Characterising Cytokine Gene Expression Signatures in Patients with Severe Sepsis

Robert Grealy,Ross Mcmanus,Dermot Kelleher,Thomas Ryan,Patrick Stordeur,Derek G Doherty,Mary White

doi:10.1155/2013/164246

Abstract

Introduction. Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. Methods. A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction. Results. Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFNγ, and TNFα gene expression. An algorithm utilising mRNA copy number for TNFα, IFNγ, IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive and gram-negative infection and was similar following medical and surgical severe sepsis. Severity of organ failure was associated with serum IL6 protein levels but not with any index of cytokine gene expression in PBMCs. Conclusions. Immune regulatory cytokine gene expression in PBMC provides a robust method of modelling patients' response to infection.

Highlights

Severe sepsis in humans may be related to an underlying profound immune suppressive state
An overwhelming inflammatory response to an underlying infection, remains a lethal disease that is present in over a third of European intensive care patients [1]. In previous studies this group reported a link between gene expression of specific immune regulatory cytokines in peripheral blood mononuclear cells (PBMC) and the presence of severe sepsis in patients with infection [2,3,4,5]
The specific cytokine groups whose differential expression were most closely associated with severe sepsis included the T-cell homeostatic cytokines IL2 and IL7 [6]; cytokines modulating the interaction between innate and adaptive immunity, namely, IL23 and IL27 [7]; and cytokines enhancing bactericidal activity, namely, TNFα and IFNγ [8]

Summary

Introduction

Severe sepsis in humans may be related to an underlying profound immune suppressive state. An overwhelming inflammatory response to an underlying infection, remains a lethal disease that is present in over a third of European intensive care patients [1] In previous studies this group reported a link between gene expression of specific immune regulatory cytokines in peripheral blood mononuclear cells (PBMC) and the presence of severe sepsis in patients with infection [2,3,4,5]. The specific cytokine groups whose differential expression were most closely associated with severe sepsis included the T-cell homeostatic cytokines IL2 and IL7 [6]; cytokines modulating the interaction between innate and adaptive immunity, namely, IL23 and IL27 [7]; and cytokines enhancing bactericidal activity, namely, TNFα and IFNγ [8] In these preliminary studies differential gene expression of a range of other cytokines, such as TGFb-1 were weakly linked, or such as IL1β, IL4, IL12, and IL18 were not linked, with the occurrence of severe sepsis in patients [9]. We derived an index of cytokine gene expression in order to test the strength of the association between cytokine gene expression and the presence of severe sepsis in patients with infection

Methods

Results

Conclusion