Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes
Year: 2014
Type: article
Study design: Observational Study
Abstract: 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.
Source: Diabetes
DOI: 10.2337/db14-0365
Authors: Sefina Arif, Pia Leete, Vy Nguyen, Katherine Marks, Nurhanani Mohamed Nor, Megan Estorninho, Deborah Kronenberg-Versteeg, Polly J. Bingley, John A. Todd, Catherine Guy, David B. Dunger, Jake Powrie, Abby Willcox, Alan K. Foulis, Sarah J. Richardson, Emanuele de Rinaldis, Noel G. Morgan, Anna Lorenc, Mark Peakman
Institutions: King's College London, University of Exeter, University of Bristol, University of Cambridge, Addenbrooke's Hospital, Wellcome Trust, National Health Service, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, Southern General Hospital, National Institute for Health and Care Research
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Awards: G1132206153, Los Angeles Basin Clinical and Translational Science Institute, UF Clinical and Translational Science Award, UT Southwestern Center for Translational Medicine (UL1/KL2/TL1), Clinical and Translational Science Institute, Type 1 Diabetes TrialNet: Clinical Centers, TrialNet: University of Florida Clinical Center and Network, Type 1 Diabetes TrialNet at Indiana University Clinical Center, Type 1 Diabetes-A Proposal for Prevention & Intervention, CLINICAL AFFILIATE OF THE TYPE 1 DIABETES TRIALNET, GCRC-General Clinical Research Center, NIHR Senior Investigator Award, Type 1 Diabetes Trialnet: Operations Coord. Center, Diabetes and Inflammation Laboratory., Spectrum Stanford Center for clinical and Translational Research and Education, Stanford Center for Clinical and Translational Education and Research (SCCTER)UL1, Type 1 Diabetes-A Proposal for Prevention & Intervention, Continuation of UCSF as a Clinical Center for TrialNet, University of Pittsburgh Clinical and Translational Science Institute, Prediction and Prevention of Type 1 Diabetes (TrialNet), Northwest Clinical Center for Type 1 Diabetes - TrialNet, Cellular Medicine at the Cambridge Institute for Medical Research., North and Central Texas Clinical and Translational Science Initiative (UL1), Indiana Clinical and Translational Science Institute (UL1), NIHR Senior Investigator Award, NIHR Senior Investigator Award, TrialNet at Stanford University, Colorado Clinical and Translational Sciences Institute, Clinical and Translational Science Institute, NIHR Senior Investigator Award, Type 1 Diabetes TrialNet: Toronto Clinical Centre, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, G7133194941, Type 1 Diabetes TrialNet: Clinical Centers (U01), Type 1 Diabetes TrialNet: Support Facilities, Type 1 diabetes TrialNet Center at Yale University, Yale University Clinical and Translational Science Award Program, Yale University Clinical and Translational Science Award Program, TrialNet: Diabetes Type 1 Prevention, G871789362, Colorado Clinical and Translational Science Institute (UL1)
OpenAlex ID: W2013100047