Sara Bruzzaniti1,2, Erica Piemonte3, Enza Mozzillo4, Dario Bruzzese5, Maria Teresa Lepore1, Fortunata Carbone1,6, Paola de Candia3, Rocky Strollo7, Antonio Porcellini2, Marco Marigliano8, Claudio Maffeis8, Maurizio Bifulco3, Johnny Ludvigsson9, Adriana Franzese4, Giuseppe Matarese1,3, Mario Galgani10,11. 1. Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy. 2. Dipartimento di Biologia, Università degli Studi di Napoli 'Federico II', Naples, Italy. 3. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli 'Federico II', Naples, Italy. 4. Dipartimento di Scienze Mediche Traslazionali, Università degli Studi di Napoli 'Federico II', Naples, Italy. 5. Dipartimento di Sanità Pubblica, Università degli Studi di Napoli 'Federico II', Naples, Italy. 6. Unità di Neuroimmunologia, Fondazione Santa Lucia, Rome, Italy. 7. Dipartimento di Scienze e Tecnologie per l'Uomo e l'Ambiente, Università Campus Bio-Medico di Roma, Rome, Italy. 8. Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics and Gynecology, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy. 9. Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, and Crown Princess Victoria Children's Hospital, Region Östergötland, Linköping, Sweden. 10. Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale 'G. Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy. mario.galgani@unina.it. 11. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli 'Federico II', Naples, Italy. mario.galgani@unina.it.
Abstract
AIMS/HYPOTHESIS: We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time. METHODS: Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups. RESULTS: We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD+ children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD- children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts. CONCLUSIONS/ INTERPRETATION: Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time.
AIMS/HYPOTHESIS: We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time. METHODS: Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups. RESULTS: We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD+ children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD- children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts. CONCLUSIONS/ INTERPRETATION: Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time.
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