{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:40:20Z","timestamp":1790005220741,"version":"4.0.1"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2002,1,1]],"date-time":"2002-01-01T00:00:00Z","timestamp":1009843200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2003,12,30]],"date-time":"2003-12-30T00:00:00Z","timestamp":1072742400000},"content-version":"vor","delay-in-days":728,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK39588"],"award-info":[{"award-number":["DK39588"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2002,1]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Patients with PBC produce a directed, specific response to a single immunodominant autoepitope of PDC-E2 within the inner lipoyl domain. In contrast, immunized animals react to multiple epitopes and rarely recognize the inner lipoyl domain. In other autoimmune diseases, apoptosis plays a critical role in antigen presentation; the caspases and granzyme B are the key proteases in the generation of autoepitopes. To determine the specific cleavage pattern of full-length recombinant PDC-E2, we performed <jats:italic toggle=\"yes\">in vitro<\/jats:italic> digestion with caspases-3, -6, -8 and granzyme B. The resulting fragments were immunoblotted and probed with an extensive panel of monoclonal anti-PDC-E2 antibodies and sera from patients with PBC. Interestingly, on granzyme B digestion, PDC-E2 lost reactivity, suggesting the destruction of the immunodominant epitope. Because this site contains the major epitope for both B cells and T cells, it suggests that granzyme B is unlikely to be involved in generation of autoepitopes in primary biliar cirrhosis (PBC). In contrast, following treatment with the caspase enzymes, immunoreactive fragments were generated. Indeed, by confocal microscopy, activated caspase-3 is found in the marginal hepatocytes and bile ducts. Moreover, caspase-3 staining was strongest in the small intrahepatic bile ducts, the major site of tissue destruction in PBC. In conclusion, these data suggest that following apoptosis, the caspase family of proteolytic enzymes have the potential to generate immunogenic fragments that contribute to the autoantigen reservoir and the production of antimitochondrial antibodies. These findings are also consistent with the generation of an autoimmune response against an intracellular antigen that evades catabolism during apoptosis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1053\/jhep.2002.30280","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T03:46:10Z","timestamp":1030247170000},"page":"14-22","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":44,"title":["Contribution to antimitochondrial antibody production: Cleavage of pyruvate dehydrogenase complex-E2 by apoptosis-related proteases"],"prefix":"10.1097","volume":"35","author":[{"given":"Shuji","family":"Matsumura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Van De Water","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroto","family":"Kita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross L.","family":"Coppel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Tsuji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhide","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab A.","family":"Ansari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Gershwin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"10.1053\/jhep.2002.30280-BIB1|cit1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1056\/NEJM195801232580407","article-title":"Primary biliary cirrhosis showing high titer of autoantibody: report of a case","volume":"254","author":"Mackay","year":"1958","journal-title":"N Engl J Med"},{"key":"10.1053\/jhep.2002.30280-BIB2|cit2","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S0140-6736(65)91372-3","article-title":"Serological tests in the diagnosis of primary biliary cirrhosis","volume":"1","author":"Walker","year":"1965","journal-title":"Lancet"},{"key":"10.1053\/jhep.2002.30280-BIB3|cit3","doi-asserted-by":"crossref","first-page":"3525","DOI":"10.4049\/jimmunol.138.10.3525","article-title":"Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis","volume":"138","author":"Gershwin","year":"1987","journal-title":"J Immunol"},{"key":"10.1053\/jhep.2002.30280-BIB4|cit4","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1084\/jem.167.6.1791","article-title":"The autoepitope of the 74-kD mitochondrial autoantigen of primary biliary cirrhosis corresponds to the functional site of dihydrolipoamide acetyltransferase","volume":"167","author":"Van de Water","year":"1988","journal-title":"J Exp Med"},{"key":"10.1053\/jhep.2002.30280-BIB5|cit5","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.4049\/jimmunol.141.7.2321","article-title":"Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function","volume":"141","author":"Van de Water","year":"1988","journal-title":"J Immunol"},{"key":"10.1053\/jhep.2002.30280-BIB6|cit6","doi-asserted-by":"crossref","first-page":"3367","DOI":"10.4049\/jimmunol.144.9.3367","article-title":"Structural requirement for autoreactivity on human pyruvate dehydrogenase-E2, the major autoantigen of primary biliary cirrhosis. 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