Etiopathogenesis of primary biliary cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver characterized by progressive bile duct destruction eventually leading to cirrhosis and liver failure. The serological hallmark of the disease is the presence of circulating antimitochondrial antibodies (AMA). These reflect the presence of autoreactive T and B cells to the culprit antigens, the E2 subunits of mitochondrial 2-oxo-acid dehydrogenase enzymes, chiefly pyruvate dehydrogenase (PDC-E2). The disease results from a combination of genetic and environmental risk factors. Genetic predisposition is indicated by the higher familial incidence of the disease particularly among siblings and the high concordance rate among monozygotic twins. Environmental triggering events appear crucial to disrupt a pre-existing unstable immune tolerance of genetic origin allowing, after a long latency, the emergence of clinical disease. Initiating mimetopes of the vulnerable epitope of the PDC-E2 autoantigen can be derived from microbes that utilize the PDC enzyme or, alternatively, environmental xenobiotics/chemical compounds that modify the structure of native proteins to make them immunogenic. A further alternative as a source of antigen is PDC-E2 derived from apoptotic cells. In the effector phase the biliary ductular cell, by reason of its proclivity to express the antigen PDC-E2 in the course of apoptosis, undergoes a multilineage immune attack comprised of CD4(+) and CD8(+) T cells and antibody. In this article, we critically review the available evidence on etiopathogenesis of PBC and present interpretations of complex data, new developments and theories, and nominate directions for future research.

Primary biliary cirrhosis and autoimmune hepatitis: apotopes and epitopes

“…c Western blots showing that PDC-E2 localizes unmodified within apoptotic bodies from HIBEC but not from other cell lineages. Cell lysates obtained from nonapoptotic BECs [2], and control cells [1,3,4], as well as apoptotic bodies from BECs [6] and controls [5,7,8] were immunoblotted with mAbs against PDC-E2 (74 kDa) by the pIgR, located on the basolateral surfaces of BECs [88,104]. Following receptor-mediated uptake, IgAs are transported through the cytoplasm in a transport vesicle (transcytosis), and secreted into the bile ducts at the apical surface [104].…”

“…PBC is a chronic cholestatic liver disease characterized by the autoimmune destruction of the small and medium-sized intrahepatic bile ducts [4]. It is considered a model autoimmune disease particularly due to the high specificity of the antimitochondrial antibodies (AMA) found in 90-95% of patients [5] and mainly directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2) [6]. Over the past decade, there have been significant advances in our understanding of PBC [7], including dissection of the autoreactive CD4 and CD8 responses [8][9][10][11] and the molecular characteristics of AMA [12,13]; the results of these studies suggest that PBC ensues from a multi-lineage loss of tolerance to PDC-E2 [14,15].…”

The Role of Pathogenic Autoantibodies in Autoimmunity

“…However, these enzymes are found throughout the body, yet the disease is limited to the biliary epithelial cells. An immunodominant epitope region has been identified in the inner lipoyl domain of PDC-E2, and initial tolerance breakdown has been attributed to xenobiotic modification of the lipoic acid cofactor causing cross-stimulation with a neo-epitope and epitope spreading to self-antigen in genetically susceptible individuals [263], but the autoantibodies associated with disease development are reactive with human PDC-E2, and not a neo-epitope [264]. Sera from patients with primary biliary cirrhosis contain very high titers of these autoantibodies, particularly anti-PDC-E2, and the autoantibodies are strongly enzyme inhibitory in vitro [171,173,265,266].…”

“…IgA anti-PDC-E2 could play a direct role in pathogenesis by binding and inhibition of enzymes during transcytosis in the cell [272] or by depleting energy levels by transport of newly synthesized PDC out of the cell [270], or by apoptosis [263,277,278]. Although apoptotic bodies have been linked to increased antigen presentation and tolerance breakdown leading to autoimmunity, apoptosis has also been described as an outcome of cell penetration by antibodies, and interference with intracellular functions [177,181].…”

Xenobiotic Induced Model of Primary Biliary Cirrhosis

“…Moreover, unique characteristics of apoptosis in BECs indicate that this process most likely plays a part in the immunopathogenesis of PBC. Autoreactive lymphocytes may be activated with neo-antigens arise from apoptotic BECs (22). When BECs undergo apoptosis, the major mitochondrial autoantigen, PDC-E2, remains immunologically intact, whereas other cells following apoptosis present a form of PDC-E2 that cannot be detected by AMAs (23; 24).…”