Dysregulated Adaptive Immunity Is an Early Event in Liver Cirrhosis Preceding Acute-on-Chronic Liver Failure

Abstract

IntroductionAcute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of Torque teno (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF.ConclusionImpaired innate and—in particular—adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.

Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management

“…Different immune cells including monocytes, macrophages, neutrophils, natural killer cells (NK cells), myeloid-derived suppressor cells (MDSCs), CD4, CD8, and Th17 cells immensely contribute to cytokine and chemokine production (16,(31)(32)(33)(34)(35)(36) leading to cytokine storm, systemic inflammation, and cell death (Figure 2). In fact, various immune surface molecules comprising chemokine receptors and coinhibitory molecules derive inflammatory responses leading to necrotic and apoptotic cell death and further aggravate hepatic damage (16,37,38). Similarly, host genetic factors, for instance, single nucleotide variants might modulate the release of inflammatory mediators by innate immune cells and can change the expression of pattern recognition receptors (PRRs).…”

“…Circulating and intrahepatic immune cells may act differently. Circulating immune cells might display inflammatory phenotype whereas hepatic immune cells may exhibit antiinflammatory phenotype since the liver is an immunotolerogenic organ ( 38 , 43 ).…”

Human Amnion-Derived Mesenchymal Stromal Cells: A New Potential Treatment for Carbapenem-Resistant Enterobacterales in Decompensated Cirrhosis

“…The clinical manifestation is characterized by a first phase, called compensated cirrhosis, followed by a progressive phase of decompensation due to the increase in portal hypertension that causes ascites, bleeding from esophageal varices, and encephalopathy until liver failure. Disease progression can be accelerated by the development of other complications, such as renal dysfunction, hepato-pulmonary syndrome, refractory ascites, and spontaneous bacterial peritonitis (SBP) [ 35 ]. SBP is bacterial infection of AF, caused by the translocation of bacteria from the intestinal tract into the ascites, and is the consequence of impairment of the hepatic reticulo-endothelial system, immune system dysregulation, and the reduced opsonic activity of AF in decompensated liver cirrhosis [ 36 ].…”

Survey of Viral Reactivations in Elite Athletes: A Case-Control Study

“…Indeed, in immunocompromised individuals, such as transplant recipients [17], the average copy numbers can be as high as 10 10 /mL of plasma [18]. For this reason, the kinetics of this virus in the blood continue to be extensively evaluated as a diagnostic and prognostic marker of immune function in different conditions [21,[27][28][29][30][31][32], and in the monitoring of immunosuppressive treatments [17,19,22,33].…”