IA‐2 antibody isotypes and epitope specificity during the prediabetic process in children with HLA‐conferred susceptibility to type I diabetes

Summary The natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to β‐cell autoantigens during the course of preclinical disease. The aim of this work was to assess the maturation of the humoral immune response to the protein tyrosine phosphatase(PTP)‐related proteins (IA‐2 and IA‐2β) in preclinical type I diabetes (TID). Forty‐five children participating in the Finnish Type I Diabetes Prediction and Prevention (DIPP) Study who had seroconverted to IA‐2 antibody positivity were analysed. Specific radiobinding assays were used to determine IA‐2/IA‐2β epitope‐specific antibodies (the juxtamembrane (JM) region of IA‐2, PTP‐like domain and βPTP‐like domain) and isotype‐specific IA‐2 antibodies. Individual areas under the curve (AUC) over the observation period were calculated for total IA‐2 antibodies, each isotype and specific epitope responses. The children who progressed to TID tended to have an initial IA‐2 JM epitope response more frequently ( P  = 0·06), and this response was more often dominant during the observation period ( P  < 0·05). The children who did not progress to TID had IgE‐IA‐2 more frequently (70%; versus progressors 27%; P  < 0·05), and had higher integrated titres of IgE‐IA‐2 antibodies ( P  < 0·05). The occurrence of IgE‐IA‐2 antibodies was protective even when combined with positivity for IA‐2 JM antibodies ( P  = 0·002). IgE‐IA‐2 antibody reactivity may be a marker of a regulatory immune response providing protection against or delaying progression to TID among IA‐2 antibody‐positive young children with HLA‐conferred disease susceptibility.