{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:01:24Z","timestamp":1790380884197,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,9,12]],"date-time":"2015-09-12T00:00:00Z","timestamp":1442016000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002541","name":"Pohang University of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002541","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Periodontal Research"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec><jats:title>Background and Objective<\/jats:title><jats:p>Epitope spreading is one of valid mechanisms operating in immunopathological processes of infection\u2010induced autoimmune diseases. We hypothesized that the peptide 19 from Porphyromonas gingivalis heat shock protein (HSP) 60 (Pep19) may be the dominant epitope from which epitope\u2010specific immune response to subdominant epitopes may diversify sequentially into autoimmune responses directed at human neoepitopes in P. gingivalis\u2010induced periodontitis and autoimmune diseases. However, the exact feature and mechanism on how Pep19 may drive epitope spreading into human autoantigens in chronic periodontitis or P. gingivalis\u2010induced experimental periodontitis has not been clarified. The present study was performed with the following specific aims: (i) to delineate retrospectively the features of epitope spreading by human cross\u2010sectional analysis; (ii) to demonstrate prospectively the epitope spreading into new antigenic determinants in an ordered, predictable and sequential manner in experimental periodontitis; and (iii) to clarify the mechanism on how immunization with Pep19 may mobilize helper T cells or elicit B\u2010cell responses to human autoantigens and neoantigen.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>The study was devised for two independent investigations \u2013 a cross\u2010sectional analysis on clinical subjects and a prospective analysis on experimental periodontitis \u2013 each being subdivided further into two additional independent observations. Cross\u2010sectional dot immunoblot pattern against a panel of peptides of <jats:italic>P.\u00a0gingivalis <\/jats:italic><jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content>60 and human <jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content>60 was performed among age\u2010dependent healthy subjects and between healthy subjects, patients with chronic periodontitis and patients with autoimmune disease, to identify epitope spreading. A peptide\u2010specific T\u2010cell line was established for phenotype analysis and for proliferation assay to an array of identical peptides. An identical prospective analysis was performed in <jats:italic>P.\u00a0gingivalis<\/jats:italic>\u2010induced experimental periodontitis or in Pep19\u2010immunized mice. Cross\u2010reactivity of anti\u2010Pep19 monoclonal antibody was also investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A dominant immune response exclusively to Pep19 prevailed in healthy human subjects (before the age of 40) and mice that persisted in chronic periodontitis and autoimmune diseases without being replaced further by subsequent subdominant epitopes. A sequential epitope spreading provoked by Pep19 to subdominant autoantigen peptide 19 from human <jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content>60 (Hu19) in most healthy human subjects and mice, and to autoantigen peptide 9 from human <jats:styled-content style=\"fixed-case\">HSP<\/jats:styled-content>60 (Hu9) and neoantigen oxidized low\u2010density lipoprotein (ox\u2010<jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content>) in <jats:italic>P.\u00a0gingivalis<\/jats:italic>\u2010induced chronic periodontitis and autoimmune diseases could be demonstrated in a reproducible and predictable manner. T\u2010cell proliferative activity to multiple autoantigens Hu19, Hu9 and ox\u2010<jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content>, and cross\u2010reactivity of anti\u2010Pep19 monoclonal antibody to these epitopes may be proposed as cellular and molecular mechanisms responsible for the phenomenon. Moreover, the predictive value of Pep19 for Hu9 increased remarkably in the disease group when compared with that of the healthy group.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Taken together, epitope spreading to Hu19, Hu9 and ox\u2010<jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content> provoked by Pep19 could be proposed as a solid phenomenon observed in <jats:italic>P.\u00a0gingivalis<\/jats:italic>\u2010induced chronic periodontitis and infection\u2010induced autoimmune diseases in a reproducible and predictable manner. T\u2010cell proliferative activity to these peptides and cross\u2010reactivity of anti\u2010Pep19 antibodies to multiple human autoantigens could be proposed as cellular and molecular mechanisms responsible for this phenomenon.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jre.12318","type":"journal-article","created":{"date-parts":[[2015,9,12]],"date-time":"2015-09-12T05:52:49Z","timestamp":1442037169000},"page":"381-394","source":"Crossref","is-referenced-by-count":16,"title":["Pep19 drives epitope spreading in periodontitis and periodontitis\u2010associated autoimmune diseases"],"prefix":"10.1111","volume":"51","author":[{"given":"E.\u2010Y.","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Periodontology School of Dentistry Pusan National University Yangsan City Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. S.","family":"Cha","sequence":"additional","affiliation":[{"name":"Department of Periodontology School of Dentistry Pusan National University Yangsan City Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology School of Natural Sciences Pusan National University Pusan Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.\u2010Y.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Periodontology School of Dentistry Pusan National University Yangsan City Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.\u2010J.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Periodontology School of Dentistry Pusan National University Yangsan City Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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