Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

180 Citations (Scopus)

Abstract

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of beta-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-gamma-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 CD2OLo." 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.

Original languageEnglish
Pages (from-to)3835-3845
Number of pages11
JournalDiabetes
Volume63
Issue number11
Early online date1 Nov 2014
DOIs
Publication statusPublished - 1 Nov 2014

Keywords

  • T-CELL RESPONSES
  • PLACEBO-CONTROLLED TRIAL
  • ZINC TRANSPORTER 8
  • KILL BETA-CELLS
  • C-PEPTIDE
  • ONSET
  • AGE
  • CLASSIFICATION
  • MODULATION
  • AUTOIMMUNE

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