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      High levels of circulating GM-CSF+CD4+ T cells are predictive of poor outcomes in sepsis patients: a prospective cohort study

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          Abstract

          Granulocyte colony-stimulating factor (GM-CSF), produced by CD4+ T cells, has recently been implicated in the pathogenesis of inflammatory diseases, such as multiple sclerosis and juvenile arthritis. However, the role of GM-CSF-producing CD4+ T cells in sepsis remains unknown. This study reports peripheral changes in GM-CSF-producing CD4+ T cells in septic patients and the possible underlying mechanism by which GM-CSF influences the outcome of sepsis. Forty-three septic patients, 20 SIRS patients, and 20 healthy controls were enrolled in this study and followed for 28 days to assess mortality. We measured the peripheral frequency of GM-CSF+CD4+ T cells and recorded their associated relationship with disease progression. Our data demonstrated that peripheral GM-CSF-producing CD4+ T cells were significantly higher in septic patients than in both SIRS patients and healthy controls. These cells exhibit a memory phenotype and impaired IFN-γ-secreting capacity in sepsis patients. Using a receiver operating curve analysis with 8.01% as a cut-off point, the percentage of GM-CSF+CD4+ T cells could predict the outcome of septic patients. Combined with the increase in GM-CSF-producing CD4+ T cells, inflammatory cytokines IL-1β and IL-6 were also upregulated. Using an in vitro neutrophil model, we found that GM-CSF inhibited C3aR expression, while inducing IL-8 production. Furthermore, this effect was transferrable in plasma from sepsis patients and was attenuated by inhibition of GM-CSF using an anti-GM-CSF antibody. These results indicate that GM-CSF-producing CD4+ T cells may serve as a marker of sepsis severity. Thus, targeting GM-CSF overproduction may benefit sepsis patients.

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          Most cited references16

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          Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.

          Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of sepsis-associated immunosuppression (primary endpoint), and improves the immunological and clinical course of patients with sepsis. In a prospective, randomized, double-blind, placebo-controlled, multicenter trial, 38 patients (19/group) with severe sepsis or septic shock and sepsis-associated immunosuppression (monocytic HLA-DR [mHLA-DR] <8,000 monoclonal antibodies (mAb) per cell for 2 d) were treated with GM-CSF (4 microg/kg/d) or placebo for 8 days. The patients' clinical and immunological course was followed up for 28 days. Both groups showed comparable baseline mHLA-DR levels (5,609 +/- 3,628 vs. 5,659 +/- 3,332 mAb per cell), which significantly increased within 24 hours in the GM-CSF group. After GM-CSF treatment, mHLA-DR was normalized in 19/19 treated patients, whereas this occurred in 3/19 control subjects only (P < 0.001). GM-CSF also restored ex-vivo Toll-like receptor 2/4-induced proinflammatory monocytic cytokine production. In patients receiving GM-CSF, a shorter time of mechanical ventilation (148 +/- 103 vs. 207 +/- 58 h, P = 0.04), an improved Acute Physiology and Chronic Health Evaluation-II score (P = 0.02), and a shorter length of both intrahospital and intensive care unit stay was observed (59 +/- 33 vs. 69 +/- 46 and 41 +/- 26 vs. 52 +/- 39 d, respectively, both not significant). Side effects related to the intervention were not noted. Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence. Use of GM-CSF may shorten the time of mechanical ventilation and hospital/intensive care unit stay. A multicenter trial powered for the improvement of clinical parameters and mortality as primary endpoints seems indicated. Clinical trial registered with www.clinicaltrials.gov (NCT00252915).
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            Interleukin-17-producing CD4(+) T cells increase with severity of liver damage in patients with chronic hepatitis B.

            Interleukin-17 (IL-17)-producing CD4(+) T cells (Th17)-mediated immune response has been demonstrated to play a critical role in inflammation-associated disease; however, its role in chronic hepatitis B virus (HBV) infection remains unknown. Here we characterized peripheral and intrahepatic Th17 cells and analyzed their association with liver injury in a cohort of HBV-infected patients including 66 with chronic hepatitis B (CHB), 23 with HBV-associated acute-on-chronic liver failure (ACLF), and 30 healthy subjects as controls. The frequency of circulating Th17 cells increased with disease progression from CHB (mean, 4.34%) to ACLF (mean, 5.62%) patients versus healthy controls (mean, 2.42%). Th17 cells were also found to be largely accumulated in the livers of CHB patients. The increases in circulating and intrahepatic Th17 cells positively correlated with plasma viral load, serum alanine aminotransferase levels, and histological activity index. In vitro, IL-17 can promote the activation of myeloid dendritic cells and monocytes and enhance the capacity to produce proinflammatory cytokines IL-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-23 in both CHB patients and healthy subjects. In addition, the concentration of serum Th17-associated cytokines was also increased in CHB and ACLF patients. Th17 cells are highly enriched in both peripheral blood and liver of CHB patients, and exhibit a potential to exacerbate liver damage during chronic HBV infection.
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              The function of neutrophils in sepsis.

              Neutrophils are an essential arm of the innate immune response. In patients with sepsis, reprogramming of neutrophil occurs, manifest by impaired recruitment of neutrophils to sites of infection, abnormal accumulation of neutrophils to remote sites, and dysregulation of neutrophil effector responses. This review examines the mechanisms underlying dysregulated neutrophil trafficking and function during sepsis. Mechanisms governing neutrophil function in sepsis are complex. Bacterial products, cytokines/chemokines, leukotrienes, and immunomodulatory hormones can modulate neutrophil migratory responses during sepsis via induction of cytoskeletal changes, disruption of polymorphonuclear leukocyte (PMN)-endothelial cell interactions, and alterations in G-protein-coupled receptor expression or signaling. Impaired chemotactic responses and alterations in neutrophil function can occur as a result of dysregulated PMN G-protein-coupled receptor and Toll-like receptor expression and/or signaling. As sepsis evolves, neutrophil gene expression is altered, leading to suppression of proinflammatory and immunomodulatory genes, as well as decreased production of reactive oxygen species. Neutrophil extracellular traps are produced to contain and kill invading pathogens, but can paradoxically promote further tissue damage. Neutrophil migration is a coordinated process that is altered at multiple stages during sepsis. In combination with impaired neutrophil function, these alterations culminate in defective innate immunity in septic patients. Defining the mechanisms involved and strategies to interrupt these deleterious responses requires further investigation.
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                Author and article information

                Journal
                Cellular & Molecular Immunology
                Cell Mol Immunol
                Springer Nature America, Inc
                1672-7681
                2042-0226
                October 16 2018
                Article
                10.1038/s41423-018-0164-2
                6804788
                30327490
                85644190-c309-4400-85ec-2541e3e61bf8
                © 2018

                http://www.springer.com/tdm

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