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)

Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1(+)CD11b(+) population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1(+) cells effectively suppress antigen-specific CD8(+) T cell interferon (IFN) gamma production but only modestly suppress antigen-specific and nonspecific CD4(+) T cell proliferation. GR-1(+) cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell-dependent and depression of Th1 cell-dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain-containing adaptor-inducing IFN-beta, or the IFN-alpha/beta receptor, is required for complete GR-1(+)CD11b(+) expansion. GR-1(+)CD11b(+) cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.
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PMID:MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. 1754 19

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8(+) T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8(+) and CD4(+) T cells) versus the liver (increased FasL expression on CD8(+) T cells and increase in percentage/number). Adoptive transfer of CLP FasL(+/+) versus FasL(-/-) mouse liver CD8(+) T cells to severe combined immunodeficient or RAG1(-/-) recipient mice indicated that these cells could induce inflammation. The FasL-mediated cytotoxic capacity of these septic mouse liver CD8(+) T cells was shown by their ability to damage directly cultured hepatocytes. Finally, although CD8(-/-) mice exhibited a reduction in both CLP-induced liver active caspase-3 staining and blood interleukin-6 levels, only FasL(-/-) (but not CD8(-/-)) protected the septic mouse spleen from increasing apoptosis. Thus, although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level.
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PMID:CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL. 1759 56

Apoptosis of CD4(+) T cells and T(H)2 polarization are hallmarks of sepsis-induced immunoparalysis. In this study, we characterized sepsis-induced adaptive immune dysfunction and examined whether improving T-cell effector function can improve outcome to sepsis. We found that septic mice produced less antigen-specific T-cell-dependent IgM and IgG(2a) antibodies than sham-treated mice. As early as 24 hours after sepsis, CD4(+) T cells proliferated poorly to T-cell receptor stimulation, despite normal responses to phorbol myristate acetate and ionomycin, and possessed decreased levels of CD3zeta. Five days following immunization, CD4(+) T cells from septic mice displayed decreased antigen-specific proliferation and production of IL-2 and IFN-gamma but showed no difference in IL-4, IL-5, or IL-10 production. Treatment of mice with anti-GITR agonistic antibody restored CD4(+) T-cell proliferation, increased T(H)1 and T(H)2 cytokine production, partially prevented CD3zeta down-regulation, decreased bacteremia, and increased sepsis survival. Depletion of CD4(+) T cells but not CD25(+) regulatory T cells eliminated the survival benefit of anti-GITR treatment. These results indicate that CD4(+) T-cell dysfunction is a key component of sepsis and that improving T-cell effector function may be protective against sepsis-associated immunoparalysis.
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PMID:Treatment with GITR agonistic antibody corrects adaptive immune dysfunction in sepsis. 1769 Feb 55

Rebuilding and maintaining immunity are paramount to the success of cancer immunotherapy and hematopoietic stem cell transplantation. If immune surveillance indeed can protect from cancer, the very manifestation of malignancy means that the disease has prevailed over immunity. Yet, often, tumor-specific T cells can be found in cancer patients irrespective of vaccination. Interestingly, patients suffering from malignancy often harbor unexpectedly high levels of immature CD14(+)HLA-DR(-) monocytes, although the abundance of CD4(+) cells, CD8(+) cells and CD4(+)CD25(high) cells may be normal. It is plausible that in cancer such cells suppress T cell function, analogous to CD14(+)HLA-DR(-) cells in sepsis and major trauma, in addition to their likely failure to re-present tumor-associated antigens once dendritic cells have initiated the T cell response. Recent evidence indicates that tumor-borne adenosine, lactate and hypoxia in the tumor environment may modulate tumor-specific immunity to a significant extent, but their effects on myeloid cell function are unclear. Thus, understanding and controlling these factors may appreciably impact the success of rebuilding and maintaining immunity in cancer patients.
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PMID:Rebuilding immunity in cancer patients. 1782 37

In this report, the authors present a detailed immunological and virological assessment of an immunocompetent 17-year-old Caucasian male with a fatal Epstein-Barr virus (EBV) infectious mononucleosis presenting with meningoencephalitis and hemophagocytic syndrome. The patient with serologically confirmed EBV infectious mononucleosis was admitted to the hospital because of 3 weeks' fever. Fine-needle aspiration of lymph nodes showed reactive hyperplasia with prominent hemophagocytosis. Percentages of intracellular interferon-gamma (IFN-gamma) in CD4(+) and CD8(+) T cells in the peripheral blood progressively increased during the course of disease (10.2% and 8.5% on day 35; 30.1% and 53.2% on day 44; 42.2% and 75.2% on day 50; 36.1% and 50.6% on day 59, respectively). On day 50, the patient developed meningoencephalitis. Brain computed tomography (CT) was normal. Brain magnetic resonance imaging (MRI) showed multifocal inflammatory lesions in frontal and temporal cortex of the right hemisphere as well as severe perivascular inflammatory reaction. The patient was treated with steroids, cyclosporin A, and methotrexate intratecally. Following treatment, EBV viremia in the blood and cerebrospinal fluid (CSF) decreased from pretreatment values (54,490 copies of EBV DNA/ml and 39,500 copies/ml, respectively) to 8715 copies/ml in the blood and 14,690 in the CSF. Despite treatment, the patient remained unconscious and died of sepsis and pneumonia 3 months after initial symptoms. Immunohistochemical staining showed the presence of EBV in both perivascular infiltrates and grey matter. Enhanced Th1 response as shown by high levels of IFN-gamma in peripheral blood lymphocytes may be a predictor of severe complications during acute EBV infection. Early implementation of immunosuppressive therapy in these patients should be considered.
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PMID:Virological and immunological characteristics of fatal Epstein-Barr virus mononucleosis in a 17-year-old Caucasian male presenting with meningoencephalitis and hemophagocytic syndrome. 1784 23

It is well established that the immune response to sepsis is mediated by leukocytes associated with the innate immune system. However, there is an emerging view that T lymphocytes can also mediate this response. Here, we observed a significant depletion of both CD4 and CD8 T cells in human patients after blunt trauma. To determine what effect the loss of these cells may have during a subsequent infection, we obtained CD4- and CD8-deficient mice and subjected them to cecal ligation and puncture (CLP). We observed that CD4 knockout (KO) mice showed increased CLP-induced mortality compared with CD8-deficient and wild-type (WT) mice especially within the first 30 h of injury. CD4 KO mice also exhibited significantly increased IL-6 concentrations after the CLP. The CD4 KO mice had an increased concentration of bacteremia as compared with WT mice. Antibiotic treatment decreased mortality in the CD4 KO mice as compared with no changes in the wild mice after CLP. Neutrophils isolated from septic CD4 KO mice showed decreased spontaneous oxidative burst compared with neutrophils taken from septic controls. We examined the role of IFN-gamma by using mice deficient in this cytokine and found these mice to have significantly higher mortality as compared with WT mice. Finally, we detected a 2-fold increase in CD11b+ cells that exhibited intracellular IFN-gamma staining in the peritoneum of WT mice after CLP. The data suggest that CD4+ cells may facilitate the early clearance of bacteria by regulating neutrophils function possibly through an IFN-gamma-dependent mechanism.
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PMID:CD4-expressing cells are early mediators of the innate immune system during sepsis. 1788 47

To study the role of T cells in gram-negative sepsis, we developed a mouse model in which i.v. injection of Escherichia coli results in severe systemic illness, with high mortality rates after day 5. A large proportion of both CD4(+) and CD8(+) T cells are activated within 1 day after infection, as evidenced by up-regulation of CD69 and down-regulation of CD62L. Even more surprisingly, T cell-deficient mice exhibit markedly decreased disease severity compared to WT mice, indicating a pathogenic role of T cells. Mice lacking IFN-gamma also show diminished disease, and exhibit reduced T cell activation. Therefore, the pathogenic role of T cells may be mediated by IFN-gamma. Both T cell- and IFN-gamma-deficient mice have reduced serum IL-6 levels compared to WT mice, suggesting that T cells may stimulate innate immune responses, resulting in enhancement of disease. These data indicate an important role for T cells in a mouse model of E. coli sepsis, and reveal an unexpected early and pathogenic T cell response to this bacterial infection.
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PMID:Role of T cells in a murine model of Escherichia coli sepsis. 1794 64

Pathogenic bacteria use quorum-sensing signal molecules to co-ordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. In the present study, we have examined the impact of these molecules on normal human immune function in vitro and compared this with immune changes in patients with sepsis where quorum-sensing signal molecules were detected in the sera of patients. Quorum-sensing signal molecules inhibited normal dendritic cell and T-cell activation and proliferation, and down-regulated the expression of co-stimulatory molecules on dendritic cells; in MLDCRs (mixed lymphocyte dendritic cell reactions), secretion of IL (interleukin)-4 and IL-10 was enhanced, but TNF-alpha (tumour necrosis factor-alpha), IFN-gamma (interferon-gamma) and IL-6 was reduced. Quorum-sensing signal molecules induced apoptosis in dendritic cells and CD4(+) cells, but not CD8(+) cells. Dendritic cells from patients with sepsis were depleted and ex vivo showed defective expression of co-stimulatory molecules and dysfunctional stimulation of allogeneic T-lymphocytes. Enhanced apoptosis of dendritic cells and differential CD4(+) Th1/Th2 (T-helper 1/2) cell apoptotic rate, and modified Th1/Th2 cell cytokine profiles in MLDCRs were also demonstrated in patients with sepsis. The pattern of immunological changes in patients with sepsis mirrors the effects of quorum-sensing signal molecules on responses of immune cells from normal individuals in vitro, suggesting that quorum-sensing signal molecules should be investigated further as a cause of immune dysfunction in sepsis.
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PMID:Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis. 1836 71

To evaluate the expression of lymphocyte subsets in newborns diagnosed as culture proven or culture negative sepsis and to investigate the differentiation. The aim of this study is to explore neonatal immunology in newborns diagnosed as culture proven or culture negative neonatal sepsis and to identify their place in the diagnosis. This prospective study was performed in newborns who were diagnosed as neonatal sepsis and hospitalized in a tertiary care hospital and who were classified as culture proven sepsis (n=12), as culture negative sepsis (n=21) and healthy (n=17). Lymphocyte subsets were obtained at time of diagnosis. Culture proven sepsis had statistically significant increase of WBC compared to culture negative sepsis and control groups (p<0.05). Significant decreases were observed of percentage of lymphocyte, when compared to culture negative sepsis and control group (p<0.05). Percentage of CD4(+) was lower in culture proven sepsis and absolute count of CD4(+) was lower in culture negative sepsis (p<0.05). Percentage and absolute count of CD45RA(+) were lower in culture negative sepsis than control and percentage of CD45RA(+) was lower in culture proven sepsis than control (p<0.05). Percentage of CD45RO(+) was higher in culture proven sepsis than control group (p<0.05). It is clear that during neonatal sepsis lymphocyte subsets are different from healthy controls. Whether the described abnormalities represent the absence of a normal maturation process, rather, pathological events is still not clear.
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PMID:Neonates with culture proven sepsis have lower amounts and percentage of CD45RA+ T cells. 1844 32

The cellular basis of immunological memory remains a controversial issue. Here we show that basophils bound large amounts of intact antigens on their surface and were the main source of interleukins 6 and 4 in the spleen and bone marrow after restimulation with a soluble antigen. Depletion of basophils resulted in a much lower humoral memory response and greater susceptibility of immunized mice to sepsis induced by Streptococcus pneumoniae. Adoptive transfer of antigen-reactive basophils significantly increased specific antibody production, and activated basophils, together with CD4(+) T cells, profoundly enhanced B cell proliferation and immunoglobulin production. These basophil-dependent effects on B cells required interleukins 6 and 4 and increased the capacity of CD4(+) T cells to provide B cell help. Thus, basophils are important contributors to humoral memory immune responses.
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PMID:Basophils enhance immunological memory responses. 2343 78


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