Primary biliary cirrhosis: an orchestrated immune response against epithelial cells

Abstract

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of PBC is the presence of antibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex. The mechanisms by which (and if) such antibodies produce liver tissue injury are unknown. However, the presence of these antibodies has allowed detailed immunological definition of the antigenic epitopes, the nature of reactive autoantibodies and the characterization of T-cell responses. Several mechanisms may now be proposed regarding the immune-mediated bile duct damage in PBC, including the possible role of T-cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies and mitochondrial autoantigens. There are major questions which remain unanswered, including, of course, etiology, but also the reasons for female predominance, the absence of PBC in children, the relative ineffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. The data so far provide suggestive evidence that PBC is a mucosal disease; this thesis provides a basis for discussion of etiology via the enterohepatic circulation of toxins and/or infection.

Caspase induction by IgA antimitochondrial antibody: IgA-mediated biliary injury in primary biliary cirrhosis

“…2 The apparent difficulty of autoantibodies coming into contact with intracellular autoantigens has fostered the argument that many such autoantibodies are merely epiphenomena and thus have no pathogenic role. Thus, there has been considerable debate for nearly 40 years regarding a pathogenic role for AMAs in PBC.…”

“…1,2 Although AMAs are found in more than 90% of patients with PBC, there has not been a specific pathogenic role defined for these autoantibodies, which often are detectable for several years before the onset of clinical disease. 3 Similarly, although infiltrating T cells have been found in the small bile ducts of PBC, the mechanisms involved in the destruction of biliary epithelial cells remain enigmatic.…”

Induction of Primary Biliary Cirrhosis in Guinea Pigs following Chemical Xenobiotic Immunization

“…At present, etiology is conceived only in general terms of genetic and environmental factors that predispose to a breakdown in tolerance characterized by autoimmune responses of great specificity. Primary biliary cirrhosis (PBC) 3 illustrates this enigma because of its high degree of concordance in identical twins, clinical uniformity, and the presence of a highly directed, specific serologic marker consisting of antimitochondrial Abs (AMA) directed at the E2 subunits of the 2-oxo-acid dehydrogenase complexes (2-OADC-E2) (1,2). This signature of PBC, the AMA, is a useful probe to enable dissection of potential environmental triggers and has led to the proposition that the inciting event of PBC is a modification of the major autoantigen, the E2 subunit of pyruvate dehydrogenase (PDC-E2), by a xenobiotic via chemical conjugation.…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…54,55 In fact, PBC shares features commonly found in autoimmunity, such as female predominance, multifactorial genetic predisposition, the presence of autoreactive T cells (CD4 and CD8) and the presence of disease-specific autoantibodies, i.e., AMAs and PBC-specific ANAs ( Table 2). Such autoantibodies, however, represent the basis for PBC being a paradox, as their direct pathogenetic role is still poorly defined.…”

“…Such autoantibodies, however, represent the basis for PBC being a paradox, as their direct pathogenetic role is still poorly defined. 55 Serum autoantibodies are detected in approximately 90% of patients, yet seronegative cases manifest similar histological features and disease progression. 56 Further, in the autoimmunity paradigm, the passive transfer of autoantibodies should reproduce disease-specific clinical features, and experimental immunization with diseasespecific antigens should reproduce a model disease.…”