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PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMAs) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility and a plethora of candidate environmental factors to trigger the disease onset. For these reasons, PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre\u2010existing conditions (mostly genetic, as recently illustrated by genome\u2010wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and\/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features shown for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA; thus, turning the non\u2010traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments.<\/jats:p>","DOI":"10.1038\/icb.2010.126","type":"journal-article","created":{"date-parts":[[2010,10,26]],"date-time":"2010-10-26T09:45:09Z","timestamp":1288086309000},"page":"70-80","source":"Crossref","is-referenced-by-count":28,"title":["The autoimmunity of primary biliary cirrhosis and the clonal selection theory"],"prefix":"10.1111","volume":"89","author":[{"given":"Carlo","family":"Selmi","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine  Davis CA USA"},{"name":"Department of Medicine and Hepatobiliary Immunopathology Unit, IRCCS Istituto Clinico Humanitas  Rozzano Milan Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R","family":"Mackay","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and 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