Post-operative infection and sepsis in humans is associated with deficient gene expression of γccytokines and their apoptosis mediators

White, Mary; Mahon, Vivienne; Grealy, Robert; Doherty, Derek G.; Stordeur, Patrick; Kelleher, Dermot; McManus, Ross; Ryan, Thomas

doi:10.1186/cc10293

Cited by 28 publications

(23 citation statements)

References 46 publications

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“…Alternatively, failure to upregulate IL-15 mRNA expression may represent evidence of an "immunoparesis" among those children with severe bronchiolitis, analogous to that demonstrated by our research group in sepsis and pneumonia in other patient cohorts [27]. Immunoparesis in this context may be genetically mediated and may, at least in part, account for the inherited susceptibility to severe bronchiolitis seen among some children [28].…”

Section: Discussionmentioning

confidence: 90%

Interleukin-15 is associated with disease severity in viral bronchiolitis

et al. 2015

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Disease severity in viral bronchiolitis in infancy is difficult to predict and has been linked to host innate immunity. The study aimed to investigate the innate cytokine interleukin-15 (IL-15) as a marker of disease severity.A prospective single-centre observational study was conducted in a university-affiliated paediatric teaching hospital, comparing children (0-18 months) hospitalised for viral bronchiolitis, those admitted to the paediatric intensive care unit with severe disease and healthy age-matched controls. IL-15-related parameters were compared between groups. PCR and microRNA (miRNA) sequencing was undertaken on natural killer (NK) cells collected from study participants.Samples from 88 children with viral bronchiolitis and 43 controls enrolled between 2009 and 2012 were analysed. Peripheral blood mononuclear cell (PBMC) IL-15 mRNA expression was significantly higher in those with moderate severity bronchiolitis compared with controls and those with severe disease. Serum IL-15 levels correlated with disease severity. The relative frequency of NK cells in peripheral blood was significantly reduced in participants with bronchiolitis. The NK cell miRNA transcriptome in bronchiolitis was distinct. Targets of de-regulated miRNA were differentially expressed in bronchiolitis, including JAK3, STAT5A and NFKB1 on the IL-15 signalling pathway.IL-15 is associated with disease severity in children hospitalised with viral bronchiolitis.@ERSpublications Interleukin-15 influences the host innate response and is associated with disease severity in viral bronchiolitis

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Section: Discussionmentioning

confidence: 90%

Interleukin-15 is associated with disease severity in viral bronchiolitis

et al. 2015

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“…IL-7 is essential for lymphocyte survival, and deficient IL-7 gene expression in peripheral blood leukocytes exists in septic patients (428). Kasten Blood filtration devices such as polymyxin B fiber columns act to absorb circulating endotoxins in an effort to reduce harmful interactions between potent bacterial components and the host in gram negative sepsis.…”

Section: New Experimental Interventionsmentioning

confidence: 99%

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Iskander

Osuchowski

Stearns-Kurosawa

et al. 2013

Physiological Reviews

358

335

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Sepsis represents the host's systemic inflammatory response to a severe infection. It causes substantial human morbidity resulting in hundreds of thousands of deaths each year. Despite decades of intense research, the basic mechanisms still remain elusive. In either experimental animal models of sepsis or human patients, there are substantial physiological changes, many of which may result in subsequent organ injury. Variations in age, gender, and medical comorbidities including diabetes and renal failure create additional complexity that influence the outcomes in septic patients. Specific system-based alterations, such as the coagulopathy observed in sepsis, offer both potential insight and possible therapeutic targets. Intracellular stress induces changes in the endoplasmic reticulum yielding misfolded proteins that contribute to the underlying pathophysiological changes. With these multiple changes it is difficult to precisely classify an individual's response in sepsis as proinflammatory or immunosuppressed. This heterogeneity also may explain why most therapeutic interventions have not improved survival. Given the complexity of sepsis, biomarkers and mathematical models offer potential guidance once they have been carefully validated. This review discusses each of these important factors to provide a framework for understanding the complex and current challenges of managing the septic patient. Clinical trial failures and the therapeutic interventions that have proven successful are also discussed.

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“…This results in a significant loss myeloid cells and lymphocytes (including CD4 + and CD8 + T-cells) creating a lymphopenic environment (5). Lymphocyte homeostasis is dependent on gamma chain (γc) cytokines such as, IL-2, IL-7 and IL-15 (28, 29). IL-2 and IL-7 are important for T-cell growth and survival, respectively, (28, 30, 31) and gene expression of both of these cytokines has been shown to be deficient in human sepsis (29).…”

Section: Introductionmentioning

confidence: 99%

“…Lymphocyte homeostasis is dependent on gamma chain (γc) cytokines such as, IL-2, IL-7 and IL-15 (28, 29). IL-2 and IL-7 are important for T-cell growth and survival, respectively, (28, 30, 31) and gene expression of both of these cytokines has been shown to be deficient in human sepsis (29). Therapeutic IL-15 administration has been shown to prevent sepsis-induced apoptosis and immunosuppression thus improving survival in sepsis (32).…”

Section: Introductionmentioning

confidence: 99%

Sustained and Incomplete Recovery of Naive CD8+ T Cell Precursors after Sepsis Contributes to Impaired CD8+ T Cell Responses to Infection

Condotta

Rai

James

et al. 2013

The Journal of Immunology

105

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Patients who survive severe sepsis often display compromised immune function with impairment in innate and adaptive immune responses. These septic patients are highly susceptible to ‘secondary’ infections with intracellular pathogens that are usually controlled by CD8+ T-cells. It is unknown when and if this observed immunoparalysis of CD8+ T-cell immunity recovers and the long-term consequences of sepsis on the ability of naïve CD8+ T-cells to respond to subsequent infections are poorly understood. Here, using the CLP mouse model of sepsis we show that sepsis induces a rapid loss of naïve CD8+ T-cells. However, IL-15-dependent numerical recovery is observed a month after initial septic insult. Numerical recovery is accompanied by IL-15-dependent phenotypic changes where a substantial proportion of naïve (antigen-inexperienced) CD8+ T-cells display a ‘memory-like’ phenotype (CD44hi/CD11ahi). Importantly, the impairment of naïve CD8+ T-cells to respond to viral and bacterial infection was sustained for month(s) after sepsis induction. Incomplete recovery of naïve CD8+ T-cell precursors was observed in septic mice, suggesting that the availability of naïve precursors contributes to the sustained impairment in primary CD8+ T-cell responses. Thus, sepsis can result in substantial and long-lasting changes in the available CD8+ T-cell repertoire affecting the capacity of the host to respond to new infections.

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Post-operative infection and sepsis in humans is associated with deficient gene expression of γccytokines and their apoptosis mediators

Cited by 28 publications

References 46 publications

Interleukin-15 is associated with disease severity in viral bronchiolitis

Interleukin-15 is associated with disease severity in viral bronchiolitis

Sepsis: Multiple Abnormalities, Heterogeneous Responses, and Evolving Understanding

Sustained and Incomplete Recovery of Naive CD8+ T Cell Precursors after Sepsis Contributes to Impaired CD8+ T Cell Responses to Infection

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