Identification of Unique Antigenic Determinants in the Amino Terminus of IA-2 (ICA512) in Childhood and Adult Autoimmune Diabetes: New Biomarker Development.
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.



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.



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 blood mononuclear cells from patients 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.



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.
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
Maria
M
Acevedo-Calado
Benaroya Research Institute, University of Washington, Seattle, WA.
Eddie A
0000-0002-7217-5729
EA
James
Department of Medicinal Chemistry, College of Pharmacy, University of Toledo, Toledo, OH.
Michael P
MP
Morran
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
Susan L
SL
Pietropaolo
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.
Qin
Q
Ouyang
Benaroya Research Institute, University of Washington, Seattle, WA.
David
D
Arribas-Layton
Diabetes Clinic, Department of Internal Medicine, and Laboratory of Microbiology & Immunology, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
Marco
M
Songini
Diabetes Clinic, Department of Internal Medicine, and Laboratory of Microbiology & Immunology, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
Marco
M
Liguori
Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione, Palermo, Italy.
Anna
A
Casu
Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
Richard J
RJ
Auchus
Department of Industrial and Systems Engineering, University of Washington, Seattle, WA.
Shuai
S
Huang
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
Liping
L
Yu
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO.
Aaron
A
Michels
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX.|Rocky Vista University College of Osteopathic Medicine, Parker, CO.
Roberto
R
Gianani
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX massimo.pietropaolo@bcm.edu.
Massimo
M
Pietropaolo
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D000939:Epitopes; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase