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

The natural history of preclinical diabetes is partly characterized, but there is still limited information on the dynamics of the immune response to beta-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-2 beta) 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-2 beta epitope-specific antibodies (the juxtamembrane (JM) region of IA-2, PTP-like domain and beta PTP-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.