Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major infections, such as sepsis and pneumonia, occur in 50-75% of patients following isolated severe head injury. Previous studies have demonstrated that this high incidence of infection following severe head injury may be related to a decrease in helper T-cell activation and function. The present study was designed to investigate the effect of severe head injury on specific subgroups of helper T cells known to enhance or suppress cellular immune function. Specifically, peripheral blood lymphocytes (PBLs) from 10 head-injured patients and 10 matched controls were evaluated following in vitro stimulation with the T-cell mitogen, phytohemagglutinin (PHA). Subsets of helper T cells evaluated included activated helper (CD4+/CD25+) T cells; helper/inducer (CD4+/CDw29+) T cells, which enhance cellular immune activity; and suppressor/inducer (CD4+/CD45R+) T-cells, which induce suppressor (CD8+) T-cells. In addition, the effect of intraventricular fluid (IVF) on PHA-stimulated in vitro CD4 and CD25 expression was investigated to determine whether severe head injury results in the production of mediators within the central nervous system capable of affecting T-cell activation. The results of this study indicate that isolated severe head injury selectively reduces the ability of PHA-stimulated PBLs to express the helper/inducer (CD4+/CDw29+) T-cell (p = 0.023) and activated helper (CD4+/CD25+) T-cell (P = 0.041) phenotypes. There was no significant change in PHA-stimulated CD4 or CD25 expression following incubation of PBLs with intraventricular fluid (IVF) from head-injured patients. The relationship between these changes in specific helper T-cell subpopulations and the infectious complications of severe head injury are discussed.
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PMID:Impairment of helper T-cell function following severe head injury. 137 52

Acute graft-versus-host disease (GVHD) is effected by donor T lymphocytes which have been stimulated by host antigens. Activated donor T lymphocytes express interleukin-2 receptor (IL-2R), which is comprised of three subunits (alpha, beta, gamma). During activation, the a IL-2R subunit (CD25) is shed from the receptor complex and can be measured in the circulation. Soluble IL-2Ralpha (sIL-2R) levels are increased in states of immune activation including GVHD, and could theoretically be used as a guide to therapy. Since IL-2Ralpha expression is an early marker of T cell activation, we investigated: (1) if an increase in sIL-2R is specific for acute GVHD; and (2) if serial sIL-2R levels can identify patients with early GVHD, prior to the onset of clinical tissue damage (effector function). Weekly sIL-2R levels were monitored in 36 patients undergoing matched related (n=23) or matched unrelated (n=13) allogeneic bone marrow transplantation (BMT). There was no significant difference in sIL-2R levels between matched related and matched unrelated recipients. Patients with acute GVHD (n=19, 53%) demonstrated higher sIL-2R levels, than those without during weeks 2 and 3 post-BMT (P=0.02 and 0.04, Mann-Whitney U test, two-tailed). In patients with acute GVHD, the rise in sIL-2R preceded the clinical signs of GVHD (16/19 patients). However, patients with sepsis demonstrated a trend towards higher sIL-2R levels at week 1 and significantly greater levels by week 4 (P=0.02). Furthermore, patients with veno-occlusive disease (VOD) (25%) also had significantly higher sIL-2R levels at week 2 (P=0.03). We conclude that although sIL-2R levels increase in patients with acute GVHD, similar increases are seen in patients with VOD and/or sepsis and therefore, as a single biochemical marker, we find that serial measurements of sIL-2R lacks sufficient specificity to guide GVHD therapy.
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PMID:Monitoring soluble interleukin-2 receptor levels in related and unrelated donor allogenic bone marrow transplantation. 960 99

Changes in the time courses of serum levels of interleukin-6 (IL6) and the soluble form of CD25 (sCD25) were evaluated in 48 burned patients (31 had sepsis, 21 died). Differences among groups along the time were assessed with ANOVA. The Pearson's r correlation coefficient was used to relate quantitative variables. ROC curves were constructed to analyse the prognostic value of IL6 and sCD25. The values of IL6 and sCD25 were related to treatment outcome and time post-burn. In general, two patterns emerged: In non-survivors, there was a depression of sCD25 with time, and an increase in IL6 levels previous to death, whereas survivors had the opposite pattern. On admission, patients with higher levels of sCD25 had a bad prognosis.
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PMID:Dynamic profiles of interleukin-6 and the soluble form of CD25 in burned patients. 1049 55

This study aims to evaluate the diagnostic utilities of four leukocyte surface antigens-two lymphocyte antigens (CD25 and CD45RO) and two neutrophil antigens (CD11b and CD64)-for identification of late-onset nosocomial bacterial infection in preterm, very low birthweight infants, and to define the optimal cutoff value for each marker so that it may act as a reference with which future studies can be compared. Very low birthweight infants in whom infection was suspected when they were >72 h of age were eligible for the study. A full sepsis screen was performed in each episode. IL-6, C-reactive protein, and leukocyte surface antigens (CD25, CD45RO, CD11b, and CD64) were measured at 0 (at the time of sepsis evaluation), 24, and 48 h by standard biochemical methods and quantitative flow cytometric analysis. The diagnostic utilities including sensitivity, specificity, and positive and negative predictive values of each marker and combination of markers for predicting late-onset neonatal infection were determined. One hundred twenty-seven episodes of suspected clinical sepsis were investigated in 80 infants. Thirty-seven episodes were proven infection. The calculated optimal cutoff values for CD25, CD45RO, CD11b, and CD64 were 3,100, 2,900, 10,450, and 4,000 phycoerythrin-molecules bound per cell, respectively. An interim analysis of data after 68 episodes suggested that CD25 and CD45RO were poor predictors of neonatal infection with sensitivity or specificity <75% during a single measurement. Thus, these two markers were excluded from further investigation. In the final analysis, CD64 has the highest sensitivity (95-97%) and negative predictive value (97-99%) at 0 and 24 h after the onset. The addition of IL-6 or C-reactive protein (0 h) to CD64 (24 h) further enhanced the sensitivity and negative predictive value to 100%, and has the specificity and positive predictive value exceeding 88% and 80%, respectively. Neutrophil CD64 expression is a very sensitive marker for diagnosing late-onset nosocomial infection in very low birthweight infants. If further validated, the use of CD64 as an infection marker should allow early discontinuation of antibiotic treatment at 24 h without waiting for the definitive microbiologic culture results. The quantitative flow cytometric analysis applied in this study could be developed into a routine clinical test with high comparability and reproducibility across different laboratories.
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PMID:Neutrophil CD64 expression: a sensitive diagnostic marker for late-onset nosocomial infection in very low birthweight infants. 1186 33

Streptococcus pneumoniae is a leading cause of gram-positive sepsis, and lipoteichoic acid (LTA) may be important in causing gram-positive bacterial septic shock. Even though pneumococcal LTA is structurally distinct from the LTA of other gram-positive bacteria, the immunological properties of pneumococcal LTA have not been well characterized. We have investigated the ability of LTAs to stimulate human monocytes by using highly pure and structurally intact preparations of pneumococcal LTA and its two structural variants. The variants were pneumococcal LTA with only one acyl chain (LTA-1) and completely deacylated LTA (LTA-0). The target cells used in the study were peripheral blood mononuclear cells (PBMCs) and two model cell lines (CHO/CD14/TLR2 and CHO/CD14/TLR4) that express human CD25 protein in response to Toll-like receptor 2 (TLR2) and TLR4 stimulation, respectively. Intact pneumococcal LTA and LTA-1 stimulated PBMC and CHO/CD14/TLR2 cells in a dose-dependent manner but did not stimulate CHO/CD14/TLR4 cells. Pneumococcal LTA was about 100-fold less potent than Staphylococcus aureus LTA in stimulating the CHO/CD14/TLR2 cells and PBMCs. LTA-0 (or pneumococcal teichoic acid) stimulated neither CHO/CD14/TLR2 nor CHO/CD14/TLR4 cells even at high concentrations. Excess teichoic acid, LTA-0, antibodies to phosphocholine, or antibodies to TLR4 did not inhibit the LTA-induced TLR2 stimulation. However, antibodies to CD14, TLR1, or TLR2 suppressed tumor necrosis factor alpha (TNF-alpha) production by PBMCs in response to LTA or LTA-1. These results suggest that pneumococcal LTA with one or both acyl chains stimulates PBMCs primarily via TLR2 with the help of CD14 and TLR1.
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PMID:Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. 1450 Apr 72

Diagnosis of congenital or neonatal infection is often based on clinical signs. However, clinical symptoms of infections may not be specific, and for this reason early diagnosis is often determined on results of laboratory tests, which may not currently be adequate. A more reliable method of detection of infection may be the demonstration of activated lymphocytes, which can be conducted rapidly and before the isolation of the infected organism. We have shown that detection of up-regulation of CD45RO, an activated/memory isoform of CD45 present on T cells, provides a reasonably sensitive screening test for neonatal infection. We also showed that dual expression of CD45RA/CD45RO was up-regulated early during the infective process in neonates with documented infection. However, other leucocytes are also activated during the infective process. To improve the sensitivity of the neonatal infection screening test and to identify the types of leucocytes involved in the immune response to the infective organism, we studied further the up-regulation of a comprehensive range of surface activation markers on T cells, monocytes and natural killer (NK) cells from a group of 17 newborn patients with positive culture, a group of 40 possibly infected patients based on clinical signs and a control group. 'Normal' ranges were established for each activation marker for each leucocyte subset from 1 to 7 and 7-14-day-old newborns <35 weeks' gestation and 35-40 weeks' gestation. There was a significant increase in the percentage of T cells expressing CD25 in the peripheral blood from infants at 2 weeks of age. Expression of HLA-DR on T cells, CD25 and CD69 on monocytes and HLA-DR on NK cells was also increased significantly in the peripheral blood from infants at 2 weeks of age and may reflect a maturation of these functional surface molecules. Up-regulation of CD69 on NK cells was the most sensitive marker for neonatal sepsis (positive in 13/16 patients). CD69 and CD25 expression was increased significantly on T cells in 11/17 and 10/17 patients, respectively. A combination of CD45RA/CD45RO and CD45RO identified 11/16 infected patients. Measurement of CD69 expression on NK cells with CD45RA, CD45RO, CD25 and CD69 expression on T cells resulted in a significant increase in at least two leucocyte activation markers from infected patients. In conclusion, this is the first report of the up-regulation of CD69 on NK cells as a sensitive marker of neonatal infection. A combination of this marker with CD45RA, CD45RO, CD25 and CD69 expression on peripheral blood derived T cells is the most sensitive and specific for neonatal infection.
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PMID:Multiple leucocyte activation markers to detect neonatal infection. 1467 73

Regulatory CD4(+)CD25(+) T cells (Tregs) suppress autoimmune and inflammatory diseases through mechanisms that are only partly understood. Previous studies suggest that Tregs can suppress bacterially triggered intestinal inflammation and respond to LPS through TLRs with enhanced suppressive activity. In this study, we have used murine cecal ligation and puncture as a model of polymicrobial sepsis to explore the effects of adoptive transfer of Tregs on septic outcome. Adoptive transfer of in vitro-stimulated Tregs in both prevention and therapeutic modes significantly improved survival of cecal ligation and puncture mice. Furthermore, the effect was dependent on both the number of Tregs adoptively transferred and the presence of host T cells. Animals that received stimulated Tregs had significantly increased peritoneal mast cells and peritoneal TNF-alpha production. More importantly, adoptive transfer of in vitro-stimulated Tregs significantly improved bacterial clearance, which resulted in improved survival. Our results suggest a novel role for Tregs in sepsis.
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PMID:Adoptive transfer of in vitro-stimulated CD4+CD25+ regulatory T cells increases bacterial clearance and improves survival in polymicrobial sepsis. 1590 57

Flagellin, the principal component of bacterial flagella, is a ligand for Toll-like receptor 5 (TLR5) or TLR11 and contributes to systemic inflammation during sepsis through activation of dendritic cells (DCs) and other cells of the innate immune system. Here, we report that flagellin and the TLR4 ligand, lipopolysaccharide (LPS), induced phenotypic and functional maturation of murine bone marrow-derived DCs and enhanced DC accumulation in the draining popliteal lymph node following their footpad injection. It is interesting that flagellin injection enhanced myeloid (CD8alpha(-1)) and plasmacytoid (plasmacytoid DC antigen(+) B220(+)) DC subsets, whereas LPS only increased myeloid DCs in the draining lymph node. In addition, the footpad injection of flagellin or LPS induced significant CD4(+) T cell activation in the draining popliteal lymph node, as judged by increased CD69 or CD25 expression. We illustrate, for the first time, that flagellin also increases natural killer (NK) cell number and activation status in the draining lymph node after footpad injection. Using coculture with enriched carboxy-fluorescein diacetate succinimidyl ester-labeled NK cells, flagellin-treated DCs induce significant NK cell proliferation and activation. In fact, direct treatment of NK cells with flagellin induces a greater increase in cell proliferation than treatment with LPS. In contrast, flagellin treatment of NK cells was not a strong inducer of interferon-gamma (IFN-gamma) production, indicating that NK cell proliferation and IFN-gamma production may be regulated differentially. These data suggest that flagellin is a capable maturation agent for murine myeloid-derived DCs, and flagellin-activated DCs and flagellin itself are potent inducers of NK cell proliferation.
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PMID:Flagellin enhances NK cell proliferation and activation directly and through dendritic cell-NK cell interactions. 1603 15

Regulatory T cells (Tregs), including natural CD4+CD25+ Tregs and inducible IL-10 producing T regulatory type 1 (T(R)1) cells, maintain tolerance and inhibit autoimmunity. Recently, increased percentages of Tregs have been observed in the blood of septic patients, and ex vivo-activated Tregs were shown to prevent polymicrobial sepsis mortality. Whether endogenous Tregs contribute to sepsis outcome remains unclear. Polymicrobial sepsis, induced by cecal ligation and puncture, caused an increased number of splenic Tregs compared with sham-treated mice. Splenic CD4+CD25+ T cells from septic mice expressed higher levels of Foxp3 mRNA and were more efficient suppressors of CD4+CD25- T effector cell proliferation. Isolated CD4+ T cells from septic mice displayed increased intracellular IL-10 staining following stimulation, indicating that T(R)1 cells may also be elevated in sepsis. Surprisingly, Ab depletion of total CD4+ or CD4+CD25+ populations did not affect mortality. Furthermore, no difference in survival outcome was found between CD25 or IL-10 null mice and wild-type littermates, indicating that Treg or T(R)1-generated IL-10 are not required for survival. These results demonstrate that, although sepsis causes a relative increase in Treg number and increases their suppressive function, their presence does not contribute significantly to overall survival in this model.
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PMID:Increased natural CD4+CD25+ regulatory T cells and their suppressor activity do not contribute to mortality in murine polymicrobial sepsis. 1711 66

Studies have indicated that there is a development of generalized immune dysfunction after septic insult. However, the mechanisms responsible for these changes remain unclear. Recently, accumulating evidence shows that several lymphocyte subpopulations such as NKT-, CD4(+)-Th2-T-, CD8(+)-T-, gammadelta-T-, and CD4+ CD25+ T regulatory cells are capable of actively contributing to the induction of septic immune suppression. Thus, our aim was to investigate the contribution of CD4+ CD25+ cells to the immune dysfunction seen in sepsis. To study this, C57BL/6J, C57BL/6-Il6(tm1Kopf) (interleukin [IL] 6 -/-), and C57BL/6-Il10(tm1Cgn) (IL-10 -/-) mice were subjected to cecal ligation and puncture (CLP) or sham operations. Twenty-four hours later, blood was collected, and splenocytes were isolated. Phenotypic expression of CD4/CD25 (by fluorescence-activated cell sorter), cell proliferation (presented as proliferation index = [with anti-CD3]/[without anti-CD3]), and immune suppressive capacity (by in vitro add-back experiments) were assessed. The results indicate a marked elevation in CD4+ CD25+ cell levels and their proliferation index after sepsis in background mice. CD4+ CD25- cells from sham and CLP mice proliferated equally. However, coculture of CD4+ CD25- with CD4+ CD25+ cells suppressed their proliferation in both sham and CLP mice. Depletion of CD25+ cells in vivo before CLP markedly restored CD4+ CD25- proliferative capacity and Th1 cytokine release while not altering plasma proinflammatory cytokine levels. Subsequently, IL-6 -/- and IL-10 -/- mice were used to elucidate the possible mediator(s) regulating the changes seen after sepsis. Although CD4+ CD25+ cells increased after septic insult in both C57BL/6J and IL-6 -/- mice, this was not observed in IL-10 -/- mice. Similarly, in vitro proliferation studies showed that proliferation index increased in CD4+ CD25+ cells from septic C57BL/6J and IL6 -/- mice, but it remained the same in IL-10 -/- mice. Surprisingly, depletion of CD25+ cells before inducing sepsis did not alter septic mortality. Together, these findings suggest that although CD4+ CD25+ T regulatory cells induced by IL-10 seem to contribute to aspects of sepsis-induced lymphoid immune suppression, the oblation of CD25+ cells does not provide a survival advantage or disadvantage.
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PMID:The contribution of CD4+ CD25+ T-regulatory-cells to immune suppression in sepsis. 1730 5


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