Antibodies to post-translationally modified insulin in type 1 diabetes.

Autor: Strollo R; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.; Endocrinology & Diabetes, University Campus Bio-Medico, via Alvaro del Portillo 21, 00128, Rome, Italy., Vinci C; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.; Endocrinology & Diabetes, University Campus Bio-Medico, via Alvaro del Portillo 21, 00128, Rome, Italy., Arshad MH; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK., Perrett D; BioAnalysis, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Tiberti C; Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy., Chiarelli F; Department of Pediatrics, University of Chieti, Ospedale Policlinico, Chieti, Italy., Napoli N; Endocrinology & Diabetes, University Campus Bio-Medico, via Alvaro del Portillo 21, 00128, Rome, Italy.; Division of Bone and Mineral Diseases, Washington University in St Louis, St Louis, MO, USA., Pozzilli P; Endocrinology & Diabetes, University Campus Bio-Medico, via Alvaro del Portillo 21, 00128, Rome, Italy. p.pozzilli@unicampus.it.; Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. p.pozzilli@unicampus.it., Nissim A; Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. a.nissim@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2015 Dec; Vol. 58 (12), pp. 2851-60. Date of Electronic Publication: 2015 Sep 08.
DOI: 10.1007/s00125-015-3746-x
Abstrakt: Aim/hypothesis: Insulin is the most specific beta cell antigen and a potential primary autoantigen in type 1 diabetes. Insulin autoantibodies (IAAs) are the earliest marker of beta cell autoimmunity; however, only slightly more than 50% of children and even fewer adults newly diagnosed with type 1 diabetes are IAA positive. The aim of this investigation was to determine if oxidative post-translational modification (oxPTM) of insulin by reactive oxidants associated with islet inflammation generates neoepitopes that stimulate an immune response in individuals with type 1 diabetes.
Methods: oxPTM of insulin was generated using ribose and various reactive oxygen species. Modifications were analysed by SDS-PAGE, three-dimensional fluorescence and MS. Autoreactivity to oxPTM insulin (oxPTM-INS) was observed by ELISA and western blotting, using sera from participants with type 1 or type 2 diabetes and healthy controls as probes. IAA was measured using the gold-standard radiobinding assay (RBA).
Results: MS of oxPTM-INS identified chlorination of Tyr16 and Tyr26; oxidation of His5, Cys7 and Phe24; and glycation of Lys29 and Phe1 in chain B. Significantly higher binding to oxPTM-INS vs native insulin was observed in participants with type 1 diabetes, with 84% sensitivity compared with 61% sensitivity for RBA. oxPTM-INS autoantibodies and IAA co-existed in 50% of those with type 1 diabetes. Importantly 34% of those with diabetes who were IAA negative were oxPTM-INS positive. Altogether, 95% of participants with type 1 diabetes presented with autoimmunity to insulin by RBA, oxPTM-INS or both. Binding to oxPTM-INS was directed towards oxPTM-INS fragments with slower mobility than native insulin.
Conclusion/interpretation: These data suggest that oxPTM-INS is a potential autoantigen in individuals with new-onset type 1 diabetes.
Databáze: MEDLINE
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