Increased serum NKG2D-ligands and downregulation of NKG2D in peripheral blood NK cells of patients with major burns.

Josef Haik,Noga Goldman,Eyal Winkler,Moti Harats,Isaac Zilinsky,Oren Weissman,Gil Nardini,Gal Markel,Gilli Galore-Haskel,Jacob Schachter

doi:10.18632/oncotarget.6789

Abstract

Immune suppression following major thermal injury directly impacts the recovery potential. Limited data from past reports indicate that natural killer cells might be suppressed due to a putative soluble factor that has remained elusive up to date. Here we comparatively study cohorts of patients with Major and Non-Major Burns as well as healthy donors. MICB and ULBP1 are stress ligands of NKG2D that can be induced by heat stress. Remarkably, serum concentration levels of MICB and ULBP1 are increased by 3-fold and 20-fold, respectively, already within 24h post major thermal injury, and are maintained high for 28 days. In contrast, milder thermal injuries do not similarly enhance the serum levels of MICB and ULBP1. This kinetics coincides with a significant downregulation of NKG2D expression among peripheral blood NK cells. Downregulation of NKG2D by high concentration of soluble MICB occurs in cancer patients and during normal pregnancy due to over production by cancer cells or extravillous trophoblasts, respectively, as an active immune-evasion mechanism. In burn patients this seems an incidental outcome of extensive thermal injury, leading to reduced NKG2D expression. Enhanced susceptibility of these patients to opportunistic viral infections, particularly herpes viruses, could be explained by the reduced NKG2D expression. Further studies are warranted for translation into innovative diagnostic or therapeutic technologies.

Highlights

Major burn injuries cause substantial clinical debilitation combined with economic impact, affecting up to 2.4 million casualties per year in the US alone [1]
Milder thermal injuries do not enhance the serum levels of MICB and ULBP1. This kinetics coincides with a significant downregulation of NKG2D expression among peripheral blood Natural Killer (NK) cells
We hypothesized that extensive thermal injury may result in increased systemic release of NKG2D ligands and thereby cause NKG2D downregulation and relative immune deficiency. In this case-controlled prospective pilot study we investigated the concentration of MICA, MICB, ULBP1 and ULBP2, the expression of NKG2D on peripheral blood NK cells, as well as adjunct clinical parameters, in cohorts of patients afflicted with major or non-major thermal injuries, over several time points post injury

Summary

Introduction

Major burn injuries cause substantial clinical debilitation combined with economic impact, affecting up to 2.4 million casualties per year in the US alone [1]. Serum concentration levels of MICB and ULBP1 are increased by 3-fold and 20-fold, respectively, already within 24h post major thermal injury, and are maintained high for 28 days. In this case-controlled prospective pilot study we investigated the concentration of MICA, MICB, ULBP1 and ULBP2, the expression of NKG2D on peripheral blood NK cells, as well as adjunct clinical parameters, in cohorts of patients afflicted with major or non-major thermal injuries, over several time points post injury.

Results

Conclusion