Identification of unique antigenic determinants in the amino terminus of IA-2 (ICA512) in childhood and adult autoimmune diabetes: New biomarker development

Maria Acevedo-Calado, Eddie A. James, Michael P. Morran, Susan L. Pietropaolo, Qin Ouyang, David Arribas-Layton, Marco Songini, Marco Liguori, Anna Casu, Richard J. Auchus, Shuai Huang, Liping Yu, Aaron Michels, Roberto Gianani, Massimo Pietropaolo

Research output: Contribution to journalArticle

Abstract

OBJECTIVE The characterization of diverse subtypes of diabetes is a dynamic field of clinical research and an active area of discussion. The objective of this study was to identify new antigenic determinants in the neuroendocrine autoantigen IA-2 (ICA512) and assess whether circulating autoantibodies directed to new IA-2 epitopes identify autoimmune diabetes in young and adult populations with diabetes. RESEARCH DESIGN AND METHODS Clinically diagnosed patients with type 2 diabetes (n = 258; diabetes duration: 0.01-31 years) were evaluated using a new biomarker detecting autoantibodies directed to the extracellular domain of the neuroendocrine autoantigen IA-2 (IA- 2ec). The proportion of IA-2ec autoantibodies was also evaluated in newly diagnosed patients with type 1 diabetes (n = 150; diabetes duration: 0.04-0.49 years). In addition, IA-2 (intracellular domain), GAD65, and zinc transporter 8 autoantibodies were assayed. RESULTS IA-2ec autoantibodies were detected in patients with type 1 diabetes and, surprisingly, in 5% of patients with type 2 diabetes without serologic responses to other IA-2 antigenic epitopes or other islet autoantigens. We also assessed the ability of IA-2ec-derived peptides to elicit CD4+ T-cell responses by stimulating peripheral bloodmononuclear cells frompatients with type 1 diabetes (n = 18) and HLA-matched healthy subjects (n = 13) with peptides and staining with the peptide/DQ8-specific tetramers, observing disease-associated responses to previously unreported epitopes within IA-2ec. CONCLUSIONS We developed a new antibody biomarker identifying novel antigenic determinants within the N terminus of IA-2. IA-2ec autoantibodies can be detected in patients with type 1 diabetes and in a subgroup of adult autoimmune patients with type 2 diabetes phenotype negative for conventional islet autoantibody testing. These observations suggest that islet autoimmunity may be more common in clinically diagnosed type 2 diabetes than previously observed.

Original languageEnglish
Pages (from-to)561-568
Number of pages8
JournalDiabetes Care
Volume40
Issue number4
DOIs
Publication statusPublished - Apr 1 2017

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing

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    Acevedo-Calado, M., James, E. A., Morran, M. P., Pietropaolo, S. L., Ouyang, Q., Arribas-Layton, D., Songini, M., Liguori, M., Casu, A., Auchus, R. J., Huang, S., Yu, L., Michels, A., Gianani, R., & Pietropaolo, M. (2017). Identification of unique antigenic determinants in the amino terminus of IA-2 (ICA512) in childhood and adult autoimmune diabetes: New biomarker development. Diabetes Care, 40(4), 561-568. https://doi.org/10.2337/dc16-1527