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However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS\/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell activation by oxPTM-INSPs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We observed antibody and T cell responses to three out of six LC-MS\/MS-identified insulin peptide candidates: A:12\u201321 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11\u201330 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21\u201330 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (\n                      <jats:italic>p<\/jats:italic>\n                      \u22640.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [\n                      <jats:sup>\u25cf<\/jats:sup>\n                      OH] and &gt;88% to in silico-oxidised peptide;\n                      <jats:italic>p<\/jats:italic>\n                      \u22640.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4\n                      <jats:sup>+<\/jats:sup>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      &lt;0.001) and CD8\n                      <jats:sup>+<\/jats:sup>\n                      (\n                      <jats:italic>p<\/jats:italic>\n                      =0.049). CD4\n                      <jats:sup>+<\/jats:sup>\n                      response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%;\n                      <jats:italic>p<\/jats:italic>\n                      =0.039). Among individuals with type 1 diabetes, the CD4\n                      <jats:sup>+<\/jats:sup>\n                      response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%;\n                      <jats:italic>p<\/jats:italic>\n                      =0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells and autoantibodies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-022-05812-4","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T15:02:42Z","timestamp":1665154962000},"page":"132-146","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes"],"prefix":"10.1007","volume":"66","author":[{"given":"Rocky","family":"Strollo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Vinci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. 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