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      Low B and T lymphocyte attenuator expression on CD4 + T cells in the early stage of sepsis is associated with the severity and mortality of septic patients: a prospective cohort study

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      Critical Care
      BioMed Central

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          Abstract

          Introduction

          B and T lymphocyte attenuator (BTLA) is an inhibitory receptor, whose primary role in CD4 + T cell is thought to inhibit cytokine production. We explore BTLA expression on CD4 + T cells in healthy controls and septic patients, and assess the correlation of BTLA expression on CD4 + T cells in the early stage of sepsis with the severity and mortality of septic patients in the emergency department (ED).

          Methods

          336 consecutive patients were included in this study. BTLA expression on CD4 + T cells was measured by flow cytometry within 24h of ED admission.

          Results

          Our results showed that the percentage of BTLA +/CD4 + T cells was high expression in healthy volunteers and it was statistically reduced in severe sepsis and septic shock compared with healthy controls(all P<0.01). The area under the receiver operating characteristic (AUC) curves of BTLA expression on CD4 + T cells was slightly lower than that of procalcitonin (PCT) and Mortality in Emergency Department Sepsis (MEDS) score. The percentage of BTLA +/CD4 +T cells was lower in non-survivors than in survivors (P<0.01), and similar results were obtained when expressed as mean of fluorescence intensities (MFI) (P<0.01). Adjusted logistic regression analysis suggested that the percentage of BTLA +/CD4 + T cells was associated with 28-day mortality in septic patients (odds ratio (OR) = 0.394).

          Conclusion

          Our study shows that the percentage of BTLA +/CD4 + T cells was high in healthy volunteers. Furthermore, lower percentage of BTLA +/CD4 + T cells during the early stage of sepsis is associated with the severity and the mortality of septic patients.

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          Most cited references19

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          The international sepsis forum consensus conference on definitions of infection in the intensive care unit.

          To develop definitions of infection that can be used in clinical trials in patients with sepsis. Infection is a key component of the definition of sepsis, yet there is currently no agreement on the definitions that should be used to identify specific infections in patients with sepsis. Agreeing on a set of valid definitions that can be easily implemented as part of a clinical trial protocol would facilitate patient selection, help classify patients into prospectively defined infection categories, and therefore greatly reduce variability between treatment groups. Experts in infectious diseases, clinical microbiology, and critical care medicine were recruited and allocated specific infection sites. They carried out a systematic literature review and used this, and their own experience, to prepare a draft definition. At a subsequent consensus conference, rapporteurs presented the draft definitions, and these were then refined and improved during discussion. Modifications were circulated electronically and subsequently agreed upon as part of an iterative process until consensus was reached. Consensus definitions of infection were developed for the six most frequent causes of infections in septic patients: pneumonia, bloodstream infections (including infective endocarditis), intravascular catheter-related sepsis, intra-abdominal infections, urosepsis, and surgical wound infections. We have described standardized definitions of the common sites of infection associated with sepsis in critically ill patients. Use of these definitions in clinical trials should help improve the quality of clinical research in this field.
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            BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1.

            During activation, T cells express receptors for receiving positive and negative costimulatory signals. Here we identify the B and T lymphocyte attenuator (BTLA), an immunoglobulin domain-containing glycoprotein with two immunoreceptor tyrosine-based inhibitory motifs. BTLA is not expressed by naive T cells, but it is induced during activation and remains expressed on T helper type 1 (T(H)1) but not T(H)2 cells. Crosslinking BTLA with antigen receptors induces its tyrosine phosphorylation and association with the Src homology domain 2 (SH2)-containing protein tyrosine phosphatases SHP-1 and SHP-2, and attenuates production of interleukin 2 (IL-2). BTLA-deficient T cells show increased proliferation, and BTLA-deficient mice have increased specific antibody responses and enhanced sensitivity to experimental autoimmune encephalomyelitis. B7x, a peripheral homolog of B7, is a ligand of BTLA. Thus, BTLA is a third inhibitory receptor on T lymphocytes with similarities to cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1).
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              Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis

              Introduction A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. Methods Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. Results Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). Conclusions In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.
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                Author and article information

                Contributors
                shaorui1008@163.com
                +86 10 85231051 , lcscyyy@163.com
                fangyingying1989@163.com
                lianxingzhao@hotmail.com
                hchch0926@126.com
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                28 August 2015
                28 August 2015
                2015
                : 19
                : 1
                : 308
                Affiliations
                Department of Emergency Medicine, Beijing Chao-yang Hospital, Capitcal Medical University, 8# Worker’s Stadium South Road, Chao-yang District, Beijing, 100020 China
                Article
                1024
                10.1186/s13054-015-1024-4
                4556404
                2b87f39d-c87c-4da9-a27f-76cb14d54e6d
                © Shao et al. 2015

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 May 2015
                : 11 August 2015
                Categories
                Research
                Custom metadata
                © The Author(s) 2015

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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