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Procalcitonin (PCT) has been widely investigated for its prognostic value in septic patients. However, studies have produced conflicting results. The purpose of the present meta-analysis is to explore the diagnostic accuracy of a single PCT concentration and PCT non-clearance in predicting all-cause sepsis mortality. We searched PubMed, Embase, Web of Knowledge and the Cochrane Library. Articles written in English were included. A 2 × 2 contingency table was constructed based on all-cause mortality and PCT level or PCT non-clearance in septic patients. Two authors independently evaluated study eligibility and extracted data. The diagnostic value of PCT in predicting prognosis was determined using a bivariate meta-analysis model. We used the Q-test and I2 index to test heterogeneity. Twenty-three studies with 3,994 patients were included. An elevated PCT level was associated with a higher risk of death. The pooled relative risk (RR) was 2.60 (95% confidence interval (CI), 2.05-3.30) using a random-effects model (I(2) = 63.5%). The overall area under the summary receiver operator characteristic (SROC) curve was 0.77 (95% CI, 0.73-0.80), with a sensitivity and specificity of 0.76 (95% CI, 0.67-0.82) and 0.64 (95% CI, 0.52-0.74), respectively. There was significant evidence of heterogeneity for the PCT testing time (P = 0.020). Initial PCT values were of limited prognostic value in patients with sepsis. PCT non-clearance was a prognostic factor of death in patients with sepsis. The pooled RR was 3.05 (95% CI, 2.35-3.95) using a fixed-effects model (I(2) = 37.9%). The overall area under the SROC curve was 0.79 (95% CI, 0.75-0.83), with a sensitivity and specificity of 0.72 (95% CI, 0.58-0.82) and 0.77 (95% CI, 0.55-0.90), respectively. Elevated PCT concentrations and PCT non-clearance are strongly associated with all-cause mortality in septic patients. Further studies are needed to define the optimal cut-off point and the optimal definition of PCT non-clearance for accurate risk assessment.

Circulating lymphocyte number was significantly decreased in patients with sepsis. However, it remains unknown which severity phase (sepsis, severe sepsis, and septic shock) does it develop and what happen on each subpopulation. Eight patients with differing severities of sepsis (31 sepses, 33 severe sepses, and 16 septic shocks) were enrolled. Quantitative real-time polymerase chain reaction (RT-PCR) of Th1, Th2, and Th17; regulatory T (Treg) cell-specific transcription factor T-bet; GATA-3; RORgammat (RORγt); forkhead box P3 (FOXP3); and IL-17 mRNA were performed, and the enzyme-linked immunosorbent assay (ELISA) was used to detect serum interferon (IFN)-γ, IL-4, and IL-10. In this study, the Th1, Th2, Treg transcription factors, and related cytokines IFN-γ, IL-4, and IL-10 levels of sepsis and severe sepsis patients in peripheral blood were significantly higher than those of the normal controls. Except for IL-17, the T-bet, GATA-3, and IFN-γ levels of septic shock patients were lower than those of sepsis patients. We also observed that the proportions of Th17/Treg in the sepsis and septic shock groups were inversed. From the above, the inflammatory response especially the adaptive immune response is still activated in sepsis and severe sepsis, but significant immunosuppression was developed in septic shock. In addition, the proportion of Th17/Treg inversed may be associated with the illness aggravation of patients with sepsis.

Objective: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs) to stimulate adaptive immune cells such as Th1 and Th17 in sepsis., Methods: Sepsis was induced by cecal ligation and puncture (CLP). CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12(+)DC, IFNγ(+)Th1, and IL-17(+)Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA., Results: Our studies here showed that C5a induced IL-12(+)DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+)DC cells induced the expansion of pathogenic IFNγ(+)Th1 and IL-17(+)Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis., Conclusion: Our data suggests that C5a regulates IL-12(+)DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.

Sepsis is an excessive inflammatory condition with a high mortality rate and limited prediction and therapeutic options. In this study, for the first time, to our knowledge, we found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sepsis in both humans and a mouse model. Blockade and/or downregulation of Tim-3 led to increased macrophage activation, which contributed to the systemic inflammatory response in sepsis, whereas Tim-3 overexpression in macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses. Cross-talk between the Tim-3 and TLR4 pathways makes TLR4 an important contributor to Tim-3-mediated negative regulation of the innate immune response. Tim-3 signaling inhibited LPS-TLR4-mediated NF-κB activation by increasing PI3K-AKT phosphorylation and A20 activity. This negative regulatory role of Tim-3 reflects a new adaptive compensatory and protective mechanism in sepsis victims, a finding of potential importance for modulating innate responses in these patients.

We previously showed that γδT cells are involved in the pathogenesis of sepsis, but, the underlying mechanisms remained unclear. The present study demonstrates, for the first time, that γδT cells express the complement C5a receptor (C5aR, CD88) and that CD88 expression in γδT cells was up-regulated in mice following sepsis both at protein and mRNA levels. Complement C5a itself contributed to the regulation of C5aR expression on γδT cells, as (i) neutralization of C5a in vivo prevented the expression of C5aR on γδT cells in septic mice and (ii) incubation of mouse spleen cells or purified γδT cells with recombinant C5a in vitro increased CD88 expression by γδT cells at both protein and mRNA levels. C5a receptor on γδT cells also mediates increased interleukin-17 (IL-17) expression as incubation of mouse spleen cells or purified γδT cells with recombinant C5a promotes the IL-17 expression by γδT cells. Ligation of the C5aR on γδT cells activated the phosphoinositide 3-kinase (PI3K)/Akt signalling pathway, which enhances CD88 expression and promotes IL-17 secretion. These results demonstrate that C5a acts directly on the C5aR expressed on γδT cells, resulting in cell activation, and subsequently enhances their capacity for IL-17 production. The up-regulation of the PI3K/Akt pathway following C5a stimulation contributes to up-regulation of γδT-cell function., (© 2011 The Authors. Immunology © 2011 Blackwell Publishing Ltd.)

Excessive complement-activated product complement 5a (C5a) has been implicated in the pathogenesis of sepsis development. Herein, we employed in vitro and in vivo models of sepsis to investigate the functional relationship between overtly produced C5a and IL-8. Our data revealed that C5a could strongly amplify IL-8 expression from human whole blood cells induced by LPS and other types of TLR agonists. ERK1/2 and p38, but not JNK, were mainly participated in signaling pathways for IL-8 production. In the whole blood stimulated by Escherichiacoli, C5a levels were quickly elevated and blockage of C5a significantly decreased E. coli-elicited IL-8 production. In the mouse model of sepsis induced by cecal ligation and puncture (CLP), the markedly increased keratinocyte-derived cytokine (KC) could be strongly suppressed by blockage of C5a. These data suggest that excessive C5a functions as a critical inflammatory mediator to enhance IL-8 production mainly through MAPK signaling pathways., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Complement 5a (C5a) and Interleukin-17 (IL-17) are two important inflammatory mediators in sepsis. Here we studied the mechanisms underlying regulation of IL-17 by anaphylatoxin C5a. We found that C5a blockade increased the survival rate of mice following cecal ligation and puncture (CLP)-induced sepsis and decreased IL-17 expression in vivo. IL-17 was secreted mainly by gammadelta T cells in this model. Importantly, our data suggest that C5a participates in the regulation of IL-17 secretion by gammadelta T cells. Dendritic cells (DC) were found to act as a "bridge" between C5a and gammadelta T cells in a mechanism involving IL-6 and transforming growth factor beta (TGF-beta). These results imply that C5a affects the crosstalk between DC and gammadelta T cells during sepsis development, and this may result in a large production of inflammatory mediators such as IL-17.

Objective: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs) to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. Methods: Sepsis was induced by cecal ligation and puncture (CLP). CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12+DC, IFNγ+Th1, and IL-17+Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. Results: Our studies here showed that C5a induced IL-12+DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12+DC cells induced the expansion of pathogenic IFNγ+Th1 and IL-17+Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. Conclusion: Our data suggests that C5a regulates IL-12+DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of C5a by antibodies has been demonstrated to dramatically improve survival in various sepsis models in mice and rats. The structural basis of C5a mediated bioactivity and C5a antibody mediated neutralization are of interesting to be investigated. In the previous study, we obtained a novel functional mouse antibody named as F20. With computer-guided modeling method, the 3-D theoretical structure of F20 Fv fragment was constructed. Using the crystal structure of C5a, the 3-D complex structure of C5a and F20 Fv fragment was modeled with molecular docking method. Based on distance geometry method and intermolecular interaction theory, the key residue Lys68 in C5a identified by F20 was predicted. The mutant experimental results showed that the residue Lys68 was the critical residue of C5a for it''s bioactivity and F20 binding activity. The present study shed new light on the structural basis of C5a mediated bioactivity. The identification of the critical residue will provide useful information for human complement C5a targeted therapeutic intervention. [Copyright &y& Elsevier]