174-LB: Autoantibodies against PTM-IA2 Extracellular Domain Are Only Associated with Late Progression of Type 1 Diabetes

Abstract

Background: Autoantibodies directed against the extracellular domain of IA2 (IA2ecA) with post-translationally modified (PTM) (deamidated) epitopes have been identified in new-onset T1D patients. The prevalence and timing of appearance of PTM-IA2ecA in pre-T1D individuals is evaluated in the current study. Methods: A PTM-IA2ec protein antigen probe containing four T-cell responsive deamidated Q>E peptides (aa 198-216, aa 467-482, aa 523-536 and aa 545-562) was produced. The study subjects included 269 children and 260 adults with new-onset T1D, 271 adults with LADA, 274 children with new-onset diabetes but negative for all islet autoantibodies (IAbs) (IAA, GADA, IA-2A and ZnT8A), and 222 pre-T1D children who were longitudinally followed from birth to stage 1-3 T1D. The longitudinal follow-up serum samples included samples prior to seroconversion, samples at the first appearance on an IAb and the last follow-up samples. All serum samples were tested for PTM-IA2ecA and the wide type (WT-IA2ecA) with a radio binding assay. Results: In new-onset T1D, positivity for PTM-IA2ecA and WT-IA2ecA were 60.6% (163/269) and 19.3% (52/269), respectively in children, while significantly less in adults, 14.2% (37/260, P<0.0001) and 8.8% (23/260, P=0.0007), respectively. The positivity for PTM-IA2ecA and WT-IA2ecA were only 4.1% (11/271) and 1.5% (4/271) in LADA patients, 1.5% (4/274) and 1.1% (3/274) in diabetic children who were otherwise IAb negative. In 222 longitudinally followed children with pre-T1D, only 13 were tested positive for PTM-IA2ecA and 8 positives for WT-IA2ecA, with most detected at diagnosis of stage 3 T1D. Conclusion: Autoantibodies against either WT-IA2ec or PTM-IA2ec were not frequently seen in pre-T1D as shown in new onset T1D. These autoantibodies develop in the late stage of T1D progression with overt clinical disease. Disclosure X. Jia: None. J. M. Wenzlau: None. M. Rewers: Research Support; Provention Bio, Juvenile Diabetes Research Foundation (JDRF), Hemsley Charitable Trust, Dexcom, Inc., Janssen Research & Development, LLC. A. W. Michels: Stock/Shareholder; Immnomolecular Therapeutics. L. Yu: None. Funding National Institute of Allergy and Infectious Diseases (AI53665); National Institute of Diabetes and Digestive and Kidney Diseases (DK032083)