A blood immune suppression index (BISI) based on IL10/IL12 and ARG1/NOS2 ratios is predictive of immune dysfunction and respiratory failure after burn injury in patients

Abstract

Abstract Few molecular markers exist that can detail the extent of an injury or predict outcomes in burn patients. Understanding the immune status of patients could minimize complications following burn injury by reducing non-emergent surgical interventions when infection risks are high and allowing more aggressive interventions in patients at higher risk for pulmonary compromise. Here we detail a novel molecular signature to identify these at-risk patients. PBMCs from healthy volunteers (n=30) or burn trauma patients (n=110) were isolated under UNC IRB 15-1662 and assayed for IL-10, arginase-1 (ARG1), IL-12 and nitric oxide synthase-2 (NOS2) using quantitative, real-time PCR (qRT-PCR) or Nanostring mRNA arrays. A blood immune suppression index (BISI) was calculated using a ratio of anti- to pro-inflammatory gene expression and molecular pathway analysis of Nanostring data was conducted using Ingenuity Pathway Analysis. PBMCs from severe burn patients had increased expression of the anti-inflammatory mediators interleukin-10 (IL-10) and arginase-1 (ARG1) within the first 48 hours of hospital admission. Conversely, the pro-inflammatory cytokines, interleukin-12 (IL-12) and nitric oxide synthase-2 (NOS2), were markedly down-regulated. The BISI for patients who eventually developed acute lung injury or suffered skin graft failures was increased by 2.2-fold and 3.1-fold, respectively. Further, large-scale mRNA profiling of key immune regulatory markers (n=596 genes) using Nanostring mRNA profiling highlighted key pathways of immune dysfunction that confirmed our initial qRT-PCR findings and added additional immunoregulatory markers that are differentially expressed in conditions of immune dysfunction.