IA-2 autoantibody affinity in children at risk for type 1 diabetes

Autoantibodies to insulinoma-associated protein 2 (IA-2A) are associated with increased risk for type 1 diabetes. Here we examined IA-2A affinity and epitope specificity to assess heterogeneity in response intensity in relation to pathogenesis and diabetes risk in 50 children who were prospectively followed from birth. At first IA-2A appearance, affinity ranged from 107 to 1011 L/mol and was high (> 1.0 × 109 L/mol) in 41 (82%) children. IA-2A affinity was not associated with epitope specificity or HLA class II haplotype. On follow-up, affinity increased or remained high, and IA-2A were commonly against epitopes within the protein tyrosine phosphatase-like IA-2 domain and the homologue protein IA-2β. IA-2A were preceded or accompanied by other islet autoantibodies in 49 (98%) children, of which 34 progressed to diabetes. IA-2A affinity did not stratify diabetes risk. In conclusion, the IA-2A response in children is intense with rapid maturation against immunogenic epitopes and a strong association with diabetes development.

► The IA-2A response in children matures rapidly to high-affinity antibodies.
► IA-2A are commonly against epitopes located in the IA-2-PTP region and on IA-2β.
► Low-affinity IA-2A, and IA-2A restricted against the IA-2-JM region are rare.
► Diabetes risk among IA-2A positive children cannot be stratified by IA-2A affinity.