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The Journal of Immunology, 1998, 161: 6963-6969.
Copyright © 1998 by The American Association of Immunologists

Early Development and Spreading of Autoantibodies to Epitopes of IA-2 and Their Association with Progression to Type 1 Diabetes1

Heike E. Naserke*, Anette-G. Ziegler*, Vito Lampasona{dagger} and Ezio Bonifacio2,{dagger}

* Diabetes Research Institute and 3rd Medical Department, Hospital München-Schwabing, Munich, Germany; and {dagger} Istituto Scientifico San Raffaele, Milan, Italy

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-2ß was examined in sequential 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 domains (13/21), and both specificity and extent of initial IA-2/IA-2ß autoantibodies were associated with HLA class II genotype. Intra-IA-2 epitope spreading and/or intermolecular spreading to IA-2ß epitopes were observed in seven offspring. In contrast, in older relatives, IA-2/IA-2ß Ab reactivity was stable and spreading rare. Development of diabetes in children 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-2ß 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.




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