Primary biliary cirrhosis and autoimmune hepatitis: apotopes and epitopes

Abstract

Autoimmune liver diseases (ALDs) represent a wide spectrum of chronic inflammatory diseases that are characterized by an immune-mediated attack against either hepatocytes (in the case of autoimmune hepatitis types 1 and 2, AIH-1, 2) or cholangiocytes (in primary biliary cirrhosis, PBC). PBC is considered a model autoimmune disease due to the homogeneity of patients, the high specificity of antimitochondrial antibodies (AMAs), and the specificity of biliary epithelial cell (BEC) destruction. It ensues from a multi-lineage loss of tolerance to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). One of the major unanswered questions in the pathogenesis of PBC is the specificity of small intrahepatic bile duct attack while PDC-E2 is present in mitochondria of nucleated cells. Recent findings suggest that the apoptosis of BECs may be of considerable importance for understanding PBC, and that they are more than simply an innocent victim of an immune attack. Rather, they attract immune attack by virtue of the unique biochemical mechanisms by which they handle PDC-E2. The role of apoptotic cells in AIH is not well defined, but advances in the study of autoreactive T cells stem mostly from AIH type 2, where the main autoantigen (CYP2D6) is known, enabling the characterization of antigen-specific immune responses. This review article is intended to provide a critical overview of current evidence on tissue specificity in ALDs, as well as the characteristics of the relevant epitopes and apotopes and their biological and clinical significance.

Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity

“…This production was inhibited by anti-CD16, an antibody against the Fc (fragment crystallizable) receptor. Our data suggest that the triad of AMAs, biliary apotopes, and innate immune response plays an important role in disease pathogenesis [38-40]. These recent findings emphasize a unique role of AMAs.…”

Pemphigus vulgaris antibodies target the mitochondrial nicotinic acetylcholine receptors that protect keratinocytes from apoptolysis

“…This paradox is not unique to PV autoimmunity. For instance, while it is well-known that AMAs produced by patients with primary biliary cirrhosis (PBC) enter biliary epithelial cells, bind mitochondrial self-antigens and induce apoptosis, the mechanism of AMA internalization and trafficking through the cytosol remains unknown (reviewed in [52,53]). Neither is it known why in PBC the autoimmune damage is confined to biliary epithelial cells, as the major PBC autoantigen -E2 subunit of the pyruvate dehydrogenase complex -is present in all nucleated cells.…”

A 50-year experience with autoimmune hepatitis: and where are we now?

“…This model resembled models in mice reported at the same meeting by Dr M.E. Gershwin of an autoimmune PBC-like cholangiolitis induced by disruption of various pathways of regulatory T-cell activity [84]. Finally, there have been occasional reports in the veterinary literature of a spontaneous chronic hepatitis in (relatively) inbred Doberman-Pinscher dogs [85], but with few details on accompanying autoimmune serological abnormalities.…”