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

Affiliation

Weiss E(1)(2)(3), de la Grange P(4), Defaye M(2), Lozano JJ(5), Aguilar F(3), Hegde P(2), Jolly A(4), Moga L(2)(6), Sukriti S(7), Agarwal B(8), Gurm H(8), Tanguy M(2), Poisson J(2), Clària J(3)(5)(9)(10), Abback PS(2), Périanin A(2), Mehta G(8)(11)(12), Jalan R(3)(8), Francoz C(6), Rautou PE(2)(6), Lotersztajn S(2), Arroyo V(3), Durand F(2)(6), Moreau R(2)(3)(6).
Author information:
(1)Assistance Publique-Hôpitaux de Paris
(AP-HP), Department of Anesthesiology and Critical Care, Beaujon Hospital, DMU Parabol, AP-HP Nord, Paris, France.
(2)Université de Paris, Institut National de la Santé et de la Recherche Médicale
(INSERM), Centre de Recherche sur l'Inflammation
(CRI), Paris, France.
(3)European Foundation for the study of Chronic Liver Failure
(EF-Clif), European Association for the Study of Chronic Liver Failure
(EASL-CLIF) Consortium and Grifols Chair, Barcelona, Spain.
(4)GenoSplice, Paris, France.
(5)CIBERehd, Barcelona, Spain.
(6)Assistance Publique-Hôpitaux de Paris
(APHP), Service d'Hépatologie & Réanimation Hépato Digestive, Hôpital Beaujon, Clichy, France.
(7)Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India.
(8)Liver Failure Group, Institute for Liver and Digestive Health, University College London, London, United Kingdom.
(9)Hospital Clínic-August Pi i Sunyer Biomedical Research Institute
(IDIBAPS), Barcelona, Spain.
(10)Universitat de Barcelona, Barcelona, Spain.
(11)Institute of Hepatology, Foundation for Liver Research, London, United Kingdom.
(12)Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.

Abstract

BACKGROUND AND AIMS: Patients 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 METHODS: Blood 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. RESULTS: Several 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. CONCLUSIONS: Genomic 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.