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The cellular immune response to lymphocytic choriomeningitis (LCM) virus in germfree adult and conventional (Cv) suckling mice with undeveloped immune systems and in Cv adult mice with developed immune systems was suppressed by a single large, sublethal dose of the calmodulin antagonistic chlorpromazine and stimulated by a 100-times smaller dose administered intraperitoneally one day before the intracerebral virus infection. CPZ thus exerted a two-directional dose-dependent immunomodulatory effect in mice with both undeveloped and developed immune system.
The human immune system consists of layer upon layer of response, communication, and coordination mechanisms added during its evolution throughout the last half billion years. Given the parsimony of nature, it is not surprising that many of the systems prominent within the human immune response are recognizable within the immune systems of less advanced species. Insights drawn from these species and common sense suggest that "autoimmune" reactivity was not the original or primary reason for the evolution of these mechanisms. Also, it becomes clear that certain functions thought to be "immune" may actually be nonspecific, really innate functions served by these ancient mechanisms. There is good evidence of communication between levels of the immune system, the innate and adaptive systems working with each other, often the former (not antigen-specific) preceding and serving to trigger or magnify the latter (antigen-specific). A future article in this series will focus more on the innate system and how it interdigitates with the adaptive system.
The "adaptive" immune repertoire functionally recognizes pathogens (and their toxic products) that the "innate" defense system misses. This requires that the self-nonself discrimination and the regulation of effector output be dependent primarily on somatic learning mechanisms (i.e. on the somatically generated, large, random "adaptive" immune paratopes repertoire).
The studies of the late effects of atomic-bomb (A-bomb) radiation on the immune system were started about 20 years after the bombings in 1945. The most remarkable late effects of radiation are the functional and quantitative abnormalities of T and B cells in survivors exposed to high doses (> or = 1.0 Gy). Abnormalities of T-cell immunity include (1) a decreased proportion of CD3+ T cells in peripheral blood lymphocytes, particularly the proportion of CD4+ CD45RA+ naive T cells (study period 1987-91); (2) an increased frequency of CD4- and CD8- (double negative) alpha beta + T cells (1987-91); and (3) functional defects in T-cell responses to mitogens and alloantigens (1974-85). B-cell abnormalities include: (1) a significant increase in the proportion of B cells among peripheral lymphocytes (1987-91); (2) an increase in serum immunoglobulin A levels in females and immunoglobulin M and the incidence of rheumatoid factor in both sexes (1987-89); and (3) an increased level of anti-Epstein-Barr virus antibody titer (1987-90). In contrast, suggestive (0.05 < p < 0.1) or not significant (p > 0.1) dose effects were observed for the number and function of natural killer cells (1983-91), and benign monoclonal gammopathy (1979-87). In addition, studies initiated sooner after the bombing such as the incidence of autoimmune diseases (1958-87), systemic bacterial infections (1954-67), and granulocyte functions (1947-79) also show little dose-effects. Thus, A-bomb radiation induced the alteration of the balance/interaction between the T- and B-cell subsets--specifically, a decrease in the T-cell population and an increase in the B-cell population in the periphery.
Systemic immune vascular pathology raises very often diagnosis and differential diagnosis difficulties generated by the multitude and polymorphism of its clinical symptomatology. Chorioretinal modifications, sometimes particular, may complete the general clinical picture of the systemic immune vasculitis, favouring a correct clinical diagnosis. At the same time, a better knowledge of the clinical picture of some general systemic affections may lead to a correct diagnostic interpretation of these chorioretinal modifications. The paper presents the author's own classification of the main systemic immune vasculitis and also several rare affections (with immunologic implications) with emphasis on the vascular chorioretinal syndrome and on the clinical general one.
This article briefly describes the network of immunity involving selected humoral and cellular elements shared between mucosal surfaces that are both exposed to and remote from antigen challenge. The mechanisms promoting the production, concentration, and secretion of specific antibody isotypes, as well as the migration and localization of various lymphoid cell populations, have been discussed with regard to host mucosal protection against pathogenic agents and other potentially harmful macromolecules.Although certain aspects of the mucosal immune system may be viewed as separate from the systemic immune system, they are not exclusively so. We have drawn attention to their interactions with systemic immune reactants and other, nonimmunological, cellular and humoral constituents of mucosal surfaces and tissues such as the liver. At another level of interaction we have considered the teleological translation of host defence and immunoregulation from one generation to the next through the medium of colostrum and breast milk.The manipulation of the mucosal immune system in order to enhance host resistance, modulate autoimmune and allergic systemic reactivity, or even modify fertility holds great promise. Achievement of these goals depends on gaining further insight into the mechanisms that contribute to mucosal immunity and their interactions with the systemic immune system. Much of our current knowledge is based upon experimental animal models or human populations living in relative prosperity. However, the results of oral vaccination, for example, are known to differ considerably in populations that suffer from parasitic infestations, lack adequate nutrition, and are very old or very young. We have chosen to focus attention on these groups because they constitute a large proportion of the world's population and because mucosal infections are a common cause of illness and death among them.Lastly, the recent discovery that immune deficiencies due to insufficient dietary zinc may extend to subsequent generations of optimally nourished offspring calls for a re-evaluation of immunization protocols in malnourished populations, and of our current understanding of disease inheritance and susceptibility.
The brain immune system, which consists mainly of astrocytes, microglia and infiltrating immune cells, is quiescent normally, but it is activated in response to pathophysiological events such as ischemia, trauma, inflammation and infection. Adenosine is an endogenous purine nucleoside that is generated at sites that are subjected to these "stressful" conditions. Adenosine interacts with specific G-protein-coupled receptors on astrocytes, microglia and infiltrating immune cells to regulate the function of the immune system in the brain. Although many of the effects of adenosine on immune-competent cells in the brain protect neuronal integrity, adenosine might also aggravate neuronal injury by promoting inflammatory processes. A more complete understanding of adenosine receptor function in the brain immune system should help develop novel therapeutic ways to treat brain disorders that are associated with a dysfunctional immune response.
Immune-system activity induces changes in animal behavior such as decreased food intake, decreased exploratory behavior, increased sleep, and impaired cognitive functioning. These changes are mediated by proinflammatory cytokines, and the administration of cytokines produces the same profile of behavior change as do infection and inflammation. Results demonstrating differential effects of immune-system activation depending on environmental contingencies and physiological states support the hypothesis that the behavioral effects of immune activity may be mediated by motivation. In this article, the author outlines the behavioral changes induced by immune-system activation and discusses evidence for a motivational analysis of immune-induced behavior change and the potential involvement of motivation in human sickness behavior.
The innate immune system existed prior to the emergence of adaptive immunity in sharks and higher vertebrates. Homologues of many mammalian innate immune-system elements such as the toll-like receptors exist in species as distant as Drosophila. Selective pressure has led to the development of highly conserved, soluble, and cell-surface receptors that recognize functionally essential molecules shared by microbial pathogens. It is thought that molecular patterns that exquisitely distinguish pathogenic cells from mammalian cells are recognized. Therefore, it would seem unlikely that innate immune-system elements should recognize mammalian tissues. However, there is increasing evidence to suggest that this is the case and that innate immunity promotes rejection of transplanted mammalian tissues, particularly those from other species (xenografts). Evidence for innate recognition of mammalian grafts, the nature of this recognition, and the bi-directional interactions between innate and adaptive immunity that contribute to graft rejection are discussed in this review, with the emphasis on nonvascular xenografts.
Synthetic glucocorticoids (GC) are widely used drugs, also in the prevention of diseases that occur in the preterm newborn. Previously we have found that GC treatment of pregnant rats resulted in a persistent increase in the ratio of AVP over CRH in the mediobasal hypothalamus, and in an increased CD4/CD8 ratio in the thymus of the newborn. The objective of the present study was to investigate whether such effects were also seen after neonatal GC exposure, given in clinically-relevant doses. Dexamethasone-21-phosphate (DEX; 1.2 microg/g BW, i.p.) was given at day 5 and day 7 after birth. At day 18, 33, and 48 after birth effects of GC on the HPA-axis, and on CD4+ and CD8+ T cells in thymus and spleen were examined. Neonatal DEX treatment temporarily increased (p < 0.01) AVP stores in the external zone of the median eminence (ZEME) on day 18 after birth, and did not affect CRH stores. Resting plasma levels of ACTH and corticosterone remained unchanged after neonatal DEX treatment at any time interval studied. In the thymus and spleen, neonatal DEX treatment decreased (p < 0.0001) T cell numbers on day 18 after birth. Furthermore, neonatal DEX treatment increased (p < 0.01) the ratio of mature CD4-CD8+ over CD4-CD8+ thymocytes on day 18 after birth, but not on day 33 and day 48 after birth. In conclusion, neonatal DEX treatment has temporary effects on peptide expression in hypothalamic CRH neurons, and on thymocyte maturation. Apparently, neonatal exposure to GC affects potentially sensitive targets within the endocrine system and immune system but these alterations are reversible and readjusted during development.
Prior systemic immunization with live Staphylococcus aureus vaccine enhances the early recruitment of neutrophils into nonlactating mammary glands infected with staphylococci. The study investigates the role of humoral and cellular mediators in this phenomenon. Intramammary infusion of bacteria suspended in immune sheep serum did not enhance the inflammatory response to infection in nonimmunized ewes despite the presence of complement in the infused serum. Infusion of complement activated by incubation with zymosan evoked a massive neutrophil influx into mammary secretions by 4 hr after infusion. Hemolytic complement activity was not detected in mammary secretions of immunized or nonimmunized ewes. These findings indicate that, despite the inflammatory effect of complement activation, humoral immune factors did not promote neutrophil migration into infected glands. Mammary glands of systemically immunized ewes stimulated 5 days previously with staphylococcal soluble antigens (SSA) supported larger neutrophil influxes during staphylococcal infection than contralateral glands stimulated with endotoxin 5 days prior to infection. Exudates of SSA-stimulated glands had significantly higher cell concentrations, prior to infection, than endotoxin-stimulated glands; however elevated cell concentrations in endotoxin-stimulated glands of nonimmune ewes did not support enhanced inflammatory responses. These findings suggest that qualitative but not quantitative characteristics of mammary leucocytes influence the inflammatory response to infection in systemically immunized ewes.
Four-week-old male C3H/HeN mice were bred with diets consisting of ovalbumin alone (OVA, control diet) or mixtures of OVA and cow's milk immunoglobulin G (IgG-added diets) as a protein source for 4 or 5 weeks, and both the cellular and humoral immune properties of the mice were investigated. The number of interleukin (IL)-12+CD11b+ cells in spleens and the formation of superoxide by peritoneal macrophages were higher in mice given the IgG-added diet than in those given the control diet. The number of natural killer cells in Peyer's patches or spleens and the cytotoxic activity of spleen cells toward an erythroleukemia cell line, K562, were also higher in mice given the IgG-added diet. In contrast, the numbers of interferon-gamma+CD4+ and IL-4+CD4+ cells in Peyer's patches or spleens and the levels of total or OVA-specific intestinal IgA and serum IgG were significantly lower in mice given the IgG-added diet than in those given the control diet. In addition, the number of cells expressing CD19 in spleens was significantly higher in mice given the IgG-added diet. These results indicate that oral ingestion of cow's milk IgG may stimulate some innate cellular immune systems, while suppressing humoral adaptive immune responses in the mouse.
Use of plasmid DNA for vaccination has been demonstrated quite successfully in small rodents. However, some of the many challenges of DNA vaccine development are the relatively low performance obtained in larger animals and a generally weak mucosal immune response. Vaccination through salivary gland (SG) cannulation and delivery of aqueous solutions of DNA is one potential solution. The scalability of SG DNA vaccination was tested in multiple animal models; antigen specific titers above 10,000 were demonstrated in dogs and rats. Immune responses were also present at a variety of mucosal sites. In conclusion, our data demonstrate that DNA vaccination to the SG presents a unique and advantageous method for eliciting systemic and mucosal immune responses.
The avian immune system operates on the same general principles as the mammalian immune system. Antigenic stimulation initiates an immune response that involves cellular cooperation most notably between macrophages, B lymphocytes and T lymphocytes. Macrophages process the antigen and present the antigen to the lymphocytes. B lymphocytes, the principal cells that mediate humoral immunity, transform into plasma cells and produce antibodies. T lymphocytes, most important for cellular immunity, differentiate into functionally diverse subpopulations. The subpopulations of avian T cells have been identified with monoclonal reagents and appear to be similar to those of mammalian T cells. Lymphokines, the soluble products secreted by immune cells, mediate the functions of these cells. Studies on avian lymphokines have lagged behind those on mammalian lymphokines because the genes coding for avian lymphokines have not been cloned. The avian lymphokines studied thus far appear to function along the same lines as the mammalian lymphokines. The immune response in birds is highly regulated and breakdown in regulation often results in immunodepression.
BACKGROUND: Little is known about the local accumulation and function of immune cells in peritoneal fluid after elective surgery of the upper and lower gastrointestinal tract. Our study was designed to investigate whether systemic immune cell response mirrors the local response. We focused on the cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha and on monocytes, natural killer (NK) cells, and T cells that play an important role in eliciting the innate and adaptive immune response. METHODS: Blood samples were taken prospectively from 25 patients 24 h before surgery, as well as 24 h and 48 h afterward. Abdominal drainage fluids were collected intraoperatively 1 h after the abdomen was opened and 24 h and 48 h postoperatively. Apart from the white blood cells, intracellular T-helper-cell (TH1/TH2) cytokine production (interferon-gamma, IL-2, IL-4, IL-13) and HLA-DR on monocytes were measured by four-color flow cytometry, IL-6, and TNF-alpha with the fast immunoluminescence method. RESULTS: Cells of the innate immune system (NK cells, monocytes, NK-T cells, CD5(+) B cells) rapidly decreased in abdominal fluids (P < 0.05: +24 h; +48 h) after surgery, which was paralleled by a concomitant decline in peripheral blood. The percentage of abdominal interferon-gamma, IL-2, IL-4, and IL-13-producing TH cells increased in a way that distinctly counteracted the decrease of the natural immune cells. HLA-DR expression on monocytes in peripheral blood declined significantly (P < 0.05: +24 h; +48 h). In contrast, monocytes in abdominal fluids had high HLA-DR expression. Furthermore, abdominal fluids contained significantly higher concentrations of TNF-alpha (P < 0.05: +24 h; +48 h) and IL-6 (P < 0.05: +24 h) compared with peripheral blood. CONCLUSIONS: Specific immune cell recruitment and cytokine production play an important role in post-trauma events. Measuring distinct local immune cell repertoires and cytokines provides answers as to how the different phases of postoperative immune events proceed. The evaluation of the local response may provide additional criteria for the evaluation of operative trauma. This knowledge may be helpful in detecting postoperative pathological aberrancies.
A good body of experimental and clinical results has supported the existence of numerous reciprocal interactions among the nervous, endocrine and immune systems. Increasing evidence has been accumulated in the last years on the interaction between pituitary-thyroid hormones and the immune system on the basis of either the existence of receptors for thyreotropic and thyroid hormones on lymphocytes or the frequent immune alteration in physiological and pathological fluctuations of thyroid hormones. The data were obtained either in animals with experimentally induced hyper- or hypothyroidism or in humans with various hyperthyroid or hypothyroid situations. Conversely, immune-derived products such as lymphokines and monokines have been shown able to influence the pituitary-thyroid axis modulating either the thyroid hormone levels or the hormone/cytokine production by thyrocytes. The present paper aims at summarizing the data available on the existence of thyroid-immune interactions, and at analyzing the possible integration between pituitary-thyroid hormones and immune factors in favoring the development and maintenance of both thymic and peripheral immune efficiency. The relevance of pituitary-thyroid-immune interactions is discussed for its implication in the ageing process.
A growing body of evidence indicates a bi-directional relationship between the neuroendocrine system and immune functions. It is well known that lymphoid organs such the thymus, the spleen and peripheral blood produce growth hormone (GH) and GH receptor is expressed on different subpopulations of lymphocytes. Many in vitro and in animal studies demonstrate an important role of GH in immunoregulation. GH stimulates T and B cells proliferation and immunoglobulin synthesis, enhances the maturation of myeloid progenitor cells and is also able to modulate cytokine response. However, in humans GH deficiency (GHD) is not usually associated with immunodeficiency and only minor abnormalities of immune function have been reported, as compared to those observed in GHD animals. It is possible that in humans the GH produced locally in the immune system compensates for the lack of endocrine GH. In this review the main actions of GH on the immune system in vitro, in animal models and in humans are summarized.