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.