Toward solving the etiological mystery of primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) is considered a model autoimmune disease due to its signature anti‐mitochondrial antibody (AMA) autoantibody, female predominance, and relatively specific portal infiltration and cholestasis. The identification and cloning of the major mitochondrial autoantigens recognized by AMA have served as an immunologic platform to identify the earliest events involved in loss of tolerance. Despite the relatively high concordance rate in identical twins, genome‐wide association studies have not proven clinically useful and have led to suggestions of epigenetic events. To understand the natural history and etiology of PBC, several murine models have been developed, including spontaneous models, models induced by chemical xenobiotic immunization, and by “designer” mice with altered interferon metabolism. Herein, we describe five such models, including 1) NOD.c3c4 mice, 2) dominant negative form of transforming growth factor receptor type II mice, 3) interleukin‐2R α−/− mice, 4) adenylate‐uridylate‐rich element Del−/− mice, and 5) 2‐octynoic acid‐conjugated bovine serum albumin immunized mice. Individually there is no perfect murine model, but collectively the models point to loss of tolerance to PDC‐E2, the major mitochondrial autoantigen, as the earliest event that occurs before clinical disease is manifest. Although there is no direct association of AMA titer and PBC disease progression, it is noteworthy that the triad of PBC monocytes, biliary apotopes, and AMA leads to an intense proinflammatory cytokine burst. Further, the recurrence of PBC after liver transplantation indicates that, due to major histocompatibility complex restriction, disease activity must include not only adaptive immunity but also innate immune mechanisms. We postulate that successful treatment of PBC may require a personalized approach with therapies designed for different stages of disease. (Hepatology Communications 2017;1:275–287)

Clinical Updates in Primary Biliary Cholangitis: Trends, Epidemiology, Diagnostics, and New Therapeutic Approaches

“…However, many aspects of the etiology and pathogenesis of the destruction of biliary epithelial cells remains incompletely explained. 4,23,34 It is known that PBC involves a predominantly T-cell mediated destruction of intrahepatic bile ducts, likely initiated when a genetically susceptible individual comes into contact with an antigen in the environment such as an infectious pathogen, medication or other compound, triggering an autoimmune event. 2 Regardless of the autoimmune trigger, the disease begins with specific AMA targeting of the lipoic acid on the 2-oxo acid dehydrogenases, which are located on the inner mitochondrial membrane.…”

“…In addition, peptides from viruses or bacteria that are structurally similar to pyruvate dehydrogenase complex-dihydrolipoyltransacetylase (referred to as PDC-E2) epitopes can trigger an autoimmune response through molecular mimicry. 2,[34][35][36] An increase in PDC-E2 may lead to a loss of humoral tolerance and increases the differentiation of T-cells in the liver, resulting in damage to the intrahepatic biliary epithelial cells, scarring, fibrosis, and ductal destruction. 2,[34][35][36] The exposure of extraductular liver parenchyma to bile acids contributes to hepatocyte injury, fibrosis, and eventually cirrhosis.…”

Unmet needs in autoimmune liver diseases

“…Despite current knowledge, several important questions regarding the etiopathogenesis of PBC remain unanswered. First of all, we may ask why there is such a female preponderance in PBC . It is known that there are sex differences in the response of the immune system to foreign vs self antigens.…”

Pathogen infections and primary biliary cholangitis

“…PBC is a multi‐factorial disease: individuals having predisposed genetic factors could develop PBC as a consequence of environmental triggers . Bacterial infection is regarded as one of the most important environmental factors that contribute to the breaking of tolerance to mitochondrial autoantigens in PBC.…”