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Diabetic medicine : a journal of the British Diabetic Association v.34 no.3, 2017년, pp.419 - 425   SCI SCIE
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β‐cell specific T‐lymphocyte response has a distinct inflammatory phenotype in children with Type 1 diabetes compared with adults

Arif, S. (Department of Immunobiology, King's College London, London ) ; Gibson, V. B. (Department of Immunobiology, King's College London, London ) ; Nguyen, V. (Department of Immunobiology, King's College London, London ) ; Bingley, P. J. (School of Clinical Sciences, University of Bristol, Bristol, UK ) ; Todd, J. A. (JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK ) ; Guy, C. (University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, UK ) ; Dunger, D. B. (University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, UK ) ; Dayan, C. M. (Institute of Molecular and Experimental Medicine, Cardiff University School of Medicine, Cardiff, UK ) ; Powrie, J. (Department of Diabetes and Endocrinology, Guy's & St Thom ) ; Lorenc, A. ; Peakman, M. ;
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    Abstract Aim To examine the hypothesis that the quality, magnitude and breadth of helper T‐lymphocyte responses to β cells differ in Type 1 diabetes according to diagnosis in childhood or adulthood. Methods We studied helper T‐lymphocyte reactivity against β‐cell autoantigens by measuring production of the pro‐inflammatory cytokine interferon‐γ and the anti‐inflammatory cytokine interleukin‐10, using enzyme‐linked immunospot assays in 61 people with Type 1 diabetes (within 3 months of diagnosis, positive for HLA DRB1*0301 and/or *0401 ), of whom 33 were children/adolescents, and a further 91 were unaffected siblings. Results Interferon‐γ responses were significantly more frequent in children with Type 1 diabetes compared with adults (85 vs 61%; P = 0.04). Insulin and proinsulin peptides were preferentially targeted in children ( P = 0.0001 and P = 0.04, respectively) and the breadth of the interferon‐γ response was also greater, with 70% of children having an interferon‐γ response to three or more peptides compared with 14% of adults ( P Conclusions At diagnosis of Type 1 diabetes, pro‐inflammatory autoreactivity is significantly more prevalent, focuses on a wider range of targets, and is more focused on insulin/proinsulin in children than adults. We interpret this as indicating a more aggressive immunological response in the younger age group that is especially characterized by loss of tolerance to proinsulin. These findings highlight the existence of age‐related heterogeneity in Type 1 diabetes pathogenesis that could have relevance to the development of immune‐based therapies.


    What's new? Type 1 diabetes development in children appears more rapid and severe compared with that in adults. This paper shows that immune responses against β cells are more common and target more autoantigens in children compared with adults. In addition, the immune response in children is particularly focused on proinsulin and insulin as the main drivers of the autoimmune response.The findings of this study suggest age‐related immunological heterogeneity in Type 1 diabetes. This may be important in developing age‐appropriate immune‐intervention strategies.


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