IA-2 antibody epitopes and isotypes during the prediabetic process in siblings of children with type 1 diabetes.

To characterize the humoral immune response to the protein tyrosine phosphatase (PTP)-like autoantigen (IA-2) in preclinical type 1 diabetes (T1D), and to assess the utility of epitope and isotype-specific IA-2 antibody responses as surrogate markers for disease development, we analyzed these antibodies in 34 initially non-diabetic siblings of affected children derived from the "Childhood Diabetes in Finland" (DiMe) Study. Half of them presented with T1D during an average observation period of 8.7 years. Radiobinding assays were used to determine IA-2/IA-2 beta epitope-specific (the juxtamembrane region, JM; the PTP-like and the beta PTP-like domain) antibodies and isotype-specific (IgG1-4, IgA, IgE and IgM) IA-2 antibodies. Initially, 30 of the 34 siblings tested positive for epitope-specific antibodies. The siblings who progressed to clinical diabetes had IA-2 JM antibodies more often (P<0.05) but IgE-IA-2 antibodies less frequently (P<0.05) than the siblings who did not progress to T1D. During the identical follow-up time, the non-progressors had higher integrated titers of IgE-IA-2 antibodies (P=0.05). The occurrence of IgE-IA-2 antibodies was protective, since despite IA-2 JM antibodies, children with IgE-IA-2 antibodies did rarely progress to T1D. This study demonstrates that JM-reactive IA-2 antibodies are associated with an increased risk of progression to overt T1D, whereas an IgE response to IA-2 confers relative protection against clinical disease.