161-OR: Autoantibodies Directed to Deamidated Post-translationally Modified IA-2 Epitopes in Type 1 Diabetes

Autoimmune disorders such rheumatoid arthritis (RA) harbor autoantibodies against a variety of post-translationally modified (PTM) proteins. We aimed to investigate whether PTM epitopes of IA-2, a major autoantigen related to type 1 diabetes (T1D), are targeted by autoantibody responses. The extracellular domain of IA-2 (IA-2-ec) was synthesized incorporating deamidated amino acid residues (IA-2ec-PTM) previously found to elicit T cell responses in T1D patients. IA-2ec-PTM was then subjected to immunoprecipitation with sera from T1D patients. Notably, autoantibody reactivity towards IA-2ec-PTM was present in 28% of T1D patients as compared to ~9% of serum reactivity against the native IA-2ec. The area under the ROC curve (ROC AUC) of IA-2ec-PTM autoantibodies revealed that these autoantibodies can adequately distinguish between T1D patient and control groups (ROC AUC: 0.7132; P < 0.0001). Relatives of T1D probands (from the TrialNet Pathway to Prevention Study) carrying both IA-2ec-PTM AAb and the high-risk HLA-DRB1*04-DQB1*03:02 haplotype progressed rapidly to onset of T1D (Stage 3) compared to those relatives who did not carry these immunologic abnormalities (P = 0.003). Understanding the mechanisms underlying PTMs of islet autoantigens, such as IA-2ec-PTM, is critical to develop new research to determine the ability of modified epitopes to induce islet autoimmunity, their potential role as biomarkers of islet cell injury as well as breaking immune tolerance to islet cell antigens through neo-antigen formation.