Virus-cell interactions in the nervous system and the role of the immune response

The outcome of a viral infection within the nervous system depends on a complex interplay between the virus, its target cell and the immune system. Recent research has elucidated a variety of mechanisms involved in these interactions and their role in the production of disease.     

Mast cell activation and migration to lymph nodes during induction of an immune response in mice

The mast cell response in skin and lymph nodes was examined during the sensitization phase of dinitrofluorobenzene (DNFB)-induced contact hypersensitivity in mice. Degranulation of 62% of mast cells in DNFB-exposed skin was evident within 30 min of a dual application of DNFB, reaching a peak of 77% at 24 h, and persisting in 42% after 5 d. Abundant expression of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta mRNAs and proteins was observed in keratinocytes, and mast cell degranulation was significantly inhibited after administration of neutralizing antibodies to MIP-1alpha, but not MIP-1beta. During DNFB sensitization, the mast cell density in the skin decreased by half, concurrent with a fivefold expansion of mast cell numbers in draining lymph nodes. Fluorescent-labeled mast cells injected into the skin appeared in draining lymph nodes after application of DNFB, followed by subsequent migration to the spleen. In lymph nodes, mast cells were an abundant and predominant source of MIP-1beta, neutralization of which partially inhibited T lymphocyte recruitment. These results indicate that mast cells contribute to the induction of this primary immune response by activation at and migration from the site of antigen encounter to draining lymph nodes, wherein they mediate T lymphocyte recruitment by production of MIP-1beta.     

Modulating the immune response to genetic immunization

Genetic immunization, also known as DNA or polynucleotide immunization, is a novel strategy for vaccine development in which plasmid DNA encoding either individual or a collection of antigens is directly administered to a host. Such immunization leads to host expression of the delivered foreign gene, resulting in the induction of a specific immune response against the in vivo produced antigen. DNA immunization has been shown to induce protective immune responses in several infectious disease and cancer experimental model systems. Furthermore, DNA vaccines have recently entered the clinic for analysis as both prophylactic and therapeutic agents. Although the mechanisms of immunity to DNA have not yet been fully elucidated, it has become apparent that the immune response achieved by DNA vaccination is quite malleable, and can be manipulated by altering the conditions under which the vaccine is administered. Either through changing the method or location of immunization, altering the number of immunostimulatory sequences in the plasmid, altering the immunization regimen, or coadministering genes for cytokines or costimulatory molecules, one can modulate both the magnitude and orientation of the subsequent immune response. Through maximization of this feature of DNA immunization, we will likely be able to design vaccines and immunotherapeutic agents that are tailored to the correlates of protection for a particular disease, resulting in a new generation of more focused and effective immune stimulating agents.     

The immune response to trauma

The response to trauma begins in the immune system at the moment of injury. The loci are the wound, with activation of macrophages and production of proinflammatory mediators, and the microcirculation with activation of endothelial cells, blood elements, and a capillary leak. These processes are potentiated by ischemia and impaired oxygen delivery and by the presence of necrotic tissue, each exacerbating the inflammatory response. Hemorrhage alone may be a sufficient stimulus. Inflammation once was considered to be a host reaction to bacteria or other irritants. This concept was expanded by the discovery of autoimmune diseases, and we are now aware that some illnesses are the result of the body's response to an invader rather than the direct effect of the invader itself. The discoveries about the response to trauma described here add another dimension, showing inflammation to be a fundamental life process that begins at the molecular level at the moment of injury and that, depending on the severity of the stimulus and the effectiveness of initial treatment, may spread to include every cell, tissue, and organ in the body, for good or ill. An important part of these expanding concepts is the notion that all noxious stimuli activate the cytokine system as a final common pathway. Sepsis, hemorrhage, ischemia, ischemia-reperfusion, and soft tissue trauma all share an ability to activate macrophages and produce proinflammatory cytokines that may initiate the SIRS. Second-message compounds and effector molecules mediate the observed clinical phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oligodendroglial response to the immune cytokine interferon gamma

The occurrence and coexistence of peptides of the insulin-like growth factor (IGF)/insulin superfamily were investigated in the ovary and gastro-intestinal tract of the protochordate Ciona intestinalis. Antisera specific for mammalian IGF-I, insulin and relaxin were used in a double-immunofluorescence method on paraffin sections and with an immunogold technique on consecutive semi-thin sections. IGF-I and relaxin immunoreactions but no insulin immunoreactions occurred in the ovary and were confined to medium-sized and mature follicle cells. Two subpopulations of reacting follicular cells were present: those containing only IGF-I immunoreactivity (5%) and those containing IGF-I and relaxin immunoreactivities (95%). In the gastro-intestinal tract, IGF-I and insulin immunoreactions coexisted, whereas no relaxin immunoreactions were obtained. Gel chromatography and radioimmunoassay in Ciona ovary revealed IGF-I immunoreactivity in two peaks with apparent molecular masses of approximately 16 kDa and 3 kDa. The present results indicate that (1) the same IGF-I-related peptide probably occurs in gastro-intestinal tract and ovary, (2) three different members of the insulin/IGF family of peptides are probably present in protochordates, (3) different types of coexistence of these peptides seem to exist in protochordates, i.e. an IGF-I-related peptide and an insulin-related peptide in the digestive tract and, as shown previously, in central nervous system, and the IGF-I-related peptide and relaxin in the ovary, (4) an IGF-I-related peptide and relaxin may be involved in oocyte maturation in the protochordate ovary.     

Cytokine production in the immune response to murine gammaherpesvirus 68

Cytokine profiles were determined following intranasal infection of C57BL/6J mice with murine gammaherpesvirus 68 (MHV-68). Spleen, mediastinal, and cervical lymph node cells from infected mice produced high levels of interleukin 6 (IL-6) and gamma interferon (IFN-gamma) and lower levels of IL-2 and IL-10 following in vitro restimulation. Little or no IL-4 or IL-5 was detected. Cytokine production was generally maximal at 10 days after infection, correlating with viral clearance from the lung, although significant levels were seen as early as 3 days after administration of the virus. In vitro infection of naive splenocytes induced B-cell- dependent secretion of IL-6 and IL-10, whereas IFN-gamma and IL-2 were produced only by cells that had been primed in vivo. Depletion of B lymphocytes from primed splenocyte populations did not, however, abrogate IL-6 and IL-10 production. Highly purified immune T cells made IL-6, IL-10. and IFN-gamma following in vitro restimulation with MHV-68. Thus, IL-6 and IL-10 are components of both the acquired and the innate host response. These cytokines have potential roles in the establishment and maintenance of persistent infection.     

Aging and immune response to exercise

Human immune function undergoes adverse changes with aging. The T cells, which have a central role in cellular immunity, show the largest age-related differences in distribution and function, with thymus involution as the apparent underlying cause. The immune responses to acute exercise and training have not been studied extensively in the elderly. The natural killer (NK) cell response to a single exercise challenge is normal in older individuals, but immediately after exercise the elderly subjects manifest less suppression of phytohemagglutinin (PHA)-induced lymphocyte proliferation than younger individuals. In contrast, a strenuous exercise seems to induce a more sustained postexercise suppression of cellular immunity in older individuals than in their young peers. A few cross-sectional comparisons of immune status between physically fit elderly individuals and young sedentary controls suggest that habitual physical activity may enhance NK cell activity, checking certain aspects of the age-related decline in T cell function, such as reduced mitogenesis in response to plant lectins and decreases in the production of certain types of cytokine. The clinical implications, however, remain to be clarified by future study.     

Humoral immune response to human papillomavirus infection

Nematodes are known to be a useful system for studies of comparative development. Here we perform a molecular phylogenetic analysis to allow for the independent interpretation of the developmental and morphological changes observed among a selected set of nematode species. Our molecular phylogenetic analysis is based on coding regions of the genes for RNA polymerase II, the small subunit rRNA and an expansion segment of the large subunit rRNA. Sequences were compared from five species in the family (Rhabditidae) that includes the developmental model organism Caenorhabditis elegans and from an outgroup taxon Aduncospiculum halicti (Diplogasterina). The phylogenetic analysis does not support the monophyly of the subfamily Mesorhabditinae and identifies the unnamed strain PS1010 as a sister taxon of C. elegans despite its morphologically divergent buccal capsule. On the basis of the inferred framework, we can begin to interpret the evolution of vulval development and of morphological differences among these nematode species.     

Human humoral immune response to Dirofilaria species

BACKGROUND: Keloids are relatively common sequelae of trauma to the skin of the head and neck. A wide variety of treatment approaches developed over the years document the difficulty in eradicating these lesions. OBJECTIVE: To review the senior author's (W.H.L) 15-year experience in treating keloids both medically and surgically. DESIGN: A retrospective analysis of 202 patients with histologically documented keloids of the head and neck with at least a 2-year follow-up. RESULTS: A combination of precise surgical excision, postoperative steroid infiltration, silicone sheeting, and conservative auricular radiotherapy has resulted in an acceptable 15% recurrence rate overall. CONCLUSIONS: The treatment of facial keloids remains a challenge for the facial plastic and reconstructive surgeon. Precise surgical techniques with adjuvant therapies have resulted in a relatively low recurrence rate.     

The equine immune response to endometrial cups

Out of all the areas of comparative immunological study in the horse, the field of reproductive immunology has proven to be one of the most fertile and exciting. Maternal immunological interactions with the fetus involve a set of events which prevent maternal rejection of trophoblastic tissue invading the uterus, and at the same time control this invasion to regulate growth and prevent damage to maternal tissues. Unique features of equine placentation make it exceptionally well-suited to studying these immunological interactions.     

Adhesion molecules during immune response to exercise

PURPOSE: The extracellular matrix serves as a structural support for the corneal stroma and mediates signaling events that regulate the intracellular environment of stromal keratocytes. We hypothesize that adhesion and injury mediate signal transduction events causing the phosphorylation of tyrosine residues of specific adhesion proteins and that phosphorylation is required for cellular adhesion and migration. METHODS: For the adhesion experiments; primary rabbit stromal fibroblasts were seeded and phosphorylation of tyrosine residues was followed from 1 min to 24 h. For the injury experiments, confluent primary cultures were rendered quiescent, wounded, and tyrosine phosphorylation was followed from 30 s to 6 h. The antibody (py-20) was used to detect proteins phosphorylated on tyrosine residues. We examined changes in the phosphorylation of focal adhesion kinase (FAK), paxillin and cortactin, using immunoprecipitation and Western blot analysis. RESULTS: In the adhesion experiments, the phosphorylation of a 68-kDa protein was detected after 1 min, and the phosphorylation of a 125-kDa protein was not detected until 15 min. These proteins were identified in re-probed blots as paxillin and FAK. In the injury experiments, FAK phosphorylation was detected within 30 s and remained elevated for 6 h when cells were cultured on fibronectin. Both FAK and paxillin phosphorylation were prominent after injury, but unlike FAK phosphorylation, paxillin phosphorylation decreased over time. Phosphorylation was prominent at the wound margin. After wound closure, it returned to background levels. Tyrosine kinase inhibitors, genistein and herbimycin, decreased the number of adherent cells and altered the rate of cell migration after injury, compared to control (DMSO alone). CONCLUSION: The results indicate that injury and cell-matrix interaction mediate the phosphorylation of specific adhesion proteins and that phosphorylation is required for wound repair.     

Eosinophil-enriched inflammatory response to schistosomula in the skin of mice immune to Schistosoma mansoni

Exposure of the mouse skin to Schistosoma mansoni cercariae gives rise to acute, exudative inflammation in both normal and immune mice, but the immune response is anamnestically accelerated and is oesinophil-enriched, thereby enhancing opportunities for tegumental contact of schistosomula with host leukocytes, particularly with eosinophils. Many of the inflammatory changes occurring within the first 48 hours after exposure are due to cercarial products, e.g., "penetration tracts," but some remain demonstrable when schistosomula metamorphosed in vitro are injected intradermally and are therefore directed against the schistosomula themselves, such as the leukocyte "streaming patterns" seen in their pathways. In contrast to earlier observations in primates, cellular responses to schistosomula in the mouse lung 4 days after penetration are minimal in either normal or immune mice. Thus, immune cellular responses to schistosomula in mice are limited to an early time period after cercarial penetration and are morphologically suggestive of an antibody-mediated response rather than of delayed hypersensitivity. Our observations complement earlier evidence suggesting that antibody-mediated host leukocyte contact with schistosomula initiates the killing of challenge parasites in immune mice, with the eosinophil probably playing a crucial role.     

Relative contribution of endothelial cell and polymorphonuclear neutrophil activation in their interactions in systemic inflammatory response syndrome

OBJECTIVE: To examine the relative contribution of polymorphonuclear neutrophil (PMN) vs endothelial cell (EC) activation on the adherence and subsequent killing of ECs by PMNs. DESIGN: In vitro comparative studies of PMN-EC adherence and cytotoxicity. SETTING: Research laboratory and the surgical intensive care unit of a tertiary-level university hospital. PATIENTS: Patients with systemic inflammatory response syndrome admitted to the surgical intensive care unit and hospitalized preoperative noninfected surgical patients. INTERVENTION: None. METHODS: Polymorphonuclear neutrophils were isolated from 21 healthy volunteers, 22 preoperative patients, and 30 patients from the surgical intensive care unit with systemic inflammatory response syndrome. The PMNs were activated with lipopolysaccharide, 100 ng/mL (Escherichia coli 0111:b4), for 40 minutes at 37 degrees C before the adherence and cytotoxicity assays. Human umbilical vein endothelial monolayers were stimulated with tumor necrosis factor alpha, 25 ng/mL, and interleukin 1 beta, 15 U/mL, for 3 hours. The PMNs or EC cells were labeled with sodium chromate Cr 51 and used in a standard adherence or killing assay as required. RESULTS: Control and preoperative patient PMN treatment with lipopolysaccharide produced a modest increase in adherence. The PMNs from patients with systemic inflammatory response syndrome showed moderately increased human umbilical vein endothelial cell adherence, and this could not be augmented further with lipopolysaccharide stimulation. There was a marked increase in PMN adherence to EC after EC activation in all study groups (P < .001). Similar to the adherence data, human umbilical vein endothelial cell cytotoxicity was significantly increased in all groups after human umbilical vein endothelial cell activation (P < .01) but not after PMN stimulation with lipopolysaccharide. CONCLUSION: These data suggest that stimulation of ECs is far more important in producing increased adherence and cytotoxicity of EC than PMN stimulation with lipopolysaccharide in all study groups. Therapeutic efforts in patients with systemic inflammatory response syndrome should be focused on the EC.     

Stress and the immune response in rats

The in vitro response of sensitized splenic lymphocytes to antigen (thyroglobulin) was increased by crowding and decreased by isolation in female rats. Both isolated and crowded male rats responded by a decrease in the in vitro reactivity of lymphocytes to antigen. The response of the lymphocytes to PHA was not altered in any consistent manner. Similar animals, both control and those immunized with thyroglobulin, were tested for an effect of in vivo injections of epinephrine on the in vitro reactivity of lymphocytes; epinephrine was given intraperitoneally 30 min before the rats were killed for removal of spleens. Incorporation of 3H-thymidine by lymphocytes was greater in control cultures (neither PHA nor antigen present) but there was a decreased response to either PHA or antigen when epinephrine had been injected.     

The maturation of the immune response

In a T-cell dependent immune response, the repertoire of antigen-activated B cells is diversified by a hypermutation mechanism. Only high-affinity variants are selected into the pool of memory cells. This maturation process takes place in a special micro-environment, the germinal centre. Here, Claudia Berek and Mike Ziegner discuss the mechanisms underlying these processes.