Aftab A. Ansari

Primary biliary cirrhosis: an orchestrated immune response against epithelial cells

Summary: 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.

Detection of Autoantibodies to Recombinant Mitochondrial Proteins in Patients with Primary Biliary Cirrhosis

Primary biliary cirrhosis is characterized by the presence of autoantibodies to mitochondria with specific reactivity to proteins of 74 and 52 kilodaltons (kd). The 74-kd mitochondrial protein is the E2 component--dihydrolipoamide acetyltransferase--of the pyruvate dehydrogenase complex, and the 52-kd protein is the equivalent E2 component--dihydrolipoamide acyltransferase--of the branched-chain alpha-keto acid dehydrogenase complex. Current methods for the detection of antibodies to these proteins lack specificity or sensitivity, or they are time-consuming and not readily available. We therefore developed an enzyme-linked immunoassay to quantify specific antimitochondrial antibodies in patients with primary biliary cirrhosis. Recombinant polypeptides coding for both the 74-kd and the 52-kd mitochondrial autoantigens were used to analyze 217 coded serum samples, including samples from 93 patients with primary biliary cirrhosis and 124 controls, for reactivity by our immunoassay, immunoblotting, and immunofluorescence testing. Serum samples from 89 of the 93 patients with primary biliary cirrhosis reacted with either the pyruvate dehydrogenase-E2 or the branched-chain alpha-keto acid dehydrogenase protein. None of the 124 control samples from healthy volunteers (n = 86) or patients with primary sclerosing cholangitis (n = 38) had significant reactivity. Our results indicate that the use of recombinant, cloned autoantigens provides a simple, accurate, and rapid method of quantifying and monitoring the levels of specific mitochondrial autoantibodies in the serum of patients with primary biliary cirrhosis.

Xenobiotic Considerations for the Development of Autoimmune Liver Diseases: Bad Genes and Bad Luck

The etiologic origins of autoimmune disease remain an enigma. Although considerable information on the mechanisms of immunopathology has been acquired, in part from murine models, such mechanisms have yet to be substantiated in human autoimmune disease. This absence of validation is especially true for organ-specific diseases like those affecting the liver. In this review we focus on the putative role of xenobiotics as inducing agents for autoimmune liver pathology. In particular, we discuss the autoantibody immune response, the humoral hallmark of autoimmune disease, as well as cellular immune responses. We believe that exposure to environmental factors, namely xenobiotics, is the initiating straw that breaks the camels back, leading to the loss of tolerance to self proteins in genetically susceptible hosts. The end result is a perpetuating process that is determined by the governing features of the genetics of the host and by exposure to the inciting environmental agent. Interestingly, the liver, an organ that plays a major role in immune tolerance, can itself become the target of autoreactivity and immune destruction.

Reply: To PMID 22996325.

1. Hohenester S, Oude-Elferink RP, Beuers U. Primary biliary cirrhosis. Semin Immunopathol 2009;31:283-307. 2. Dhirapong A, Yang GX, Nadler S, Zhang W, Tsuneyama K, Leung P, et al. Therapeutic effect of CTLA4-Ig on a murine model of primary biliary cirrhosis. HEPATOLOGY 2013;57:708-715. 3. Beuers UH, Boberg KM, Chapman RW, Chazouillères O, Invernizzi P, Jones DE, et al. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237-267. 4. Oertelt S, Lian ZX, Cheng CM, Chuang YH, Padgett KA, He XS, et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor II dominant-negative mice. J Immunol 2006;177: 1655-1660. 5. Irie J, Wu Y, Wicker LS, Rainbow D, Nalesnik MA, Hirsch R, et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006;203:1209-1219. 6. Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I, et al. Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 2008; 134:1482-1493.We appreciate the kind comments regarding our work on murine models of PBC but, with due respect, there are a number of points the authors should consider prior to conclusions. Firstly, our position has always been that AMA alone is insufficient to make a diagnosis of PBC in either humans or murine models; the diagnosis relies on evidence of autoimmune cholangitis identified on coded slides by a blinded pathologist (1). Importantly, cholangitis can be transferred to naive Rag recipients using CD8 T cells from dnTGFβRII mice demonstrating an autoimmune component, data consistent with flow cytometry of liver subpopulations and cytokine analysis. Third, AMA standardization uses not only ELISA, but also enzyme inhibition, immunoblotting, absorption, peptide microarrays, affinity purified antisera, and generation of large panels of mAbs (1), not just the ELISA data of Hohenester. In fact, definition and measurement of AMAs Hepatology