Aspects of ZnT8 autoimmunity in childhood type 1 diabetes

Abstract: Type 1 diabetes is one of the most common chronic diseases in childhood and adolescence with an increasing incidence worldwide. It is an autoimmune disease with many autoimmune markers, where the zinc transporter 8 autoantibody (ZnT8A) is the most recent autoantibody discovered. The most important genetic susceptibility towards type 1 diabetes is found within the HLA-region on chromosome 6. We showed that all three ZnT8A are common among children and adolescents at type 1 diabetes diagnosis and that 3.4% of the children in Sweden displayed only ZnT8A at diagnosis. Only 7% of the Swedish children were autoantibody negative at diagnosis. Additionally, 0.3% of type 1 diabetes patients in Sweden had an isolated positivity for the islet cell cytoplasm autoantibodies (ICA). This is an autoantibody with an unspecified reaction pattern to most of the other antigens involved in autoantibody formation in type 1 diabetes. The fact that children can still be diagnosed with ICA as the only autoantibody suggests that another yet unidentified autoantigen or autoantigens may contribute to ICA and the search for additional autoantigens should continue. We propose that the glutamine variant of the ZnT8A (ZnT8QA) is not cost effective as a diagnostic marker, as it was found as a single islet autoantibody only in one patient among 3851 analyzed children. However, comparing young healthy children with multiple autoantibodies with normal and impaired glucose metabolism we found that significantly more children with impaired glucose metabolism were positive for ZnT8QA compared to children with normal glucose metabolism. Hence, the ZnT8QA analysis is important in screening of populations for type 1 diabetes risk and for secondary prevention studies. All variants of ZnT8A were positively associated with either HLA DQA1-B1'X-0604 (DQ6.4) or HLA DQA1'0301-DQB1'0302 (DQ8) but dominantly negative with HLA DQA1'0501-DQB1'0201 (DQ2). The association between DQ 6.4 and all three ZnT8A may be related to ZnT8 antigen-presentation by the DQ6.4 heterodimer.