The X and why of xenobiotics in primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by inflammation and destruction of intrahepatic biliary epithelial cells, ultimately leading to liver failure. The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The initiating events triggering the autoimmune response are not yet identified but the hypothesis of molecular mimicry is a widely proposed mechanism for the development of autoimmunity in PBC. Several candidates, including bacteria and viruses, have been suggested as causative agents, but also environmental factors, such as chemical xenobiotics, have been implicated in the pathogenesis of primary biliary cirrhosis. In this review, we will discuss our current knowledge of the immunoreactivity of xenobiotically modified PDC peptide antigens. In addition, we will provide a working hypothesis how xenobiotic modification of antigens might occur that ultimately leads to the breaking of self-tolerance and the induction of PBC.

Fig. 1

Schematic of microarray based assay utilizing xenobiotic modified peptide-agarose conjugates.

Fig. 2

IgM reactivity of n-octynamide- or 2-alkynanide-modified PDC-E2 peptide with PBC sera. PBC patient sera (A, C) and healthy control sera (B, D) were analyzed by microarray for IgM reactivity against PDC-E2 peptide that has been modified with n-octynoic (A, B) or 2-alkynoic acids (C, D). Reactivity of individual samples and mean reactivity are shown. Asterisk indicates a significant difference (p < 0.05, unpaired t test) in IgM reactivity between PBC and control sera.

Fig. 3

Proposed model of breaking of tolerance in PBC.

Fig. 4

Schematic of possible xenobiotic modifications of PDC-E2 or carrier proteins. Xenobiotics may alter PDC-E2 by either replacing the lipoic acid moiety or by chemically modifying lipoic acid itself and/or modifying PDC-E2 proximal to the lipoyl domain creating an immunological mimic (A). In addition, xenobiotics might be able to modify carrier proteins, such as albumin, which elicits an immune response against the xenobiotic cross-reacting against native PDC-E2 (B). LA, lipoic acid; X, xenobiotic; Lip, lipoyl domain.