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Decreased sialidase activity in alveolar macrophages of guinea pigs exposed to coal mine dust.

The origin of immune dysfunctions that are observed in pneumoconiotic miners still remains unknown. There is evidence that the carbohydrate moiety of membrane glycoconjugates is of primary importance in many functions of immunocompetent cells. The glycosylation, and especially the sialylation level of membrane components of various lymphocyte and macrophage subsets, vary depending on the state of cellular differentiation and activation. Sialidases, which may regulate the amount of sialic acids exposed on the cell membrane, can thus be considered as immunoregulatory enzymes. In this report, the sialidase activity has been measured in alveolar macrophages (AM) and in cell-free bronchoalveolar lavage fluid (BALF) from guinea pigs exposed for 4 months to coal mine dust at a concentration of 300 mg/m3. The samples were collected by bronchoalveolar lavage 2 months after cessation of exposure. The sialidase activity in the cell-free fluid and in the purified alveolar macrophages showed a 10-fold decrease (p less than 0.001). Kinetic parameters of the enzyme such as Km and optimum pH did not change. This changed activity was specific for sialidase, as two other lysosomal glycosidases, beta-galactosidase and N-acetylglucosaminidase, showed unchanged activities. These results suggest the possibility that, by inducing a decreased sialidase activity, exposure to coal mine dust may lead to a modified expression of AM membrane-associated sialic acids giving rise to altered immune functions (i. e., phagocytosis, antigen processing, response to cytokines, etc.).

Animals↗

Homocysteine induces DNA damage and alterations in proliferative capacity of T-lymphocytes: a model for immunosenescence?

Homocysteine (Hcy) appears to exert different effects on immune functions possibly contributing to age-related pathological states, including vascular diseases, immune dysfunction, and Alzheimer's disease. However, molecular mechanisms underlying Hcy toxicity need to be better characterized. Since T cells are a suitable model to address the possible role of replicative senescence during the in vivo aging, we investigated the effects of high Hcy concentrations on mitogen-activated lymphocytes, with regard to evaluation of DNA damage and cell cycle alterations. Cultured human peripheral blood lymphocytes were stimulated with mitogenic concanavalin A (5 microg/ml) for 48 h in the presence or absence of Hcy (1 mM). Both flow cytometric analysis and caspase-3 activity assay showed an increased rate of apoptosis in Hcy-treated lymphocyte cultures compared to controls. Further, Hcy exposure caused DNA fragmentation as evaluated by single cell gel electrophoresis showing the occurrence of comets. Cytokinesis-block micronucleus assay, performed after addition of cytochalasin B (5 microg/ml) and incubation up to 72 h, revealed a significantly higher frequency of micronucleated/binucleated cells in Hcy-treated cultures compared to controls (P < 0.001). Hcy also reduced cyclin B expression in comparison to control cultures, while cyclin D levels were not significantly affected. Cell cycle alterations, such as the inability of cells to enter into mitosis, could be related with DNA damage. These findings provided a link between perturbation of lymphocyte proliferation homeostasis and commitment towards apoptosis. Our results suggest the involvement of Hcy in the altered immune function associated with age and disease pathology.

Aging↗

Energetics of defective macrophage antigen presentation after hemorrhage as determined by ultraresolution 31P nuclear magnetic resonance spectrometry: restoration with adenosine triphosphate-MgCl2.

BACKGROUND: The purpose of this study was to determine whether a decrease in macrophage energetics contributes to the profound immune dysfunction that occurs after hemorrhage and, if so, whether adenosine triphosphate (ATP)-MgCl2 treatment has any beneficial effects on the above parameters. METHODS: C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 minutes, resuscitated with their own shed blood and Ringer's lactate, and treated with ATP-MgCl2 (80 mumol/kg body weight) or saline solution (vehicle). Peritoneal macrophages were harvested 1 hour after resuscitation and ATP levels were determined by 31P nuclear magnetic resonance spectrometry. In addition, macrophage functions were determined by measuring antigen presentation capacity (AP), as well as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) synthesis. RESULTS: Hemorrhage caused a significant decrease in peritoneal macrophage AP function, as well as IL-1, IL-6, and TNF synthesis, by 52% +/- 14%, 91% +/- 12%, 78% +/- 8%, and 89% +/- 8%, respectively, which was correlated with a 78% +/- 6% decrease in macrophage ATP levels (p less than 0.05). Treatment with ATP-MgCl2 after hemorrhage restored macrophage ATP levels (p less than 0.05) and significantly increased (p less than 0.05) macrophage AP, IL-1, IL-6, and TNF release by 110% +/- 21%, 130% +/- 38%, 124% +/- 17%, and 66% +/- 24%, respectively. CONCLUSIONS: The decreased macrophage ATP levels may be the cause of defective macrophage AP and cytokine release after hemorrhage, and both macrophage ATP levels and macrophage immune functions can be restored with adjuvant ATP-MgCl2 treatment after hemorrhage.

Adenosine Triphosphate↗

Cellular immune correlates of clinical severity in oral lichen planus: preliminary association with mood states.

OBJECTIVES: We investigated cellular immune and psycho-immune dysfunctions in patients with erosive and non-erosive oral lichen planus (OLP) lesions. METHODS: Patients with erosive or non-erosive OLP were screened at the UCLA Dental Clinic. The profile of mood states (POMS) was administered. T lymphocyte subpopulations were monitored by dual fluorescence. T lymphocytes were stimulated with phytohemagglutinin (PHA) for assessment of markers of activation by flow cytometry and of interleukin (IL)-2 production by ELISA. Plasma cortisol and neopterin levels were assessed by radioimmunoassay. RESULTS: Circulating T cells that express the cluster of differentiation no. 4 (CD4+) but devoid of the CD45RA marker, and POMS score were significantly associated (r = 0.83, P < 0.05) in the patients we studied. We found a significantly higher (P < 0.05) per cent and absolute lymphocyte numbers of circulating CD4+CD45RA- cells in the OLP patients with erosive lesions, compared to OLP patients with non-erosive lesions. The ratio of CD4+ CD45RA+ over CD4+CD45RA- cells was significantly (P < 0.05) biased toward the CD4+CD45RA- subpopulation in OLP patients with erosive lesions (ratio = 0.19 +/- 0.09) compared to patients with non-erosive OLP lesions (ratio = 0.47 +/- 0.15). The expression of CD54, but not that of CD69, was significantly blunted (P < 0.05) in OLP patients following CD3+ cell stimulation. IL-2 production and plasma neopterin were normal in these patients. There was no correlation between plasma cortisol and T cell populations. CONCLUSIONS: We find fine differences in psycho-immune interactions between patients afflicted with non-erosive OLP lesions compared to those with erosive OLP lesions.

Adult↗

Prenatal HgCl2 exposure in BALB/c mice: gender-specific effects on the ontogeny of the immune system.

Because mercury is highly toxic to developing organisms, we tested the hypothesis that prenatal exposure to HgCl(2) can induce persistent immune dysfunction. Pregnant BALB/c mice were administrated every other day, for 11 days with HgCl(2) (200 microg/kg). Their offspring were studied at PND10, 14, 21, and 60. Lymph nodes (LN), spleens, and thymus were harvested and proliferation and cytokine production were studied in vitro. We report that prenatal HgCl(2) exposure exerts organ-specific effects on cell number, proliferation, and cytokine production in pre-weaning pups. At adulthood (PND60), effects of prenatal HgCl(2) exposure were still observed, but expressed differently in females and males. In adult females, an inhibitory effect was observed on cytokine production by thymocytes, LN cells, and splenocytes. In males, a stimulatory effect was observed. Overall, we conclude that in vivo exposures to low doses of HgCl(2) can induce persistent sex-specific immunotoxic effects, observable in adulthood.

Animals↗

Thermal injury alters macrophage responses to prostaglandin E2: contribution to the enhancement of inducible nitric oxide synthase activity.

Prostaglandin E2 (PGE2) and macrophage (Mphi)-derived reactive nitrogen intermediates (RNI) have been implicated in T cell dysfunction after thermal injury. Normally, Mphi inducible nitric oxide synthase (iNOS) activity can be regulated by PGE2, however, it is unknown whether PGE2 modulates Mphi iNOS activity after thermal injury. Splenic Mphi isolated from mice 7 days after thermal injury produced higher levels of RNI than Mphi from sham mice when stimulated with lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in combination. PGE2, when added concurrently with LPS, suppressed RNI production by Mphi from sham mice, whereas Mphi from injured mice were unaffected. When Mphi were pretreated with PGE2 before LPS, RNI production was suppressed in both populations. RNI production in response to IFN-gamma or IFN-gamma and TNF-alpha in combination was enhanced by PGE2 in both populations, however, the effect was markedly greater in Mphi from injured mice. The PGE2-mediated changes in RNI production were paralleled by similar changes in iNOS protein expression, suggesting that the effect of PGE2 was at the level of enzyme expression rather than activity. Dibutryl cAMP induced similar effects as PGE2, suggesting the response to PGE2 after thermal injury is independent of potential changes in PGE2-induced adenylate cyclase activity and is cAMP-mediated. The results indicate that Mphi from burned mice display an altered sensitivity to PGE2, resulting in enhanced iNOS activity. Thus, PGE2, which is elevated after thermal injury and can directly suppress T cell function, may also contribute to immune dysfunction through the enhancement of Mphi iNOS activity.

Animals↗

A systematic review and critical evaluation of the immunology of chronic fatigue syndrome.

OBJECTIVE: Immune dysfunction in patients with chronic fatigue syndrome (CFS) has been widely but inconsistently reported. Traditional reviews of the literature have produced a variety of conclusions. We present the results of the first systematic review of the subject. METHODS: EMBASE, MEDLINE and PSYCHINFO databases were searched, and leading researchers in the field were contacted. Inclusion criteria were applied, and studies were then divided into groups based on the quality of their methodology. Study results were collated and described. RESULTS: Studies ranged widely in quality. There was an inverse association between study quality and finding low levels of natural killer cells, suggesting that the association may be related to study methodology. On the other hand, reports of abnormalities in T cells and cytokine levels were not related to study quality. CONCLUSIONS: The conclusions of this systematic review differ from a recent traditional narrative review of the immunology of CFS. No consistent pattern of immunological abnormalities is identified.

Cytokines↗

Signalling molecules and cytokine production in T cells of multiple myeloma-increased abnormalities with advancing stage.

T-cell immune dysfunction in patients with malignant tumours has been attributed to the altered expression of components of the T-cell receptor (TCR)/CD3 complex and their associated intracellular protein tyrosine kinases. In this study, four-colour flow cytometry was applied to study the surface bound molecules TCRalphabeta, CD28, CD152 and CD154 involved in T-cell signalling and the signal transduction molecules CD3zeta, p56lck, p59fyn, ZAP-70 and phosphatidyl-inositol-3 kinase (PI3-k) as well as the intracellular cytokines interferon-gamma (IFN-gamma), interleukin (IL)-4 and IL-2 as a functional read-out of non-stimulated and superantigen (staphylococcus enterotoxin B)-stimulated blood T cells of multiple myeloma (MM) patients at different stages of the disease. Multiple abnormalities were demonstrated in the CD4 and CD8 populations, both under non-stimulated and superantigen-stimulated conditions. There was a marked reduction, particular in advanced stage MM, in the proportion of CD4 and CD8 cells expressing CD28, CD152, CD3zeta, p56lck, ZAP-70 and PI3-k. The level of intracellular T-cell cytokines (IFN-gamma, IL-2 and IL-4) was normal or increased in non-stimulated cells but activation-induced cytokine production was impaired. These results illustrated profound and multiple T-cell signalling defects, from the surface and down-stream, consistent with involvement of a master T-cell function, especially in advanced stage MM. These data should be taken into consideration when developing immune-based therapeutic approaches and when applying new emerging technologies that aim to restore T-cell functions.

Aged↗

An overview of chronic fatigue syndrome.

BACKGROUND: Psychological and immunologic factors both appear to contribute to chronic fatigue syndrome (CFS). By comparing CFS with other disorders in which fatigue is a prominent symptom, the association between fatigue, psychological vulnerability, depression, and immune function may be further defined. Recent data from psychological, neurologic, and immunologic studies that address these issues are reviewed. METHOD: Articles and abstracts covering CFS and related topics of fatigue, depression, and postinfectious syndromes were identified through MEDLINE and Index Medicus (1980-1990) and by bibliographic review of pertinent review articles. RESULTS: The 1988 definition of CFS by the Centers for Disease Control encompasses several conditions in which the major characteristic is severe fatigue associated with constitutional symptoms. Several studies have identified immune dysfunction in CFS patients, but the specificity of these findings remains unclear. Most studies have shown that CFS patients, compared with other patients with chronic medical illness, experience more disabling fatigue. Some investigators have found a higher incidence of concurrent and past psychiatric illness in CFS patients compared with other medical patients, thereby suggesting an underlying psychopathology in CFS. However, other studies have not found a higher than expected incidence of past depression in CFS patients and have further shown that many CFS patients have no identifiable psychopathology. CONCLUSION: CFS appears to be a heterogenous entity. Although there may be a high coincidence of major depression in CFS, a substantial proportion of patients lack any identifiable DSM-III-R psychiatric disorder yet still manifest the syndrome, thereby suggesting it has an autonomous entity. Despite the evolving nature of our current understanding of CFS, a rational diagnostic and therapeutic approach to CFS is possible.

Comorbidity↗

Neuroendocrine responses mediate macrophage function after trauma.

BACKGROUND: Clearly understanding the interactions between macrophage (M phi)-generated inflammatory mediators and the neuroendocrine system in regulating immune function after traumatic injury may aid in reversing trauma-mediated immune dysfunction and diminish the incidence and severity of infection in the traumatized patient. METHODS: Trauma consisted of an open femur fracture and 40% retro-orbital hemorrhage (Trauma) or anesthesia alone (Control). Female Balb/C mice (6-8 weeks) with intact adrenal glands (Intact) or a bilateral adrenalectomy (ADX) were used. For glucocorticoid studies, corticosterone or a vehicle was administered via intraperitoneal (ip) injection 2 hours before the trauma. Splenic M phis were harvested and prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6) production, and mRNA, cyclooxygenase-2 (COX-2) protein, and nuclear factor kappa B (NF-kappa B) activity were measured. RESULTS: M phi, PGE(2) and IL-6 production in Trauma+Intact mice was significantly increased compared with Control+Intact mice. Adrenalectomy decreased these levels to Control levels. Similar changes were observed for COX-2 and IL-6 expression. M phi nuclear NF-kappa B levels were increased in Trauma+Intact mice compared with controls. Adrenalectomy abrogated this increase. Treating Trauma+Intact mice with RU-486 did not restore PGE(2) and IL-6 production or COX-2 and IL-6 messenger RNA to control levels. Administering exogenous glucocorticoid to Intact mice did not increase PGE(2) and IL-6 production or COX-2 and IL-6 mRNA to Trauma levels. CONCLUSIONS: The neuroendocrine system upregulates certain M phi inflammatory mediators, including PGE(2), IL-6, and NF-kappa B, after trauma. This upregulation does not seem to be mediated via glucocorticoids and possibly may be mediated via catecholamines. Elucidation of the interactions between the neuroendocrine system, the immune system, and inflammatory mediator secretion might provide novel therapeutic strategies for the injured patient.

Animals↗

Adenosine-deaminase-associated immunodeficiency. I. Differential sensitivities of lymphocyte subpopulations exposed to 2-deoxycoformycin in vivo.

In order to obtain a better understanding of the degree of immune dysfunctions caused by the absence of adenosine deaminase, we gave a single i.p. injection of 2'-deoxycoformycin (2-dcf), a potent inhibitor of the enzyme ADA at various doses into adult Syrian hamsters. These animals were examined for their ability to mount primary in vivo antibody responses to helper T cell dependent (Th-d) and helper T cell independent (Th-ind) antigens. Hamsters treated with 0.5 mg/kg of 2-dcf mounted enhanced splenic plaque-forming cell (PFC) responses to sheep erythrocytes, a Th-d antigen, and to pneumococcal polysaccharide type III (SIII), a Th-ind antigen. Treatment of animals with 1.0 mg/kg of 2-dcf resulted in a significantly depressed (P less than 0.001) PFC response to Th-d antigen, but a further enhanced response to Th-ind antigen. One mechanism which may be responsible for such a dichotomous response to these two types of antigens was selective dysfunction of T cell subpopulations. At higher doses (1.5-4.0 mg/kg), PFC responses to both types of antigens were significantly suppressed. Immunoenhancement at low doses of 2-def was attributed to an increased susceptibility of T suppressor cells to 2-dcf. This hypothesis was confirmed by priming the 2-dcf-treated animals with low-dose Th-ind antigens. These animals failed to induce low-dose tolerance by stimulation of antigen-specific suppressor T cell subsets. At low doses, B cells and T helper cell functions were found to be intact, as further confirmed by priming the animals with the carrier keyhole limpet haemocyanin (KLH) and challenging with trinitrophenyl-KLH. This dose-dependent selective susceptibility of various T cell subpopulations and B cells may explain the heterogeneity of clinical, biochemical and immunological parameters observed in children with ADA deficiency severe combined immunodeficiency.

Adenosine Deaminase↗

Altered cytokine expression in tissues of mice subjected to simulated microgravity.

Space flight is known to induce microgravity-associated immune dysfunction in humans, non-human primates and rodents. To understand the mechanism underlying these defects, several studies in rodents have been conducted in a ground-based antiorthostatic suspension (AOS) model that would mimic the effects of microgravity. In all these in vivo studies that showed the effects on cytokine profiles actually investigated the ex vivo production from culturing the cells isolated from whole organism that was exposed to space flight and/or microgravity. So, the purpose of the study was to examine the in vivo expression of cytokines in mice in immunologically important tissue environments of mice that were subjected to AOS. Cytokines such as Interleukin-1beta, (IL-1beta), IL-2, IL-3, IL-6, Interferon-gamma (IFN-gamma) and Tumor Necrosis Factor-alpha (TNF-alpha) were measured by Enzyme Linked Immunosorbent Assay (ELISA) in the homogenates of spleen tissue, lymph nodes and also in serum of AOS mice and compared with that of control mice. AOS induced no change in the IL-3 levels, but IL-1beta was increased significantly whereas IL-2 levels decreased in spleen, lymph nodes and serum. IL-6 levels did not differ in spleen but were significantly increased in lymph nodes and serum of AOS mice. IFN-gamma levels in spleen did not change but showed nonsignificant reduction in lymph nodes and significant reduction in serum in response to AOS. TNF-alpha levels in spleen and serum were unchanged and increased in lymph nodes. This in vivo cytokine study confirms the earlier findings that microgravity-simulated conditions induce tissue-specific immune response.

Animals↗

Altered CD46-mediated T cell co-stimulation in haemodialysis patients.

While most of our understanding of immune dysfunction in dialysis patients involves alterations in CD28-CD80/86 signalling, nothing is known of CD46-mediated co-stimulation of T cells in these patients. Because C3b/C4b bind to CD46 and complement activation occurs during haemodialysis (HD), we addressed whether CD46-mediated T cell activation is altered in HD (n = 9), peritoneal dialysis (PD) (n = 10) and predialysis patients (n = 8) compared to healthy controls (HC) (n = 8). T cell surface markers, T cell proliferation and interleukin (IL)-10 production were studied in CD4(+)T cells. In addition, CD46 splice-variants and IL-10 promoter gene polymorphisms were studied by reverse transcription (RT) or amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), respectively. In all uraemic patients, irrespective of the stage of renal insufficiency or dialysis modality, a significant increase in the percentage of CD25 positivity in naive CD4(+)T cells was found (64% +/- 21%versus 23% +/- 18%, P < 0.001). Lymphocytes of HD patients proliferated in greater numbers and produced more IL-10 after co-stimulation with anti-CD46 than after co-stimulation with anti-CD28. This was also found in CD4(+)T cells of PD patients, albeit to a lesser extent. In contrast, with T cells of predialysis patients and of HC, co-stimulation via CD28 was more efficient. The observed alterations in T cell proliferation and IL-10 production were associated neither with CD46 splice variants nor with IL-10 promoter gene polymorphisms. Lymphocytes of HD patients show an increased response on CD46 co-stimulation. These data suggest that ongoing complement activation in HD patients may lead to alterations in acquired immunity.

Aged↗

Isolated peripheral T cells from GvHR recipients exhibit defective IL-2R expression, IL-2 production, and proliferation in response to activation stimuli.

Graft-vs-host reactions (GvHR) following the injection of class I/II MHC disparate parental cells into unirradiated F1 recipient mice result in the development of marked immune dysfunction. Following negative selection using adherence and antibody and complement depletion, highly purified T cells were examined to determine their ability to undergo activation. Three weeks after GvHR initiation, unstimulated splenic T cells from GvHR mice displayed normal CD3 and IL-2R expression but elevated expression of class I MHC and Ly-6A/E antigens. Despite culture with normal F1 accessory cells, both CD4+ and CD8+ GvHR T cells exhibited low levels of proliferation to both Con A and anti-CD3 mAb. Although following exposure for 12 h to either of these stimuli, GvHR T cells expressed normal levels of IL-2R, expression was greatly decreased vs normal T cells between 24 and 48 h. In addition, at no timepoint was detectable IL-2 produced by GvHR T cells. Importantly, mixing experiments did not demonstrate detectable suppressive activity in the purified GvHR T cell subsets. GvHR T cells were also tested for their ability to respond to stimuli in the absence of any accessory cell population. These cells again did not proliferate to levels equivalent to normal T cells. Incubation with PMA and either cytokines (Con A supernatant, rIL-7) or anti-CD3 mAb resulted in only low levels of proliferation in GvHR T cells. Notably, at high ionomycin concentrations together with PMA, GvHR T cells did proliferate to equivalent levels as normal cells. However, with decreasing concentrations of ionophore, these cells failed to proliferate as well as normal cells. In total, these findings demonstrate that GvHR T cells are phenotypically and functionally distinct from normal T cells. The results suggest that GvHR T cells themselves may contribute to the well-characterized immune depression occurring in recipients undergoing GvHR.

Animals↗

Alterations in sympathetic innervation of thymus and spleen in aged mice.

Age is associated with reduced immune reactivity, contributing to increased rates of infectious disease and cancer in old age. We have begun to assess the potential for sympathetic nervous system involvement in age-related immune dysfunction by characterizing sympathetic noradrenergic (NA) innervation in lymphoid organs in old animals. In the present study noradrenergic innervation of spleen and thymus was examined histologically and neurochemically in 2-, 12- and 24-month old BALB/c mice. In the thymus of 2-month old animals, NA nerve fibers were found in the subcapsular, cortical, and cortico-medullary regions associated with blood vessels and septa; occasional branches from these nerve fibers entered the parenchyma. With increasing age and thymic involution, NA nerve fibers increased in density; by 24 months of age, dense plexuses were compacted among septa and blood vessels, and numerous linear, varicose nerve fibers were observed branching into the parenchyma. Thymic norepinephrine (NE) concentration (per mg wet weight) increased approximately 4-fold in 12-month old animals and 15-fold in 24-month old animals. Taking the reduced thymus weight into account, total thymic NE at 12- and 24-month of age was equivalent to total thymic NE at 2-month of age, suggesting that NA innervation is maintained as the thymus involutes. In the spleen from 2-month old animals, NA innervation entered the white pulp with the central artery to innervate the periarteriolar lymphatic sheath and the marginal zone. At 12-month of age, histologically and neurochemically there was no change in splenic NA innervation. By 24-month of age, NE was increased significantly, independent of changes in spleen weight. Histologically, increased catecholamine-containing fibers were apparent at 24-month of age, particularly in the parenchyma surrounding the central artery. The alterations in sympathetic NA innervation of lymphoid organs with age suggest that the sympathetic nervous system and NE may play a role in age-associated immune dysregulation. Alternatively, the changes in NA innervation may be secondary to functional changes within the immune system.

Age Factors↗

African trypanosomiasis alters prostaglandin production by murine peritoneal macrophages.

Many factors contribute to the severe immunosuppression associated with African trypanosomiasis. Macrophages have been shown to be important target cells which after uptake of parasites, mediate immune dysfunction in vivo. We observed that infection of mice with Trypanosome brucei brucei (clone NIM 6) induces profound changes in arachidonic acid metabolism and prostaglandin (PG) secretion by macrophages. Normal macrophages release more PGI2 than PGE2 and production of both these prostaglandins is stimulated equally by endotoxin (LPS). Macrophages taken from NIM 6 infected mice at the peak of the first parasitaemia, release increased amounts of PGE2 and are hyperresponsive to LPS stimulation, while PGI2 secretion remains normal. As the infection progresses, there is a striking decrease in both basal PGE2 and PGI2 secretion and the ability of macrophages to respond to LPS. By the third week of infection, shortly before death, peritoneal macrophages resemble thioglycollate elicited macrophages in their inability to be stimulated by LPS to synthesize prostaglandins. Infection with a more virulent clone of T. brucei (NIM9) results in suppression of both PGE2 and PGI2 release by day 9 of infection. The increased production of PGE2 by macrophages during the height of infection is likely to contribute to the general immunosuppression associated with African trypanosomiasis.

Animals↗

Immunologic aspects of West syndrome and evidence of plasma inhibitory effects on T cell function.

STUDY OBJECTIVE: The purpose of this study was to assess the extent of immune dysfunction in a well-defined group of epileptic patients: children with diagnosis of West syndrome (WS) or with transitions to another age-related EEG patterns, the multifocal independent spikes (MIS), and the slow spike-wave complexes (Lennox-Gastaut syndrome - LGS). Thus, WS was studied at different points of the natural evolutive history of the disease. METHOD: A group of 50 patients (33 with WS, 10 with LGS and 7 with MIS) and 20 age-matched healthy controls were submitted to enumeration of T lymphocyte subsets: CD1, CD3, CD4, CD8, CD4/CD8 ratio and lymphocyte proliferation assay to phytohaemagglutinin (PHA), in the presence of autologous and AB, homologous plasma. Dinitrochlorobenzene (DNCB) skin test sensitization was performed only in patients. Determinations of IgG, IgA, and IgM serum levels were compared to standard values for Brazilian population in different age ranges. RESULTS: Sensitization to DNCB showed absent or low skin reactions in 76% of the patients. High levels of IgG (45.7%) and IgM (61.4%), and lower levels of IgA (23.9%) were detected in the serum of the patients. Enumeration of lymphocyte subsets in peripheral blood showed: low CD3+ (p<0.05), low CD4+ (p<0.05), high CD8+ (p<0.01) and low CD4+ / CD8+ ratio (p<0.001). The proportion of CD1+ cells in the control group was less than 3%, while ranged between 6 and 11 % in 18% of the patients. The in vitro PHA-induced T cell proliferation showed significantly low blastogenic indices only when patients, cells were cultured in presence of their own plasma. No differences in blastogenic indices were observed when the cells of patients and controls were cultured with human AB plasma. CONCLUSION: The immunodeficiency in WS was mainly characterized by anergy, impaired cell-mediated immunity, altered levels of immunoglobulins, presence of immature thymocytes in peripheral blood and functional impairment of T lymphocytes induced by plasma inhibitory factors.

Antigens, CD↗

Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients.

In an attempt to define potential immunological dysfunctions in schizophrenia, we determined the production of interleukin-2 (IL-2), interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and soluble IL-2 receptor (sIL-2R) in a whole-blood assay after stimulation with phytohemagglutinin (PHA) as well as the serum concentrations of sIL-2R. Because CD4+CD45RO+T cells are the main producers of IFN-gamma, we determined the percentage of these cells, as well as of panT, CD4+T, and CD8+T cells, by flow cytometry. A whole-blood count was performed in addition. Two groups of patients were examined, paranoid-type and residual-type schizophrenics. The numbers of both monocytes and neutrophils, but not of lymphocytes, were increased significantly in the schizophrenic sample. The IFN-gamma production of the schizophrenics as a whole group, and of the paranoid patients, was reduced significantly in comparison with the control group (p < or = 0.05). The residual patients produced less IFN-gamma than the controls, but more than the paranoid patients. The latter differences did not reach statistical significance. The production of IL-4, which physiologically antagonizes the production of IFN-gamma, was not significantly higher in the patient group. No changes in the lymphocyte subpopulations were observed. The production of IL-2 showed a trend toward reduction in paranoid patients, but not in residual schizophrenics. The serum sIL-2R levels were elevated slightly in schizophrenics when compared with controls. In order to rule out a possible effect of cortisol on cytokine production, 20 schizophrenics were compared with 20 age- and gender-matched controls. However, neither elevated cortisol levels were detected in the schizophrenic sample, nor significant intercorrelations between cortisol levels and cytokine production, or levels of sIL-2R, respectively. In summary, our data reinforce the possibility of immune dysfunction in schizophrenia and point to the possible relevance of disease subgroups in this respect.

Adult↗