Primary biliary cholangitis: pathogenic mechanisms

Abstract

Purpose of review Primary biliary cholangitis (PBC) is characterized by autoimmune damage of intrahepatic bile ducts associated with a loss of tolerance to mitochondrial antigens. PBC etiopathogenesis is intriguing because of different perplexing features, namely: a) although mitochondria are present in all cell types and tissues, the damage is mainly restricted to biliary epithelial cells (BECs); b) despite being an autoimmune disorder, it does not respond to immunosuppressive drugs but rather to ursodeoxycholic acid, a bile salt that induces HCO 3 − rich choleresis; c) the overwhelming female preponderance of the disease remains unexplained. Here we present an etiopathogenic view of PBC which sheds light on these puzzling facts of the disease. Recent findings PBC develops in patients with genetic predisposition to autoimmunity in whom epigenetic mechanisms silence the Cl − /HCO 3 − exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO 3 − secretion with disruption of the protective alkaline umbrella that normally prevents the penetration of toxic apolar bile salts into cholangiocytes. AE2 dysfunction also causes increased intracellular pH (pHi) in cholangiocytes, leading to the activation of soluble adenylyl cyclase, which sensitizes BECs to bile salt-induced apoptosis. Recently, mitophagy was found to be inhibited by cytosolic alkalization and stimulated by acidification. Accordingly, we propose that AE2 deficiency may disturb mitophagy in BECs, thus, promoting the accumulation of defective mitochondria, oxidative stress and presentation of mitochondrial antigens to the immune cells. As women possess a more acidic endolysosomal milieu than men, mitophagy might be more affected in women in an AE2-defective background. Apart from affecting BECs function, AE2 downregulation in lymphocytes may also contribute to alter immunoregulation facilitating autoreactive T-cell responses. Summary PBC can be considered as a disorder of Cl − /HCO 3 − exchange in individuals with genetic predisposition to autoimmunity.

Selected Aspects of the Intricate Background of Immune-Related Cholangiopathies—A Critical Overview

“…Moreover, increased intracellular pH in the biliary epithelium induces the activation of adenylyl cyclase, resulting in further bile salt-associated cholangiocyte apoptosis. It was proposed recently that the AE2 defect may also disrupt cholangiocyte mitophagy, leading to mitochondrial dysfunction and oxidative stress, as well as host immune cell exposure to mitochondrial antigens with anti-mitochondrial antibody (AMA) production [ 3 , 14 ]. AE2 downregulation is also present in immune cells, particularly in CD8+ T cells, and may cause autoimmune T-cell reactions.…”

“…As mentioned before, miR-506 upregulation and methylation of the AE2 promoter have a critical role in PBC etiopathogenesis [ 12 ]. Moreover, changes in the DNA methylation pattern could account for the differences found in the concordance rate between monozygotic twins with PBC [ 3 ].…”

“…Herein, we provide a comprehensive summary of the potential role of various factors, such as the gut–liver axis, intestinal barrier integrity, BA synthesis and circulation, and microbiome composition, which seem to be strongly associated with PBC and PSC outcomes. Since the etiopathogenesis of both disorders remains poorly understood, therapeutic options are limited and not satisfactory [ 3 , 4 , 5 ]. Our review looks into recent evidence elucidating the role of various factors involved in PBC and PSC development and discusses their potential therapeutic implications.…”

A change of paradigm in PBC: Pursuing normal alkaline phosphatase

“…It is well accepted that the pathogenesis of PBC is the result of the interaction of immune and biliary pathways, leading to an inter-dependent and chronic cycle of cholestasis and liver fibrosis. 8 The signature identified by the Jones and colleagues include chemokines (CXCL11, 9 and 10), cytokine modulators (IL-4RA, IL-18-R1), the High Affinity Scavenger Receptor CD163, and Angiotensin Converting Enzyme 2 (ACE2). All markers that have been involved in the pathogenesis of PBC in independent studies.…”

The gamma-glutamyl transferase to platelet ratio for noninvasive evaluation of liver fibrosis in patients with primary biliary cholangitis

“…Primary biliary cholangitis (PBC) is an autoimmune disorder characterized by the extermination of the intrahepatic bile ducts, often leading to cirrhosis and liver failure. [ 1 , 2 ] Although the underlying causes remain unclear, genetic predisposition, various nucleotide polymorphisms, and environmental factors are thought to be responsible. [ 3 , 4 ] The course of PBC can progress to chronic cholestasis, portal inflammation, fibrosis, cirrhosis, liver failure, and even liver cancer, which develops as a result of damage to the small and medium-sized bile ducts.…”