Strong Association of Autoantibodies Targeting Deamidated Extracellular Epitopes of Insulinoma Antigen-2 (IA-2) with Clinical Onset of Type 1 Diabetes

Increasing evidence shows that pathogenic T cells in type 1 diabetes (T1D) that may have evaded negative selection recognize post-translational modified (PTM) epitopes of self-antigens. We have investigated the profiles of autoantibodies specifically targeting the deamidated epitopes of insulinoma antigen-2 extracellular domain (IA-2ec) to explore their relationship with T1D development. We compared the characteristics of autoantibodies targeting the IA-2ec Q>E epitopes (PTM IA-2ecA) as well as those targeting the IA-2ec unmodified epitopes (IA-2ecA) in participants across different stages of T1D development and in individuals with other types of diabetes and other kinds of autoimmunity. In patients with new-onset T1D, the prevalence of PTM IA-2ecA (26.1%) was significantly higher than that of IA-2ecA (19.5%, P<0.0001). In a longitudinal newborn cohort, both IA-2ecAs were present, but rare in preclinical stage 1 T1D, and with much lower positivity in individuals with stage 3 T1D who had been closely followed from birth in a clinical study compared to patients diagnosed in routine clinical settings with overt symptoms. In participants with latent autoimmune diabetes in adults, type 2 diabetes, and celiac disease autoimmunity, we did not observe significant positivity of either IA-2ecAs. These results indicate that PTM and unmodified IA-2ecA are predominantly present in clinical new-onset T1D patients, at late stages of T1D development.