The Immune Pathogenesis of Acute-On-Chronic Liver Failure and the Danger Hypothesis

Abstract

Acute-on-chronic liver failure (ACLF) is a group of clinical syndromes related to severe acute liver function impairment and multiple-organ failure caused by various acute triggering factors on the basis of chronic liver disease. Due to its severe condition, rapid progression, and high mortality, it has received increasing attention. Recent studies have shown that the pathogenesis of ACLF mainly includes direct injury and immune injury. In immune injury, cytotoxic T lymphocytes (CTLs), dendritic cells (DCs), and CD4+ T cells accumulate in the liver tissue, secrete a variety of proinflammatory cytokines and chemokines, and recruit more immune cells to the liver, resulting in immune damage to the liver tissue, massive hepatocyte necrosis, and liver failure, but the key molecules and signaling pathways remain unclear. The “danger hypothesis” holds that in addition to the need for antigens, damage-associated molecular patterns (DAMPs) also play a very important role in the occurrence of the immune response, and this hypothesis is related to the pathogenesis of ACLF. Here, the research status and development trend of ACLF, as well as the mechanism of action and research progress on various DAMPs in ACLF, are summarized to identify biomarkers that can predict the occurrence and development of diseases or the prognosis of patients at an early stage.

A clinical study of non-bioartificial liver DPMAES support system in hepatitis B-related acute-on-chronic liver failure

“…While the “three-hit” and “second-hit” hypothesis 15 , 16 explain aspects of liver failure, cytokine storms play a crucial role in its development 17 , 18 . IL-6, a key inflammatory cytokine, regulates T-cell activation, differentiation, and hepatocyte regeneration.…”

Mitochondrial-Related Genes May Be an Important Factor in the Immune Microenvironment of Decompensated Cirrhosis and Acute-on-Chronic Liver Failure: New Findings Based on Double Disease Analysis

“…During immune injury, cytotoxic T lymphocytes (CTL), dendritic cells (DC), and CD4 + T cells amass in the liver tissue at the very start and subsequently secrete diverse pro-in ammatory cytokines and chemokines, conversely recruiting more immune cells to the liver. Changes in the immune microenvironment cause liver immune injury under the interaction of immune cells and cytokines, which leads to massive liver cell necrosis, mitochondrial destruction, and, eventually, liver failure [38][39][40]. In a clinical cohort of multiple liver diseases, including HBV-ACLF, acute-on-chronic hepatic dysfunction (ACHD), liver cirrhosis (LC), or chronic hepatitis B (CHB), the PBMC transcriptome sequencing results showed that immune dysregulation was the most remarkable and pernicious feature that further leads to the development of HBV infection, CHB, or LC into ACHD and ACLF, with signi cantly upregulated signals of neutrophil-and monocyte-related pathways and downregulated signals related to adaptive immune response.…”

Targeted modulation of gut microbiota by traditional Chinese medicine and natural products for liver disease therapy

“…Therefore, preventing and eliminating ALI has become an urgent issue to be solved globally. At present, epigenetics, oxidative stress, inflammatory immunity and other pathological mechanisms have been confirmed to be widely involved in the abnormal activities of hepatocytes and inflammatory immune cells and metabolism-induced ALI, and promising targets and potential therapeutic strategies have also been hotly discussed ( 79 ). Meanwhile, the role of gut microbiota in ALI has become increasingly prominent and has gradually attracted attention ( 80 ).…”