Characterization of Blood Immune Cells in Patients With Decompensated Cirrhosis Including ACLF

Abstract

Background and AimsPatients with cirrhosis and acute-on-chronic liver failure (ACLF) have immunosuppression, indicated by an increase in circulating immune-deficient monocytes. The aim of this study was to investigate simultaneously the major blood-immune cell subsets in these patients.Material and MethodsBlood taken from 67 patients with decompensated cirrhosis (including 35 critically ill with ACLF in the intensive care unit), and 12 healthy subjects, was assigned to either measurements of clinical blood counts and microarray (genomewide) analysis of RNA expression in whole-blood; microarray (genomewide) analysis of RNA expression in blood neutrophils; or assessment of neutrophil antimicrobial functions.ResultsSeveral features were found in patients with ACLF and not in those without ACLF. Indeed, clinical blood count measurements showed that patients with ACLF were characterized by leukocytosis, neutrophilia, and lymphopenia. Using the CIBERSORT method to deconvolute the whole-blood RNA-expression data, revealed that the hallmark of ACLF was the association of neutrophilia with increased proportions of macrophages M0-like monocytes and decreased proportions of memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells and natural killer cells. Microarray analysis of neutrophil RNA expression revealed that neutrophils from patients with ACLF had a unique phenotype including induction of glycolysis and granule genes, and downregulation of cell-migration and cell-cycle genes. Moreover, neutrophils from these patients had defective production of the antimicrobial superoxide anion.ConclusionsGenomic analysis revealed that, among patients with decompensated cirrhosis, those with ACLF were characterized by dysregulation of blood immune cells, including increases in neutrophils (that had a unique phenotype) and macrophages M0-like monocytes, and depletion of several lymphocyte subsets (including memory lymphocytes). All these lymphocyte alterations, along with defective neutrophil superoxide anion production, may contribute to immunosuppression in ACLF, suggesting targets for future therapies.

Suppressor CD4+T cells expressing HLA-G are expanded in the peripheral blood from patients with acute decompensation of cirrhosis

“…In addition to quantitative impairment in circulating T cells reported in AD, including AD-ACLF, 51 our findings indicate that elevated proportions of the remaining T cells are typified by increased inhibitory receptor expression. Understanding the combination of the quantitative and qualitative impairments in the T cell compartment and its contribution to immuneparesis in chronic liver failure is of crucial importance in providing insights into potential therapeutic targets.…”

Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

“…We could not perform in vivo pharmacology studies on patients and did not attempt rodent experiments; these models share many of the features of acute decompensation, but are not wholly representative of the human phenotype (42). We only examined peripheral blood monocytes and other immune cells are also dysfunctional in decompensated cirrhosis, for example lymphoid cells (including T, B and NK cells) are decreased (43,44) and neutrophils may have defective production of antimicrobial superoxide anion (45). Furthermore, we focused on solely on PGE2 and there are other potential targets to reverse monocyte-macrophage dysfunction in liver disease, such as Mer tyrosine kinase (46).…”

An Immune Signature Robustly Predicts Clinical Deterioration for Hepatitis C Virus-Related Early-Stage Cirrhosis Patients

“…Innate immune cells, including Kupffer cells, mast cells, and resident masters, are the first defense mechanisms against pathogens. However, with the deterioration of cirrhosis, the antibacterial function of circulating neutrophils and monocytes is gradually damaged, end-stage cirrhosis patients were susceptible to bacterial infection ( 27 ). Meanwhile, chronic viral infection led to persistent specific immune inflammation stimulation, which aggravating fibrosis and may cause acute compensatory dysfunction and liver failure, both of which are associated with high short-term mortality.…”