Autoantigen IA-2 Heightens the Risk of Type 1 Diabetes Humoral Autoimmunity against the Extracellular Domain of the Neuroendocrine

Laboratory of Immunogenetics (M.P.M., S.P., Y.-J.Z., M.P.), The Brehm Center for Diabetes Research,Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan48105; Department of Internal Medicine, Department of Pharmacology (L.S.S.), and Center forComputational Medicine and Bioinformatics (P.N., G.S.O.), Department of Internal Medicine Departmentof Human Genetics and School of Public Health, University of Michigan Medical School, Ann Arbor,Michigan 48109; Division of Immunogenetics (A.C., M.T.), Department of Pediatrics, Rangos ResearchCenter, and Division of Pediatric Endocrinology (D.J.B.), Department of Pediatrics, Children’s Hospital ofPittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213; andDepartment of Biostatistics (V.C.A.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261Theobjectiveofthisstudywastodeterminewhetherantigenicdeterminantslocalizedwithintheextracellular domain of the neuroendocrine autoantigen tyrosine phosphatase-like protein IA-2are targets of humoral responses in type 1 diabetes (T1DM). Previous studies indicated that theimmunodominant region of IA-2 is localized within its intracellular domain (IA-2ic; amino acids601–979).Weanalyzed333subjectsfromtheChildren’sHospitalofPittsburghstudy,102ofwhomprogressed to insulin-requiring diabetes (prediabetics). Autoantibodies from these individualswere initially assayed for ICA512bdc (Barbara Davis Center amino acids 257–556; 630–979), IA-2ic(amino acids 601–979), and IA-2 full-length (amino acids 1–979) in addition to islet cell antibody(ICA), glutamic acid decarboxylase, 65-kDa isoform, and insulin autoantibodies. We identified anautoantibody response reactive with the extracellular domain of IA-2 that is associated with veryhighriskofT1DMprogression.RelativeswithnodetectableautoantibodiesagainstICA512bdc(orIA-2ic)exhibitedantibodyresponsesagainsttheIA-2full-lengthpeptide(logrank,