The pathogenesis of primary biliary cirrhosis

ABSTRACT

Primary biliary cirrhosis (PBC) would develop when the immunesystem comes across a microorganism with proteins similarto those in the piruvate dehydrogenase complex E2 (PDC-E2), ora neoantigen resulting from a xenobiotic-modified autoantigen.This would lead to an innate immune response where TLRswould play a pivotal mediating role, which would give rise to a localmicroenvironment favoring an adaptive immune response.Such response would be particularly strong in individuals with selectedgenetic characteristics. The genetic characteristics underlyingthis predisposition remain unknown, but they likely entailsmall numbers of scarcely-active regulatory T cells. The AE2 anionexchanger, which is deficient in patients with PBC, may reducethe number and activity of regulatory T cells. NK cells arealso pivotal in the preparation of an adaptive response, as they releasea number of cytokines and chemokines that favor and recruitantigen-presenting cells to activate B and T cells – CD4+ Th1 andCD8+. An activation of the former would increase the productionof IgM and anti-mitochondrial IgG and IgA antibodies againstPDC-E2. An activation of CD8+ cells, also sensitive to PDC-2 asaberrantly expressed on the surface of BECs and SECs, would resultin apoptosis for these epithelial cells, and in small bile-duct destruction.Immune response is likely inadequately suppressed becauseof the small numbers of scarcely-active regulatory T cells,the latter resulting from low genetic expression and activity of theAE2 transporter(AU)