Role for mycobacterial infection in pathogenesis of primary biliary cirrhosis?

Abstract

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the immune-mediated destruction of biliary epithelial cells in small intrahepatic bile ducts. The disease is characterized by circulating antimitochondrial antibodies (AMAs) as well as disease-specific antinuclear antibodies, cholestatic liver function tests, and characteristic histological features, including granulomas. A variety of organisms are involved in granuloma formation, of which mycobacteria are the most commonly associated. This has led to the hypothesis that mycobacteria may be involved in the pathogenesis of PBC, along with other infectious agents. Additionally, AMAs are found in a subgroup of patients with mycobacterial infections, such as leprosy and pulmonary tuberculosis. Antibodies against species-specific mycobacterial proteins have been reported in patients with PBC, but it is not clear whether these antibodies are specific for the disease. In addition, data in support of the involvement of the role of molecular mimicry between mycobacterial and human mitochondrial antigens as triggers of cross-reactive immune responses leading to the loss of immunological tolerance, and the induction of pathological features have been published. Thus, antibodies against mycobacterial heat shock protein appear to cross-recognize AMA-specific autoantigens, but it is not clear whether these autoantibodies are mycobacterium-species-specific, and whether they are pathogenic or incidental. The view that mycobacteria are infectious triggers of PBC is intriguing, but the data provided so far are not conclusive.

Keywords: Antimitochondrial antibodies; Autoantibody; Autoimmunity; Cholestasis; Heat shock; Infection; Liver disease; Liver failure; Mycobacterium; Tuberculosis.

Figure 1

Epithelioid granuloma in liver biopsy. A, B: Liver specimens from patients with primary biliary cirrhosis show granuloma (arrows) close to bile ducts (BD) in portal tracts; C: Granuloma in sarcoidosis is more discrete and large in size; D: Granuloma associated with schistosomiasis contains a large number of eosinophils.