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The autonomic nervous system and the immune system in juvenile rheumatoid arthritis.

This study demonstrates that juvenile rheumatoid arthritis is associated with a dysregulation of the autonomic nervous system as well as with disturbances in the capacity of the immune system to respond to mediators of the autonomic nervous system. In patients with active disease heart rate at rest is higher than in healthy controls. In addition, 3-hydroxy-4-phenoxyphenylglycol levels in urine are higher in all patients than in the control group. Cardiovascular responses to an orthostatic stress test (tilt up) are reduced in patients with active and nonactive disease. Plasma norepinephrine responses to tilt up are reduced in subjects with active juvenile rheumatoid arthritis. In summary, our data show that patients with juvenile rheumatoid arthritis have an altered function of the autonomic nervous system associated with increased central noradrenergic outflow, presumably leading to increased vasoconstriction, resulting in a decreased response to an orthostatic stressor. The altered function of the autonomic nervous system is associated with changes in the response of leukocytes to mediators of the autonomic nervous system via beta2-adrenergic receptors. Leukocytes of patients with active juvenile rheumatoid arthritis have a lower cAMP response to a beta2-adrenergic agonist, presumably due to increased cAMP-phosphodiesterase activity in these cells.

Adolescent↗

[Organization and function of the immune system (I)].

An immune reaction is a complex process. Nonspecific resistance is always induced besides specific humoral and cellular defense reactions. After binding to an antigen (antigen-antibody reaction) antibodies can activate complement. If the entire complement cascade occurs, for example at the surface of cells (bacteria), this leads to complement-induced lysis and to destruction of the antigen. Complement cleavage products which are formed during the activation of complement have biological activities. They can attract granulocytes, macrophages and lymphocytes chemotactically or induce and accelerate processes of phagocytosis. In consequence of the activation of T-lymphocytes sensitized T-cells are formed. T-helper-cells intensify both the humoral cellular immune response mediated by B-cells and the cellular immune response mediated by cytotoxic T-cells. They effect this by secretion of substances resembling hormones, the so-called lymphokines. Cytotoxic T-cells (killer cells) can kill their target cells directly. Immune reactions are regulated in multifarious ways. T-suppressor-cells slow down the immune reactions of B- and T-cells. The close interaction of the T-helper and T-suppressor-cells designated as "regulatory T-cells" ensures the functional equilibrium within the immune system.

Antibody Formation↗

Heteropentameric cholera toxin B subunit chimeric molecules genetically fused to a vaccine antigen induce systemic and mucosal immune responses: a potential new strategy to target recombinant vaccine antigens to mucosal immune systems.

Noninvasive mucosal vaccines are attractive alternatives to parenteral vaccines. Although the conjugation of vaccine antigens with the B subunit of cholera toxin (CTB) is one of the most promising strategies for vaccine delivery to mucosal immune systems, the molecule cannot tolerate large-protein fusion, as it severely impairs pentamerization and loses affinity for GM1-ganglioside. Here we report a new strategy, in which steric hindrance between CTB-antigen fusion subunits is significantly reduced through the integration of unfused CTB "molecular buffers" into the pentamer unit, making them more efficiently self-assemble into biologically active pentamers. In addition, the chimeric protein took a compact configuration, becoming small enough to be secreted, and one-step affinity-purified proteins, when administered through a mucosal route, induced specific immune responses in mice. Since our results are not dependent on the use of a particular expression system or vaccine antigen, this strategy could be broadly applicable to bacterial enterotoxin-based vaccine design.

Animals↗

Atherosclerosis and the immune system.

The immune system is involved at all stages of the atherosclerotic disease process. Innate immunity, represented by macrophages and other cells, is directly activated by microbial components and possibly also by autologous lipids and proteins. It elicits inflammatory activity, which is a key component of the atherosclerotic lesion. Adaptive immunity is initiated by recognition of disease-related antigens, which include oxidatively modified lipoproteins, heat shock proteins and microbial macromolecules. In the artery wall, adaptive immune recognition mainly leads to Thl effector responses, which are characterized by secretion of proinflammatory cytokines and by activation of macrophages and vascular cells. Therefore, both the innate and adaptive arms of the immune system lead to inflammation in the developing atherosclerotic lesion. Interestingly, several effector pathways of cellular as well as humoral immunity tend to counteract proatherogenic, proinflammatory immunity. The notion that immunity plays an important role in the development of atherosclerosis has focused attention on a number of potential novel targets for intervention based on modulation of such immune responses.

Arteriosclerosis↗

RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems.

The immune system consists of two evolutionarily different but closely related responses, innate immunity and adaptive immunity. Each of these responses has characteristic receptors-Toll-like receptors (TLRs) for innate immunity and antigen-specific receptors for adaptive immunity. Here we show that the caspase recruitment domain (CARD)-containing serine/threonine kinase Rip2 (also known as RICK, CARDIAK, CCK and Ripk2) transduces signals from receptors of both immune responses. Rip2 was recruited to TLR2 signalling complexes after ligand stimulation. Moreover, cytokine production in Rip2-deficient cells was reduced on stimulation of TLRs with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA, indicating that Rip2 is downstream of TLR2/3/4 but not TLR9. Rip2-deficient cells were also hyporesponsive to signalling through interleukin (IL)-1 and IL-18 receptors, and deficient for signalling through Nod proteins-molecules also implicated in the innate immune response. Furthermore, Rip2-deficient T cells showed severely reduced NF-kappaB activation, IL-2 production and proliferation on T-cell-receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (TH1) cells, indicating that Rip2 is required for optimal TCR signalling and T-cell differentiation. Rip2 is therefore a signal transducer and integrator of signals for both the innate and adaptive immune systems.

Adaptor Proteins, Signal Transducing↗

Modulation of the lung local immune response by systemic immunization.

The present study describes the respiratory immune response of mice to locally administered antigen, and the modulation of this response by systemic immunization. Intranasal immunization of mice with the A/PR/8/34 strain of influenza virus evoked local antibody response of the IgA type. The titer of the IgA antibodies declined to a nondetectable level in 40--50 days. If at that time a second intranasal dose was administered, a secondary IgA response was evoked. On the other hand, administration by the intramuscular route resulted in a mixed population of IgA and IgG antibodies. The relevance of this finding to problems of immunization against respiratory viral infections is discussed.

Administration, Intranasal↗

The probiotic bacterium Lactobacillus casei induces activation of the gut mucosal immune system through innate immunity.

The mechanisms by which probiotic bacteria affect the immune system are unknown yet, but many of them are attributed to an increase in the innate or in the acquired immune response. To study the influence of the probiotic bacterium Lactobacillus casei in the expression of receptors involved in the innate immune response, this bacterium was orally administered to BALB/c mice. After, they were sacrificed; the small intestine and intestinal fluids were collected to measure secretory immunoglobulin A (IgA) specific for L. casei. Mononuclear cells from Peyer's patches were isolated to determine the CD-206 and TLR-2 receptors. In histological slices we determined the number of IgA+, CD4+, CD8+, and CD3+ cells and two cytokines (interleulin-5 [IL-5] and IL-6). CD-206 and TLR-2 increased with respect to the untreated control. We did not observe an increase in the T population or in the IL-5-positive cells. IgA+ cells and IL-6-producing cells increased after 7 days of L. casei administration. We did not find specific antibodies against L. casei. The main immune cells activated after oral L. casei administration were those of the innate immune response, with an increase in the specific markers of these cells (CD-206 and TLR-2), with no modification in the number of T cells.

Administration, Oral↗

The art of the probable: system control in the adaptive immune system.

The immune system provides very effective host defense against infectious agents. Although many details are known about the cells and molecules involved, a broader "systems engineering" view of this complex system is just beginning to emerge. Here the argument is put forward that stochastic events, potent amplification mechanisms, feedback controls, and heterogeneity arising from spatially dispersed cell interactions give rise to many of the gross properties of the immune system. A better appreciation of these underlying features will not only add to our basic understanding of how immunity develops or goes awry, but also illuminate new directions for manipulating the system in prophylactic and therapeutic settings.

Adaptation, Physiological↗

Effect of photoperiod on the fish innate immune system: a link between fish pineal gland and the immune system.

The pineal gland via its secretory product, melatonin, influences the light-dark rhythm in most vertebrates including fish. Apart from the information concerning this circadian rhythm, the interrelation of the melatonin with other physiological processes has not been considered in fish. Thus, we evaluated the changes in the humoral innate immune system of seabream (Sparus aurata L.) and sea bass (Dicentrarchus labrax L.) specimens exposed to a constant light-dark photoperiod (12 hr L:12 hr D). Serum was obtained from blood samples collected at 02:00, 08:00 hr (light-on), 14:00, 20:00 hr (light-off) and at 08:00 hr again. Among the humoral innate immune responses, complement, lysozyme and peroxidase activities were determined. Complement activity was higher during the day than during the night in both fish species. Seabream lysozyme activity reached its maximum at 20:00 and 02:00 hr but was hardly affected in sea bass. Finally, the peroxidase activity of seabream was significantly higher at 08:00 hr than during the rest of the cycle while, in sea bass, it showed little variation. The present results demonstrate that the humoral innate immune system has a circadian rhythm based on the light-dark cycle and that this cycle might be affected by the pineal gland.

Animals↗

Evolution of the innate and adaptive immune systems: relationships between potential immune molecules in the lowest metazoan phylum (Porifera) and those in vertebrates.

Porifera (sponge) form the lowest metazoan phylum and share a common ancestor with other metazoan phyla. In the present study, it is reported that sponges possess molecules that are similar in structure to those molecules involved in the immune system in mammals. Experiments with the marine sponges Geodia cydonium and Suberites domuncula have been performed on tissue (auto- and allografting) as well as on a cellular level. The studies revealed that sponges are provided with elements of the mammalian innate immune system, such as molecules containing scavenger receptor cysteine-rich domains. Furthermore, macrophage-derived cytokine-like molecules have been identified that are up-regulated during the grafting process. In addition, the (2'-5')oligoadenylate synthetase system exists in sponges. "Precursors" of the second type of immune response in mammals, the adaptive immune system, have been traced in sponges. It is shown that the expression of a lymphocyte-derived cytokine from mammals is up-regulated during non-self-recognition in S. domuncula. Finally, in G. cydonium, two classes of receptors that comprise Ig-like domains have been identified: the receptor tyrosine kinases and the non-enzymic sponge adhesion molecules. They contain two polymorphic Ig-like domains that are grouped to the variable set of immunoglobulins. The expression of these molecules is also up-regulated during the grafting process. It is concluded that sponges are already provided with a series of elements used in higher vertebrates for both the innate and the adaptive immune recognition.

2',5'-Oligoadenylate Synthetase↗

Naturally occurring IgA antibodies to ocular and oral microorganisms in tears saliva and colostrum: evidence for a common mucosal immune system and local immune response.

In this study, levels of naturally occurring secretory IgA (sIgA) antibodies to bacterial isolates representative of the microflora of the human eye (Staphylococcus epidermidis and a Corynebacterium species) and the oral cavity (Streptococcus mutans serotypes c and d) were assessed in three different human external secretions. Tears and parotid saliva samples collected at the same time from 22 healthy subjects and colostrum from 11 healthy women (1-14 days post partum) were assessed for sIgA anti-bacterial antibody levels by an enzyme-linked immunosorbent assay. Significantly higher levels (P less than 0.001) of IgA antibodies to Staphylococcus epidermidis and the Corynebacterium sp. were found in tears than in parotid saliva. Furthermore, higher levels of sIgA antibodies to Streptococcus mutans serotype d occurred in parotid saliva than in tears of these subjects. Although levels of salivary sIgA antibodies to S. mutans serotype c were lower than those seen to serotype d, they were not significantly different from those in tears. However, absolute sIgA anti-serotype c antibodies per mg IgA were higher in saliva than in tears. When sIgA antibody levels to the four bacterial strains were assessed in colostrum, the proportion of sIgA antibodies per mg IgA were much lower than seen in tears or saliva. These results suggest that natural sIgA antibodies which occur in human external secretions are induced by antigen ingestion and stimulation of the common mucosal immune system. However, the local presence of antigen at a mucosal site induces greater clonal expression and results in higher levels of sIgA antibodies than at mucosal sites not exposed to local antigenic stimulation.

Adolescent↗

Special feature for the Olympics: effects of exercise on the immune system: modification of immune responses to exercise by carbohydrate, glutamine and anti-oxidant supplements.

Immunosuppression in athletes involved in heavy training is undoubtedly multifactorial in origin. Training and competitive surroundings may increase the athlete's exposure to pathogens and provide optimal conditions for pathogen transmission. Heavy prolonged exertion is associated with numerous hormonal and biochemical changes, many of which potentially have detrimental effects on immune function. Furthermore, improper nutrition can compound the negative influence of heavy exertion on immunocompetence. An athlete exercising in a carbohydrate-depleted state experiences larger increases in circulating stress hormones and a greater perturbation of several immune function indices. The poor nutritional status of some athletes may predispose them to immunosuppression. For example, dietary deficiencies of protein and specific micronutrients have long been associated with immune dysfunction. Although it is impossible to counter the effects of all of the factors that contribute to exercise-induced immunosuppression, it has been shown to be possible to minimize the effects of many factors. Athletes can help themselves by eating a well-balanced diet that includes adequate protein and carbohydrate, sufficient to meet their energy requirements. This will ensure a more than adequate intake of trace elements without the need for special supplements. Consuming carbohydrate (but not glutamine or other amino acids) during exercise attenuates rises in stress hormones, such as cortisol, and appears to limit the degree of exercise-induced immunosuppression, at least for non-fatiguing bouts of exercise. Evidence that high doses of anti-oxidant vitamins can prevent exercise-induced immunosuppression is also lacking.

Antioxidants↗

Intestinal and systemic immune responses to an oral cholera toxoid B subunit whole-cell vaccine administered during zinc supplementation.

Zinc plays a critical role in the normal functioning of the immune system. We investigated whether zinc sulfate administered orally to adult zinc-replete volunteers modulates systemic and intestinal immune responses to an oral killed cholera toxoid B subunit (CTB) whole-cell cholera vaccine. The 30 participants were immunized twice, with a 17-day interval. The vaccinees in the intervention group ingested 45 mg of elemental zinc thrice daily for 9 days starting 2 days before each vaccine dose. The median serum anti-CTB immunoglobulin A (IgA) and IgG responses from day 0 to day 30, i.e. after two vaccine doses, were 13-fold lower (P value for identical distribution, <0.005) in the zinc-supplemented compared to the nonsupplemented vaccinees. The median serum vibriocidal responses from baseline to after one (day 0 to day 17) and two (day 0 to day 30) vaccine doses were at least sixfold (P = 0.033) and fourfold (P = 0.091) higher, while the median fecal anti-CTB IgA response after two doses was estimated to be fourfold higher (P = 0.084) in the zinc-supplemented vaccinees. These observations show that zinc reduces the antitoxin and may enhance the antibacterial responses in serum. Zinc may also improve the intestinal antitoxin immune response. Oral zinc administration has the potential to modify critical immune responses to antigens applied to mucosal surfaces.

Administration, Oral↗

Target organs and systems: methodologies to assess immune system function.

Immunotoxicity encompasses both reduced and heightened immune function. Diverse chemicals can impair functioning of the immune system. Both monographs and books have been devoted to detailed descriptions of immunotoxicity. This paper gives a brief overview of the methods currently used to assess the immunotoxic potential of chemicals. It also discusses the trend toward the use of alternative methods to mammalian models, such as feral species, in vitro assays, and computational models. The strategy of using a tier approach to screen chemicals for immunotoxicity is described, together with the rationale for, and limitations of, this approach. Interpretation of data with regard to clinical disease and human health is addressed. The immune system poses substantial complexities in this regard as the system has functional reserve and functional redundancy.

Animal Testing Alternatives↗

[Malnutrition and the immune system].

The immune system is governed by a large number of influences. An important support of the nutritional dependent changes of the reaction to immunity is represented by the prostaglandin and leukotriene system. The basis are essential and non-essential highly unsaturated fatty acids which are transformed by the body's own enzyme system in oxidative steps. As coenzyme and cosubstrate, for instance Vitamin B6 and zinc, are needed--tests show the influence of pyridoxine and folic acid on the immune system. The significance of minerals, especially zinc, iron and selenium, for the immune metabolism will be demonstrated. Selenium deficiency leads, evidently, to a reduction in the ability to stimulate the lymphocytes and decreases the phagocytosis index of the macrophages--some risk groups, responsible for the appearance of the state of malnutrition, will be pointed out and pharmaco-therapeutic prevention measures will be described.

Avitaminosis↗

The human hair follicle immune system: cellular composition and immune privilege.

The immunology of the hair follicle, its relationship with the 'skin immune system' and its role in hair diseases remain biologically intriguing and clinically important. In this study, we analysed the immunoreactivity patterns of 15 immunodermatological markers to determine the cellular composition and immune privilege of the human hair follicle immune system in anagen VI (growth phase). The most prominent cells located in or around the hair follicle were Langerhans cells, CD4+ or CD8+ T cells, macrophages and mast cells, whereas B cells, natural killer cells and gammadelta T cells were found very rarely. Langerhans cells (CD1a+, major histocompatibility complex, MHC class II+), and T cells (CD4+ or CD8+) were predominantly distributed in the distal hair follicle epithelium, whereas macrophages (CD68+, MHC class II+) and mast cells (Giemsa+) were located in the perifollicular connective tissue sheath. Transmission electron microscopy confirmed low numbers of immune cells in the proximal hair follicle epithelium, and very few macrophages and Langerhans cells were seen in the dermal papilla. Melanophages were observed in the connective tissue sheath and dermal papilla. MHC class I (HLA-A, -B, -C) and beta2-microglobulin immunoreactivity was found on most skin cells, but was substantially reduced on isthmus keratinocytes and virtually absent in the proximal hair follicle epithelium. Apart from the absence of Fas ligand immunoreactivity, the sharply reduced numbers of T cells and Langerhans cells, and the virtual absence of MHC class I expression all suggest that the anagen proximal hair follicle constitutes an area of immune privilege within the hair follicle immune system, whose collapse may be crucial for the pathogenesis of alopecia areata.

Adolescent↗

[Interactions between the nervous and the immune system].

The immune and nervous systems have the capacity to modulate inflammatory processes in an additive, synergistic or antagonistic way. In addition to direct effects, feed-back systems connecting immune and nervous systems exist which provide the basis for a better understanding of the modulation of inflammatory reactions by the central nervous system (nervous as well as neuropsychological influences). It is well established that immunocompetent cells, but also endothelial, epithelial and mesenchymal cells induce and regulate inflammation by production of cytokines. However, the expression, synthesis and secretion of neuropeptides by cells of the immune system or even connective tissue cells has only been recognized recently. These findings indicate that non-neuronal cells in the periphery can feedback to the nervous system by secretion of neuropeptides (e.g. modulation of an afferent signal by interaction of peripherally produced neuropeptides with nerve endings). Nitrogen monoxide has recently been shown to act as an important mediator of inflammatory phenomena and to play an important role in neurotransmission. The rapidly accumulating knowledge of the nature metabolism of this highly reactive substance indicate new therapeutic options in the area of neuroimmunology.

Central Nervous System↗