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Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naive T-cells but no enduring cell-autonomous defects in T-cell function.

ABSTRACT: Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T-cell dysfunction at later disease stages in sepsis survivors. However, despite these appreciations, the precise nature of the evoked defect in T-cell immunity in post-acute phases of SIRS remains unknown. Here we present an in-depth functional analysis of T-cell function in post-acute SIRS/sepsis. We document that T-cell function is not compromised on a per cell basis in experimental rodent models of infection-free SIRS (LPS or CpG) or septic peritonitis. Transgenic antigen-specific T-cells feature an unaltered cytokine response if challenged in vivo and ex vivo with cognate antigens. Isolated CD4(+)/CD8(+) T-cells from post-acute septic animals do not exhibit defects in T-cell receptor-mediated activation at the the level of receptor-proximal signalling, activation marker upregulation or expansion. However, SIRS/sepsis induced transient lymphopenia and gave rise to an environment of immune attenuation at post acute disease stages. Thus, systemic inflammation has an acute impact on T-cell numbers and adaptive immunity, but does not cause major cell-autonomous enduring functional defects in T-cells.

SUBMITTER: Markwart R

PROVIDER: S-EPMC4277344 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function.

Markwart Robby R Condotta Stephanie A SA Requardt Robert P RP Borken Farina F Schubert Katja K Weigel Cynthia C Bauer Michael M Griffith Thomas S TS Förster Martin M Brunkhorst Frank M FM Badovinac Vladimir P VP Rubio Ignacio I

PloS one 20141226 12

Sepsis describes the life-threatening systemic inflammatory response (SIRS) of an organism to an infection and is the leading cause of mortality on intensive care units (ICU) worldwide. An acute episode of sepsis is characterized by the extensive release of cytokines and other mediators resulting in a dysregulated immune response leading to organ damage and/or death. This initial pro-inflammatory burst often transits into a state of immune suppression characterised by loss of immune cells and T- ...[more]

PMID: 25541945

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Project description:OBJECTIVES:We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis. DESIGN:Prospective cohort study. SETTING:Tertiary PICU. PATIENTS:Children with 100 separate admission episodes of severe sepsis were enrolled. INTERVENTIONS:Blood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2?×?2 contingency table using C-reactive protein and ferritin thresholds was developed. MEASUREMENTS AND MAIN RESULTS:A C-reactive protein of 4.08?mg/dL and a ferritin of 1,980?ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08?mg/dL and ferritin greater than or equal to 1,980?ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08?mg/dL and ferritin less than 1,980?ng/mL or C-reactive protein less than 4.08?mg/dL and ferritin greater than or equal to 1,980?ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08?mg/dL and ferritin less than 1,980?ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 24.20 [95% CI, 5.50-106.54]). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 [35%]; p < 0.05). CONCLUSIONS:A C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08?mg/dL and ferritin of 1,980?ng/mL appeared to be a desired response in children with severe sepsis.

Dataset Information

Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naive T-cells but no enduring cell-autonomous defects in T-cell function.

Publications

Immunosuppression after sepsis: systemic inflammation and sepsis induce a loss of naïve T-cells but no enduring cell-autonomous defects in T-cell function.

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