Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes

Autoimmunity precedes clinical type 1 diabetes, and indicators of maturing autoimmune responses may be useful markers for disease prediction, To study this, epitope maturation of autoantibodies to the related protein tyrosine phosphatase (PTP)-like autoantigens IA-2 and IA-2 beta was examined in seq uential samples from birth in a cohort of 21 offspring developing multiple islet autoantibodies and a similar cohort of 48 relatives of patients with type 1 diabetes recruited at an older age. Initial reactivity in offspring was heterogeneous against the IA-2 juxtamembrane region (10/21) and PTP dom ains (13/21), and both specificity and extent of initial IA-2/IA-2 beta aut oantibodies were associated with HLA class II genotype, Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2 beta epitopes were observ ed in seven offspring. In contrast, in older relatives, IA-2/IA-2 beta Ab r eactivity was stable and spreading rare. Development of diabetes in childre n was associated with the presence of Abs to the IA-2 juxtamembrane region (risk by age 5 yr, 52% vs 0% in those with PTP domain Abs only; p < 0.02), and 5 of 26 relatives who developed diabetes had IA-2 Abs only against the juxtamembrane region, The findings show that autoantibody reactivity to IA- 2/IA-2 beta is dynamic in the young, show that the juxtamembrane region of IA-2 is an early IA-2 autoantibody target, and suggest that these Abs are a risk factor for development of type 1 diabetes in infancy.