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 HCO3- 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-/HCO3- exchanger AE2 in both cholangiocytes and lymphoid cells. Defective AE2 function can produce BECs damage as a result of decreased biliary HCO3- 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-/HCO3- exchange in individuals with genetic predisposition to autoimmunity.

Box 1

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FIGURE 1

PBC: Etiopathogenic mechanisms. Epigenetic, genetic and environmental factors concur in causing PBC. Epigenetic mechanisms (including microRNAs and promoter hypermethylation) induce downregulation of AE2 in both cholangiocytes and lymphocytes. Defective AE2 function in cholangiocytes decreases biliary bicarbonate secretion while increasing intracellular pH (pHi). The disruption of the protective bicarbonate umbrella allows penetration of apolar bile salts into hepatocytes promoting cell apoptosis, which is favored by the activation of soluble adenylyl cyclase (sAC) because of the elevation of pHi. This alteration may also affect mitophagy, especially in women (in whom the endolysosomal milieu is more acidic than in men). Impaired mitophagy would lead to oxidative stress, accumulation of defective mitochondria, PDC-E2 overexpression and presentation of mitochondrial antigens to the immune system. These changes lead to immuno-mediated cell damage specially in individuals with genetic predisposition to autoimmunity. On the other hand, AE2 deficiency in lymphocytes, particularly in CD8 T cells, may contribute to enhance autoreactive T-cell responses.