Etiopathogenesis of primary biliary cirrhosis: an overview of recent developments

Abstract

Substantial advancements in the field of primary biliary cirrhosis (PBC) research have broadened our understanding of this enigmatic disease. Genome-wide studies have identified several new candidate genes involved in the immunoregulatory process, particularly those responsible for antigen presentation and lymphocyte signaling. Examples include the HLA class-II region and genes implicated in IL12-JAK/STAT signaling, and the NF-κB and TNF signaling pathways. Environmental triggers appear to disrupt the pre-existing, unstable immune tolerance in genetically susceptible individuals, and molecular mimics of the PBC-specific autoantigen (PDC) may be derived from microbes or xenobiotic compounds, which modify native proteins, making them immunogenic. Although the vast majority of patients with PBC are AMA-positive, a variety of disease-specific antinuclear antibodies have been recognized in conferring a worse clinical outcome. There has also been a revived interest in the role of antibody-secreting B cells in murine models suggesting that depletion of these cells paradoxically exacerbates cholangiopathy. Biliary specificity in PBC is most likely driven by the uniqueness of cholangiocyte apoptosis in which the PDC-E2 autoantigen undergoes differential glutathiolation. Cholangiocytes also possess the ability to phagocytose neighboring apoptotic cells, present intact immunoreactive antigen, and undergo attack from autoantibodies, the innate immune system, and autoreactive lymphocytes. Cellular senescence and a lack of functioning T-regulatory cells are proposed mechanisms by which this multi-lineage process is thought to be enhanced. This review summarizes these key advances as the true complexities of the disease process begin to be unraveled.

Keywords: Animal models; Apoptosis; Autoantibodies; Cholestasis; Genetics; Immunopathogenesis; Molecular mimicry.