{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:29:40Z","timestamp":1792758580358,"version":"4.5.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Antimitochondrial antibodies (AMAs) are the hallmark of primary biliary cholangitis (PBC) but can be identified also in patients with connective tissue disease, namely, systemic sclerosis (SSc). Protein immunoprecipitation (IP) and IP-Western blot (WB) can be used to confirm AMA positivity directed at the pyruvate dehydrogenase complex (PDC) subunits E1\u03b1, E1\u03b2, E2\/E3, and E3BP in patients showing a cytoplasmic reticular pattern at indirect immunofluorescence when performed in a screening setting before the onset of overt cholestasis in rheumatic patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>We studied sera from 285 patients affected by connective tissue disease [SSc, n = 144; dermato\/polymyositis (DM\/PM), n = 56; and undifferentiated connective tissue disease (UCTD), n = 85] by indirect immunofluorescence (IIF), protein-IP, and IP-WB to identify specific PDC subunits recognized by AMA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty percent (57\/285) of sera from patients with connective tissue disease had a cytoplasmic reticular pattern at IIF, and in 77% (44\/57, including 20 SSc, 12 PM\/DM, and 12 UCTD) of these, we detected different titers of autoantibodies against the PDC subunits, specifically against PDC-E2. Among these sera, 4 (9%) tested positive for anti-E1\u03b1, 15 (34%) for anti-E1\u03b2, and 16 (36%) for anti-E3BP. Four of the 20 AMA-positive SSc cases (20%) had been already diagnosed with PBC, and all were positive for autoantibodies against the subunits PDC-E2, E3, and E3BP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Using IIF and IP, we confirm that autoantibodies against the PDC components are detected in rheumatic patients with PBC or without liver dysfunction. In view of the strong predictive value of AMA for PBC, a strict follow-up of these latter patients is warranted for an early diagnosis of the disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.822996","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T06:06:51Z","timestamp":1646028411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["Antigen Reactivity and Clinical Significance of Autoantibodies Directed Against the Pyruvate Dehydrogenase Antigen Complex in Patients With Connective Tissue Disease"],"prefix":"10.3389","volume":"13","author":[{"given":"Angela","family":"Ceribelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasa","family":"Isailovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Gorlino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Assandri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Vecellio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"De Santis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Satoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Selmi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2008.02.009","article-title":"Antimitochondrial Antibodies and Other Antibodies in Primary Biliary Cirrhosis: Diagnostic and Prognostic Value","volume":"12","author":"Muratori","year":"2008","journal-title":"Clin Liver Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S1089-3261(03)00132-6","article-title":"Primary Biliary Cirrhosis and Autoimmune Cholangiopathy","volume":"8","author":"Vierling","year":"2004","journal-title":"Clin Liver Dis"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/08916930802709133","article-title":"Multiple Nuclear Dots and Rim-Like\/Membranous IgG Isotypes in Primary Biliary Cirrhosis","volume":"42","author":"Muratori","year":"2009","journal-title":"Autoimmunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21172","article-title":"Correlation of Initial Autoantibody Profile and Clinical Outcome in Primary Biliary Cirrhosis","volume":"43","author":"Wesierska-Gadek","year":"2006","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1080\/10446670410001722113","article-title":"Serial Analysis of Antimitochondrial Antibody in Patients With Primary Biliary Cirrhosis","volume":"11","author":"Benson","year":"2004","journal-title":"Clin Dev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2016.11.021","article-title":"Clinical Relevance of Combined Anti-Mitochondrial M2 Detection Assays for Primary Biliary Cirrhosis","volume":"464","author":"Han","year":"2017","journal-title":"Clin Chim Acta"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00309","article-title":"The Importance of Autoantibody Detection in Primary Biliary Cirrhosis","volume":"6","author":"Cancado","year":"2015","journal-title":"Front Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510300106","article-title":"Characterization of the Autoantibody Responses to Recombinant E3 Binding Protein (Protein X) of Pyruvate Dehydrogenase in Primary Biliary Cirrhosis","volume":"30","author":"Palmer","year":"1999","journal-title":"Hepatology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jim.2017.10.001","article-title":"Detection of Anti-Mitochondrial Antibodies by Immunoprecipitation in Patients With Systemic Sclerosis","volume":"452","author":"Ceribelli","year":"2018","journal-title":"J Immunol Methods"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2017-1152","article-title":"Reference Standards for the Detection of Anti-Mitochondrial and Anti-Rods\/Rings Autoantibodies","volume":"56","author":"Calise","year":"2018","journal-title":"Clin Chem Lab Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-eular.238","article-title":"Classification Criteria for Systemic Sclerosis: An American College of Rheumatology\/European League Against Rheumatism Collaborative Initiative","volume":"72","author":"van den Hoogen","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1097\/00002281-199711000-00008","article-title":"Classification Criteria for the Idiopathic Inflammatory Myopathies","volume":"9","author":"Targoff","year":"1997","journal-title":"Curr Opin Rheumatol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2014.01.019","article-title":"The Diagnosis and Classification of Undifferentiated Connective Tissue Diseases","author":"Mosca","year":"2014","journal-title":"J Autoimmun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.01.041","article-title":"The Diagnosis of Primary Biliary Cirrhosis","volume":"13","author":"Bowlus","year":"2014","journal-title":"Autoimmun Rev"},{"key":"B15","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1002\/hep.22906","article-title":"Primary Biliary Cirrhosis","volume":"50","author":"Lindor","year":"2009","journal-title":"Hepatology"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200002)43:2<444::AID-ANR27>3.0.CO;2-G","article-title":"Systemic Sclerosis Sine Scleroderma: Demographic, Clinical, and Serologic Features and Survival in Forty-Eight Patients","volume":"43","author":"Poormoghim","year":"2000","journal-title":"Arthritis Rheum"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-203716","article-title":"Preliminary Analysis of the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) EUSTAR Multicentre Study: Evidence for Puffy Fingers as a Pivotal Sign for Suspicion of Systemic Sclerosis","volume":"73","author":"Minier","year":"2014","journal-title":"Ann Rheum Dis"},{"key":"B18","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1752-699X.2010.00228.x","article-title":"Bronchoalveolar Lavage Fluid and Progression of Scleroderma Interstitial Lung Disease","volume":"6","author":"De Santis","year":"2012","journal-title":"Clin Respir J"},{"key":"B19","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1186\/1465-9921-6-96","article-title":"Functional, Radiological and Biological Markers of Alveolitis and Infections of the Lower Respiratory Tract in Patients With Systemic Sclerosis","volume":"6","author":"De Santis","year":"2005","journal-title":"Respir Res"},{"key":"B20","doi-asserted-by":"publisher","first-page":"R97","DOI":"10.1186\/ar3822","article-title":"Anti-MJ\/NXP-2 Autoantibody Specificity in a Cohort of Adult Italian Patients With Polymyositis\/Dermatomyositis","volume":"14","author":"Ceribelli","year":"2012","journal-title":"Arthritis Res Ther"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.100316","article-title":"Anti-Th\/To Are Common Antinucleolar Autoantibodies in Italian Patients With Scleroderma","volume":"37","author":"Ceribelli","year":"2010","journal-title":"J Rheumatol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2017.06.004","article-title":"Inflammatory Myopathy Associated With Anti-Mitochondrial Antibodies: A Distinct Phenotype With Cardiac Involvement","volume":"47","author":"Albayda","year":"2018","journal-title":"Semin Arthritis Rheum"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29059","article-title":"The Fingerprint of Antimitochondrial Antibodies and the Etiology of Primary Biliary Cholangitis","volume":"65","author":"Shuai","year":"2017","journal-title":"Hepatology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.8b00357","article-title":"Atomic Structure of the E2 Inner Core of Human Pyruvate Dehydrogenase Complex","volume":"57","author":"Jiang","year":"2018","journal-title":"Biochemistry"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1055\/s-2007-1007183","article-title":"Antimitochondrial Antibodies in Primary Biliary Cirrhosis","volume":"17","author":"Leung","year":"1997","journal-title":"Semin Liver Dis"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2014.08.024","article-title":"Autoantibody Profiling of Patients With Primary Biliary Cirrhosis Using a Multiplexed Line-Blot Assay","volume":"438","author":"Villalta","year":"2015","journal-title":"Clin Chim Acta"},{"key":"B27","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1055\/s-2007-1007182","article-title":"Biochemistry and Autoimmune Response to the 2-Oxoacid Dehydrogenase Complexes in Primary Biliary Cirrhosis","volume":"17","author":"Bassendine","year":"1997","journal-title":"Semin Liver Dis"},{"key":"B28","article-title":"The Diagnostic Value of Anti-Mitochondrial Antibodies, Especially in Primary Biliary Cirrhosis","volume":"48","author":"Tanaka","year":"2002","journal-title":"Cell Mol Biol (Noisy-le-grand)"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1056\/NEJM198301063080101","article-title":"The Prognostic Importance of Clinical and Histologic Features in Asymptomatic and Symptomatic Primary Biliary Cirrhosis","volume":"308","author":"Roll","year":"1983","journal-title":"N Engl J Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840060609","article-title":"Positive Antimitochondrial Antibody But Normal Alkaline Phosphatase: Is This Primary Biliary Cirrhosis","volume":"6","author":"Mitchison","year":"1986","journal-title":"Hepatology"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2018.03.014","article-title":"Comment on: Inflammatory Myopathy Associated With Anti-Mitochondrial Antibodies: A Distinct Phenotype With Cardiac Involvement","volume":"48","author":"Ceribelli","year":"2019","journal-title":"Semin Arthritis Rheum"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.822996\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T06:06:55Z","timestamp":1646028415000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.822996\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,28]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2022.822996"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.822996","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,28]]},"article-number":"822996"}}