK cells due to the recognition of self-MHC [33]. This now appears as an emerging common principle in innate immunity. Sponges have phagocytic cells for defence. Another form of this strategy relies on cell expression of terminal sialic acid on cell surface molecules versus the lack of sialic acid on most microorganisms [59]. Sialic acid binding siglecs are inhibitory receptors bearing tyrosine-based inhibitory motifs (ITIMs). The lack of, or reductions in sialic acid on pathogens, some virally infected or transformed cells and apoptotic cells may act as missing self, allowing phagocytosis to proceed.

Complement, the major noncellular system of innate immunity in humans, exhibits wide ranging and potent biological activities which are under heavy regulation employing several different strategies. Since complement can react ubiquitously by binding covalently to self and non-self, regulator recognition of self can provide one strategy for preventing attack on the host. In this regard inhibition based on terminal sialic acid again contributes in the form of sialic acid-bind ing factor H of the alternate complement activation pathway, which promotes the inactivation of C3b and spares self cells [30,60], Furthermore, additional complement inhibitors, which are broadly expressed and important in the control of complement activation on self cells are membrane expressed CD46 and CD55 (decay-accelerating factor, DAF) and the soluble and secreted CI inhibitor and clusterin [61, 62], All of these molecules are considered to constitute "don't eat me" signaling markers (SAMPs) [61]. These contrast with "eat me" markers in the form of soluble or secreted bridging molecules of the innate immune system binding to pathogen-associated molecular patterns (PAMPs) on pathogens and from apoptotic cell-associated molecular patters (ACAMP). Additional "don't eat me" signals result from normal host cell expression of CD200, CD47 and CD31, all of which engage inhibitory pattern recognition receptors (PRRs) and down-regulate phagocyte activities [61]. While complex, this form of control is well adapted for attack on pathogens not previously encountered. Furthermore, the lack of complement-receptor 1-related gene/protein y (Crry), a membrane-bound complement-regulatory protein structurally similar to decay accelerating factor (DAF/CD55) and membrane cofactor protein (MCP/CD46), resulted in complement deposition at the fetomaternal interface and fetal loss in mice [63], clearly supporting the essential nature of such 'self' expression in normal reproductive physiological processes. Thus, normal self must also include complement regulatory molecules.

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