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Diabetes. 2014 Nov;63(11):3835-45. doi: 10.2337/db14-0365. Epub 2014 Jun 17.

Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes.

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Department of Immunobiology, King's College London School of Medicine, London, U.K.
Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, Devon, U.K.
School of Clinical Sciences, University of Bristol, Bristol, U.K.
JDRF/Wellcome Trust Diabetes and Inflammation Laboratory, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K.
University Department of Paediatrics, Addenbrooke's Hospital, Cambridge, U.K.
Department of Diabetes and Endocrinology, Guy's & St Thomas' Hospital NHS Foundation Trust, London, U.K.
Greater Glasgow and Clyde Pathology Department, Southern General Hospital, Glasgow, U.K.
National Institute for Health Research Biomedical Research Centre at Guy's and St Thomas' Hospital Foundation Trust and King's College London, London, U.K.
Department of Immunobiology, King's College London School of Medicine, London, U.K.


Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology. We sought evidence for different immunological phenotypes using two approaches. First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes. Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses. Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering. Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically. This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed "hyper-immune CD20Hi" and "pauci-immune CD20Lo." Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger. These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease. We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

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