{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T03:48:58Z","timestamp":1790480938678,"version":"4.1.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T00:00:00Z","timestamp":1678320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009873","name":"Regione Autonoma della Sardegna","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009873","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003390","name":"Fritz Thyssen Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003390","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014810","name":"Fondazione di Sardegna","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014810","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>T cell reactivity against pancreatic autoantigens is considered one of the main contributors to the destruction of insulin-producing cells in type 1 diabetes (T1D). Over the years, peptide epitopes derived from these autoantigens have been described in NOD mice and in both HLA class II transgenic mice and humans. However, which ones are involved in the early onset or in the progressive phases of the disease is still unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this work we have investigated, in early-onset T1D pediatric patients and HLA-matched controls from Sardinia, the potential of preproinsulin (PPI) and glutamate decarboxylase 65 (GAD65)-derived peptides to induce spontaneous T cell proliferation responses of peripheral blood mononuclear cells (PBMCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Significant T cell responses against PPI1-18, PPI7-19 and PPI31-49, the first two belonging to the leader sequence of PPI, and GAD65271-285 and GAD65431-450, were found in HLA-DR4, -DQ8 and -DR3, -DQ2 T1D children.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data show that cryptic epitopes from the leader sequence of the PPI and GAD65271-285 and  GAD65431-450 peptides might be among the critical antigenic epitopes eliciting the primary autoreactive responses in the early phases of the disease. These results may have implications in the design of immunogenic PPI and GAD65 peptides for peptide-based immunotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1130019","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T07:26:44Z","timestamp":1678346804000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Peripheral blood mononuclear cells reactivity in recent-onset type I diabetes patients is directed against the leader peptide of preproinsulin, GAD65271-285 and GAD65431-450"],"prefix":"10.3389","volume":"14","author":[{"given":"Rita D.","family":"Jores","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Baldera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Schirru","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Muntoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossano","family":"Rossino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Manchinu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria F.","family":"Marongiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristian A.","family":"Caria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Ripoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria R.","family":"Ricciardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Cucca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Congia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81106-X","article-title":"Insulin-dependent diabetes mellitus","volume":"85","author":"Tisch","year":"1996","journal-title":"Cell"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abh1654","article-title":"Immunotherapy: Building a bridge to a cure for type 1 diabetes","volume":"373","author":"Bluestone","year":"2021","journal-title":"Science"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.abi4742","article-title":"Preventing type 1 diabetes in childhood","volume":"373","author":"Dayan","year":"2021","journal-title":"Science"},{"key":"B4","first-page":"55","article-title":"HLA and diabetes","volume":"103","author":"Svejgaard","year":"1982","journal-title":"Prog Clin Biol Res"},{"key":"B5","article-title":"HLA DR antigens and susceptibility to insulin-dependent diabetes mellitus","volume":"36","author":"Thomson","year":"1984","journal-title":"Am J Hum Genet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/329599a0","article-title":"HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus","volume":"329","author":"Todd","year":"1987","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI114569","article-title":"A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus","volume":"85","author":"Khalil","year":"1990","journal-title":"J Clin Invest"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113965","article-title":"A diabetes-susceptible HLA haplotype is best defined by a combination of HLA-DR and -DQ alleles","volume":"83","author":"Sheehy","year":"1989","journal-title":"J Clin Invest"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/ng0493-358","article-title":"HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families","volume":"3","author":"Erlich","year":"1993","journal-title":"Nat Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"17016","DOI":"10.1038\/nrdp.2017.16","article-title":"Type 1 diabetes mellitus","volume":"3","author":"Katsarou","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2015.07.014","article-title":"Immunogenetics of type 1 diabetes: A comprehensive review","volume":"64","author":"Noble","year":"2015","journal-title":"J Autoimmun"},{"key":"B12","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/0198-8859(93)90146-R","article-title":"Combinations of specific DRB1, DQA1, DQB1 haplotypes are associated with insulin-dependent diabetes mellitus in Sardinia","volume":"37","author":"Cucca","year":"1993","journal-title":"Hum Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/0198-8859(95)00042-3","article-title":"The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci","volume":"43","author":"Cucca","year":"1995","journal-title":"Hum Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/S0003-3995(02)01104-8","article-title":"HLA polymorphism in type 1 diabetes tunisians","volume":"45","author":"Abid Kamoun","year":"2002","journal-title":"Ann Genet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/ng.3353","article-title":"Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk","volume":"47","author":"Hu","year":"2015","journal-title":"Nat Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.19.2025","article-title":"A correlation between the relative predisposition of MHC class II alleles to type 1 diabetes and the structure of their proteins","volume":"10","author":"Cucca","year":"2001","journal-title":"Hum Mol Genet"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2249.2006.03244.x","article-title":"Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes","volume":"148","author":"Di Lorenzo","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI94549","article-title":"Autoreactive T cells in type 1 diabetes","volume":"127","author":"Pugliese","year":"2017","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4308-1","article-title":"Early prediction of autoimmune (type 1) diabetes","volume":"60","author":"Regnell","year":"2017","journal-title":"Diabetologia"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2337\/dbi17-0030","article-title":"Immune recognition of beta-cells: Neoepitopes as key players in the loss of tolerance","volume":"67","author":"James","year":"2018","journal-title":"Diabetes"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.667989","article-title":"Neoepitopes in type 1 diabetes: Etiological insights, biomarkers and therapeutic targets","volume":"12","author":"Rodriguez-Calvo","year":"2021","journal-title":"Front Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1023\/B:JOCI.0000029120.77824.41","article-title":"T Cells recognize multiple GAD65 and proinsulin epitopes in human type 1 diabetes, suggesting determinant spreading","volume":"24","author":"Ott","year":"2004","journal-title":"J Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1196\/annals.1337.003","article-title":"CD4+ T cell proliferation in response to GAD and proinsulin in healthy, pre-diabetic, and diabetic donors","volume":"1037","author":"Mannering","year":"2004","journal-title":"Ann N Y Acad Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aao4013","article-title":"Islet-reactive CD8(+) T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors","volume":"3","author":"Culina","year":"2018","journal-title":"Sci Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1999.tb01377.x","article-title":"HLA class II transgenic mice: models of the human CD4+ T-cell immune response","volume":"172","author":"Sonderstrup","year":"1999","journal-title":"Immunol Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.15.8082","article-title":"Identification of immunodominant T cell epitopes of human glutamic acid decarboxylase 65 by using HLA-DR(\u03b11*0101,\u03b21*0401) transgenic mice","volume":"94","author":"Patel","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.7.3833","article-title":"T Cell epitopes of insulin defined in HLA-DR4 transgenic mice are derived from preproinsulin and proinsulin","volume":"95","author":"Congia","year":"1998","journal-title":"Proc Natl Acad Sci USA"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.11.6275","article-title":"Determination of glutamic acid decarboxylase 65 peptides presented by the type I diabetes-associated HLA-DQ8 class II molecule identifies an immunogenic peptide motif","volume":"163","author":"Herman","year":"1999","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-019-04994-8","article-title":"Proinsulin peptide promotes autoimmune diabetes in a novel HLA-DR3-DQ2-transgenic murine model of spontaneous disease","volume":"62","author":"Verhagen","year":"2019","journal-title":"Diabetologia"},{"key":"B30","doi-asserted-by":"publisher","first-page":"621693","DOI":"10.1155\/2013\/621693","article-title":"Application of IgG-derived natural treg epitopes (IgG tregitopes) to antigen-specific tolerance induction in a murine model of type 1 diabetes","volume":"2013","author":"Cousens","year":"2013","journal-title":"J Diabetes Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809208115","article-title":"Proinsulin c-peptide is an autoantigen in people with type 1 diabetes","volume":"115","author":"So","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901079","article-title":"Characterization of proinsulin T cell epitopes restricted by type 1 diabetes\u2013associated HLA class II molecules","volume":"204","author":"Ihantola","year":"2020","journal-title":"J Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S0198-8859(97)00212-7","article-title":"T Cell recognition of human pre-proinsulin peptides depends on the polymorphism at HLA DQ locus: A study using HLA DQ8 and DQ6 transgenic mice","volume":"58","author":"Raju","year":"1997","journal-title":"Hum Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.20.2959","article-title":"The inter-regional distribution of HLA class II haplotypes indicates the suitability of the sardinian population for case-control association studies in complex diseases","volume":"9","author":"Lampis","year":"2000","journal-title":"Hum Mol Genet"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.2337\/dbi19-0022","article-title":"T-Cell epitopes and neo-epitopes in type 1 diabetes: A comprehensive update and reappraisal","volume":"69","author":"James","year":"2020","journal-title":"Diabetes"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000003129","article-title":"Low-risk human leukocyte antigen genes and mild villous atrophy typify celiac disease with immunoglobulin a deficiency","volume":"72","author":"Schirru","year":"2021","journal-title":"J Pediatr Gastroenterol Nutr"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050893","article-title":"The sardinian IDDM study: 1. epidemiology and geographical distribution of IDDM in Sardinia during 1989 to 1994","volume":"41","author":"Songini","year":"1998","journal-title":"Diabetologia"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.2337\/db11-0270","article-title":"Single insulin-specific CD8+ T cells show characteristic gene expression profiles in human type 1 diabetes","volume":"60","author":"Luce","year":"2011","journal-title":"Diabetes"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2107208118","article-title":"Human islet T cells are highly reactive to preproinsulin in type 1 diabetes","volume":"118","author":"Anderson","year":"2021","journal-title":"Proc Natl Acad Sci USA"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1172\/JCI8525","article-title":"A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin","volume":"107","author":"Alleva","year":"2001","journal-title":"J Clin Invest"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0666","article-title":"Increased effector memory insulin-specific CD4(+) T cells correlate with insulin autoantibodies in patients with recent-onset type 1 diabetes","volume":"66","author":"Spanier","year":"2017","journal-title":"Diabetes"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416864111","article-title":"Autoreactive T cells specific for insulin B:11-23 recognize a low-affinity peptide register in human subjects with autoimmune diabetes","volume":"111","author":"Yang","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05130-7","article-title":"GAD-alum immunotherapy in type 1 diabetes expands bifunctional Th1\/Th2 autoreactive CD4 T cells","volume":"63","author":"Arif","year":"2020","journal-title":"Diabetologia"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.49.2.202","article-title":"Maturation of the humoral autoimmune response to epitopes of GAD in preclinical childhood type 1 diabetes","volume":"49","author":"Bonifacio","year":"2000","journal-title":"Diabetes"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/j.0300-9475.2004.01402.x","article-title":"Antibodies to GAD65 epitopes at diagnosis and over the first 10 years of clinical type 1 diabetes mellitus","volume":"59","author":"Ronkainen","year":"2004","journal-title":"Scand J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s001250050031","article-title":"Epitope spreading and a varying but not disease-specific GAD65 antibody response in type I diabetes. the childhood diabetes in Finland study group","volume":"43","author":"Sohnlein","year":"2000","journal-title":"Diabetologia"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3514-y","article-title":"The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: The TEDDY study","volume":"58","author":"Krischer","year":"2015","journal-title":"Diabetologia"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.48.3.469","article-title":"Major DQ8-restricted T-cell epitopes for human GAD65 mapped using human CD4, DQA1*0301, DQB1*0302 transgenic IA(null) NOD mice","volume":"48","author":"Liu","year":"1999","journal-title":"Diabetes"},{"key":"B49","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s002510050238","article-title":"Identification of immunogenic epitopes of GAD 65 presented by Ag7 in non-obese diabetic mice","volume":"46","author":"Chao","year":"1997","journal-title":"Immunogenetics"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0405500101","article-title":"Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells","volume":"101","author":"Kim","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)04241-9","article-title":"Incidence of insulin-dependent diabetes mellitus among sardinian-heritage children born in Lazio region, Italy","volume":"349","author":"Muntoni","year":"1997","journal-title":"Lancet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1130019\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T07:26:48Z","timestamp":1678346808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1130019\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,9]]},"references-count":51,"alternative-id":["10.3389\/fimmu.2023.1130019"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1130019","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,9]]},"article-number":"1130019"}}