{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T10:56:28Z","timestamp":1788173788930,"version":"build-2803163510"},"reference-count":74,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,12,12]],"date-time":"2021-12-12T00:00:00Z","timestamp":1639267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,12,12]],"date-time":"2021-12-12T00:00:00Z","timestamp":1639267200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>The increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross\u2010reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC\u2010E2) and <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic> PDC\u2010E2 (ePDC\u2010E2) have long suggested a role of <jats:italic toggle=\"yes\">E<\/jats:italic>. <jats:italic toggle=\"yes\">coli<\/jats:italic> in causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human and <jats:italic toggle=\"yes\">E. coli<\/jats:italic> PDC\u2010E2, we would be able to assess the specificity of autoantibody responses and define whether exposure to <jats:italic toggle=\"yes\">E. coli<\/jats:italic> in susceptible hosts is the basis for the antimitochondrial antibody (AMA) response.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Importantly, the reactivity of hPDC\u2010E2 LD (hPDC\u2010E2LD) affinity\u2010purified antibodies against hPDC\u2010E2LD could only be removed by prior absorption with hPDC\u2010E2LD and not ePDC\u2010E2, suggesting the presence of unique human PDC\u2010E2 epitopes distinct from <jats:italic toggle=\"yes\">E. coli<\/jats:italic> PDC\u2010E2. To identify the autoepitope(s) present in hPDC\u2010E2LD, a more detailed study using a variety of PDC\u2010E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC\u2010E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti\u2010LA), but in contrast, anti\u2010LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>In conclusion, our data are consistent with an exposure to <jats:italic toggle=\"yes\">E. coli<\/jats:italic> that elicits specific antibody to ePDC\u2010E2 resulting in determinant spreading and the classic autoantibody to hPDC\u2010E2LD. We argue this is the first step to development of human PBC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32172","type":"journal-article","created":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T05:23:13Z","timestamp":1633497793000},"page":"266-279","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":42,"title":["E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants"],"prefix":"10.1097","volume":"75","author":[{"given":"Yao","family":"Yang","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"},{"name":"School of Food Science and Pharmaceutical Engineering,Nanjing Normal University,Nanjing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjung","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"},{"name":"Division of Rheumatology,CHA University Medical Center,Bundang,Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Food Science and Pharmaceutical Engineering,Nanjing Normal University,Nanjing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Invernizzi","sequence":"additional","affiliation":[{"name":"International Center for Digestive Health,Department of Medicine and Surgery,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guoxiang","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3193-6851","authenticated-orcid":false,"given":"Weici","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ti\u2010hong","family":"Shao","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Chemistry,Rutgers University,Newark,New Jersey,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia\u00a0S.","family":"Nemeria","sequence":"additional","affiliation":[{"name":"Department of Chemistry,Rutgers University,Newark,New Jersey,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ross L.","family":"Coppel","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nursing and Health Sciences,Monash University,Clayton,Victoria,Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William M.","family":"Ridgway","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Kurth","sequence":"additional","affiliation":[{"name":"Department of Chemisrty,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aftab A.","family":"Ansari","sequence":"additional","affiliation":[{"name":"Department of Pathology,Emory University School of Medicine,Atlanta,Georgia,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick S.C.","family":"Leung","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy and Clinical Immunology,University of California Davis,Davis,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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