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Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb<jats:sup>+<\/jats:sup>) children to identify molecules related to type 1 diabetes progression.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We measured the levels of 14 sICM in the sera of AAb<jats:sup>+<\/jats:sup> children (<jats:italic>n<\/jats:italic>=57) compared to those with recent-onset type 1 diabetes (<jats:italic>n<\/jats:italic>=79) and healthy children (<jats:italic>n<\/jats:italic>=44), obtained from two cohorts. AAb<jats:sup>+<\/jats:sup> children were followed up and divided based on their progression to type 1 diabetes (AAb<jats:sup>P<\/jats:sup>) or not (AAb<jats:sup>NP<\/jats:sup>) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAb<jats:sup>P<\/jats:sup> children.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We found that AAb<jats:sup>+<\/jats:sup> children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb<jats:sup>+<\/jats:sup> children who progressed to type 1 diabetes (AAb<jats:sup>P<\/jats:sup>) had higher sICM concentrations than non-progressors (AAb<jats:sup>NP<\/jats:sup>). Further, sICM levels decreased in AAb<jats:sup>P<\/jats:sup> children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; <jats:italic>p<\/jats:italic>=0.007).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions\/interpretation<\/jats:title>\n                <jats:p>This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical Abstract<\/jats:title>\n                \n              <\/jats:sec>","DOI":"10.1007\/s00125-023-06075-3","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T07:02:35Z","timestamp":1705042955000},"page":"714-723","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Progression of type 1 diabetes is associated with high levels of soluble PD-1 in islet autoantibody-positive children"],"prefix":"10.1007","volume":"67","author":[{"given":"Sara","family":"Bruzzaniti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Piemonte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dario","family":"Bruzzese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Lepore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocky","family":"Strollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lavinia","family":"Izzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Di Candia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Franzese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Bifulco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enza","family":"Mozzillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnny","family":"Ludvigsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Matarese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Galgani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,1,12]]},"reference":[{"issue":"11","key":"6075_CR1","doi-asserted-by":"publisher","first-page":"a007641","DOI":"10.1101\/cshperspect.a007641","volume":"2","author":"MA Atkinson","year":"2012","unstructured":"Atkinson MA (2012) The pathogenesis and natural history of type 1 diabetes. 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Marigliano and G. Caterino (Laboratorio di Immunogenetica dei Trapianti Azienda Ospedaliera Federico II, Naples, Italy) for HLA typing assistance. We would also like to acknowledge M. Montagna and S. De Simone (Istituto per l'Endocrinologia e l'Oncologia Sperimentale \u2018G. Salvatore\u2019, Consiglio Nazionale delle Ricerche [IEOS-CNR], Naples, Italy), and all members of the IEOS-CNR for their technical support. Figure a was developed using adapted images from Smart Servier Medical Art ().","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Any additional information required to reanalyse the data reported in this paper is available from Mario Galgani upon request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This study was supported by grants from the European Foundation for the Study of Diabetes\/Novo Nordisk Programme for Diabetes Research in Europe 2020, the Fondazione Italiana Sclerosi Multipla (grant agreement 2020\/R\/13), the Progetti di Rilevante Interesse Nazionale (grant agreement 202077EYN7) and the \u2018Inflammation in human early life: targeting impacts on life-course health\u2019 (INITIALISE) consortium, funded by the Horizon Europe Program of the European Union under grant agreement 101094099 to MG, plus grants to GM from Fondazione Italiana Sclerosi Multipla (grant 2018\/S\/5), Progetti di Rilevante Interesse Nazionale (grant 2017 K55HLC 001), Ministero della Salute (grant RF-2019-12371111) and Ministero dell\u2019Universit\u00e0 e Ricerca (INF-ACT grant PE00000007 and MYNESYS grant PE00000006). The ABIS study was supported by the Barndiabetesfonden (Swedish Child Diabetes Foundation), the Swedish Council for Working Life and Social Research (grant\/award number FAS2004-1775), the Swedish Research Council (grant\/award numbers K2005-72X-11242-11A, and K2008-69X-20826-01-4), the \u00d6stg\u00f6ta Brandstodsbolag, the Medical Research Council of Southeast Sweden, the JDRF Wallenberg Foundation (grant\/award K 98-99D-12813-01A), ALF-Region \u00d6sterg\u00f6tland and LFoU-Link\u00f6ping University, Sweden grants.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"MG designed and supervised the study. SB, EP and LI performed experiments. FDC, AF, EM and JL were responsible for recruitment of the children and the collection of clinical data. SB, EP and MTL contributed to the analysis and interpretation of results. DB performed the statistical analyses. SB, EP, EM, RS, MB, GM, JL and MG were involved in the data discussion and revised the work for its intellectual content. SB, GM and MG performed the final data interpretation and wrote the manuscript. All authors reviewed the results and approved the final version of the manuscript. MG is the guarantor of this work, and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}