{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T08:07:43Z","timestamp":1759133263529,"version":"3.37.3"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T00:00:00Z","timestamp":1637020800000},"content-version":"vor","delay-in-days":1890,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003793","name":"Swedish Heart-Lung Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003793","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004348","name":"Stockholm County Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004348","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004047","name":"Karolinska Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004047","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007949","name":"Swedish Rheumatism Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007949","id-type":"DOI","asserted-by":"publisher"}]},{"name":"King Gustaf the Vth 80 year Foundation"},{"name":"Freemason Children Foundation Stockholm"},{"DOI":"10.13039\/100007464","name":"Torsten and Ragnar S\u00f6derberg Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007464","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,11,9]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1\u20132% of anti-Ro\/Sj\u00f6gren's-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies.<\/jats:p>","DOI":"10.1111\/cei.12854","type":"journal-article","created":{"date-parts":[[2016,8,22]],"date-time":"2016-08-22T13:37:38Z","timestamp":1471873058000},"page":"284-291","source":"Crossref","is-referenced-by-count":6,"title":["Identification of discrete epitopes of Ro52p200 and association with fetal cardiac conduction system manifestations in a rodent model"],"prefix":"10.1093","volume":"186","author":[{"given":"A","family":"Hoxha","sequence":"first","affiliation":[{"name":"Department of Medicine, Rheumatology Unit, University of Padua, Padua, Italy"},{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Ruffatti","sequence":"additional","affiliation":[{"name":"Department of Medicine, Rheumatology Unit, University of Padua, Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Ambrosi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"Ottosson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Hedlund","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Ottosson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Anandapadamanaban","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, Link\u00f6ping University, Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Sunnerhagen","sequence":"additional","affiliation":[{"name":"Department of Medical Biophysics, Link\u00f6ping University, Link\u00f6ping, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S-E","family":"Sonesson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M","family":"Wahren-Herlenius","sequence":"additional","affiliation":[{"name":"Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2016,9,13]]},"reference":[{"key":"2021120807482613800_cei12854-bib-0001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.yexcr.2014.01.003","article-title":"Molecular mechanisms of congenital heart block","volume":"325","author":"Ambrosi","year":"2014","journal-title":"Exp Cell Res"},{"key":"2021120807482613800_cei12854-bib-0002","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/ar3787","article-title":"Congenital heart block: evidence for a pathogenic role of maternal autoantibodies","volume":"14","author":"Ambrosi","year":"2012","journal-title":"Arthritis Res 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disease","volume":"382","author":"Wahren-Herlenius","year":"2013","journal-title":"Lancet"},{"key":"2021120807482613800_cei12854-bib-0006","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/art.11430","article-title":"Immunohistologic evidence supports apoptosis, IgG deposition, and novel macrophage\/fibroblast crosstalk in the pathologic cascade leading to congenital heart block","volume":"50","author":"Clancy","year":"2004","journal-title":"Arthritis Rheum"},{"key":"2021120807482613800_cei12854-bib-0007","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1056\/NEJM198501103120206","article-title":"Maternal connective tissue disease and congenital heart block. Demonstration of immunoglobulin in cardiac tissue","volume":"312","author":"Litsey","year":"1985","journal-title":"N Engl J Med"},{"key":"2021120807482613800_cei12854-bib-0008","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/uog.7343","article-title":"Anti-Ro52\/SSA antibody-exposed fetuses with prolonged atrioventricular time intervals show signs of decreased cardiac performance","volume":"34","author":"Bergman","year":"2009","journal-title":"Ultrasound Obstet Gynecol"},{"key":"2021120807482613800_cei12854-bib-0009","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/ar1690","article-title":"Anti-SSA\/Ro antibodies and the heart: more than complete congenital heart block? A review of electrocardiographic and myocardial abnormalities and of treatment options","volume":"7","author":"Costedoat-Chalumeau","year":"2005","journal-title":"Arthritis Res Ther"},{"key":"2021120807482613800_cei12854-bib-0010","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/S0735-1097(01)01697-7","article-title":"Outcome of children with fetal, neonatal or childhood diagnosis of isolated congenital atrioventricular block. A single institution's experience of 30 years","volume":"39","author":"Jaeggi","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"2021120807482613800_cei12854-bib-0011","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/art.20126","article-title":"Signs of first-degree heart block occur in one-third of fetuses of pregnant women with anti-SSA\/Ro 52-kd antibodies","volume":"50","author":"Sonesson","year":"2004","journal-title":"Arthritis Rheum"},{"key":"2021120807482613800_cei12854-bib-0012","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1038\/nrrheum.2015.29","article-title":"The clinical spectrum of autoimmune congenital heart block","volume":"11","author":"Brito-Zeron","year":"2015","journal-title":"Nat Rev Rheumatol"},{"key":"2021120807482613800_cei12854-bib-0013","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1002\/1529-0131(200108)44:8<1832::AID-ART320>3.0.CO;2-C","article-title":"Risk of congenital complete heart block in newborns of 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block","volume":"55","author":"Tonello","year":"2015","journal-title":"Transfusion"},{"key":"2021120807482613800_cei12854-bib-0024","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1002\/art.10232","article-title":"A serologic marker for fetal risk of congenital heart block","volume":"46","author":"Salomonsson","year":"2002","journal-title":"Arthritis Rheum"},{"key":"2021120807482613800_cei12854-bib-0025","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jaut.2003.11.004","article-title":"Cloning and characterization of two human Ro52-specific monoclonal autoantibodies directed towards a domain associated with congenital heart block","volume":"22","author":"Salomonsson","year":"2004","journal-title":"J Autoimmun"},{"key":"2021120807482613800_cei12854-bib-0026","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1002\/art.21289","article-title":"Maternal antibody responses to the 52-kd SSA\/RO p200 peptide and the development of fetal conduction defects","volume":"52","author":"Clancy","year":"2005","journal-title":"Arthritis Rheum"},{"key":"2021120807482613800_cei12854-bib-0027","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1002\/acr.21704","article-title":"Umbilical cord blood levels of maternal antibodies reactive with p200 and full-length Ro 52 in the assessment of risk for cardiac manifestations of neonatal lupus","volume":"64","author":"Reed","year":"2012","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"2021120807482613800_cei12854-bib-0028","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1203\/01.PDR.0000155947.82365.E4","article-title":"Effect of maternal autoantibodies on fetal cardiac conduction: an experimental murine model","volume":"57","author":"Suzuki","year":"2005","journal-title":"Pediatr Res"},{"key":"2021120807482613800_cei12854-bib-0029","doi-asserted-by":"crossref","first-page":"3574","DOI":"10.4049\/jimmunol.1001396","article-title":"Maternal MHC regulates generation of pathogenic antibodies and fetal MHC-encoded genes determine susceptibility in congenital heart block","volume":"185","author":"Strandberg","year":"2010","journal-title":"J Immunol"},{"key":"2021120807482613800_cei12854-bib-0030","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1136\/annrheumdis-2011-200207","article-title":"Development of heart block in children of SSA\/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern","volume":"71","author":"Ambrosi","year":"2012","journal-title":"Ann Rheum Dis"},{"key":"2021120807482613800_cei12854-bib-0031","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1161\/CIRCULATIONAHA.107.707661","article-title":"Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR Interval and Dexamethasone Evaluation (PRIDE) prospective study","volume":"117","author":"Friedman","year":"2008","journal-title":"Circulation"},{"key":"2021120807482613800_cei12854-bib-0032","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1002\/1529-0131(200102)44:2<487::AID-ANR70>3.0.CO;2-D","article-title":"The rate of recurrence of isolated congenital heart block: a population-based study","volume":"44","author":"Julkunen","year":"2001","journal-title":"Arthritis Rheum"}],"container-title":["Clinical and Experimental 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