Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis

• Authors: Ana Lleo, University of California; Christopher L. Bowlus, University of California; Guo-Xiang Yang, University of California; Pietro Invernizzi, University of California; Mauro Podda, IRCCS-Istituto Clinico Humanitas; Judy Van de Water, University of California; Aftab A Ansari, Emory University; Ross L. Coppel, Monash University; Howard J. Worman, Columbia University; Gregory J. Gores, Mayo Clinic College of Medicine; M. Eric Gershwin, University of California
• Journal Title: Hepatology
• Volume: Volume 52, Number 3
• Publisher: Wiley-Blackwell | 2010-09, Pages 987-998
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1002/hep.23783
• Subjects: Health Sciences, Pathology; Biology, Microbiology; Health Sciences, Medicine and Surgery
• Keywords: autoimmunity; biliary epithelial cell; macrophages; cytokines; Fc receptor

Abstract

Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage T and B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage in PBC is confined to small biliary epithelial cells (BEC). We have previously demonstrated that BEC translocate immunologically intact PDC-E2 to apoptotic bodies, creating an apotope. To define the significance of this observation, we studied the ability of biliary or control epithelial apotopes to induce cytokine secretion from mature monocyte derived macrophages (MDMΦ) from either patients with PBC or controls in the presence or absence of anti-mitochondrial antibodies (AMA). We demonstrate that there is intense inflammatory cytokine production in the presence of the unique triad of BEC apotopes, macrophages from patients with PBC and AMA. The cytokine secretion is inhibited by anti-CD16 and not due to differences in apotope uptake. Moreover, MDMΦ from PBC patients cultured with BEC apoptotic bodies in the presence of AMA markedly increased TNF-related apoptosis-inducing ligand expression.Conclusion These results provide a mechanism for the biliary specificity of PBC, the recurrence of disease following liver transplantation and the success of ursodiol in treatment. They further emphasize a critical role of the innate immune system in the perpetuation of this autoimmune disease.