Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.
Aims/hypothesis
Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesized that ZnT8 is also recognized by CD8+ T cells and aimed at identifying HLA-A2 (A*02:01)-restricted epitope targets.
Methods
Candidate epitopes were selected by ZnT8 plasmid DNA immunization of HLA-A2/DQ8-transgenic mice and tested for T-cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy subjects by IFN-γ enzyme-linked immunospot.
Results
Caucasian HLA-A2+ type 1 diabetic patients, both adults (83%) and children (60%),displayed ZnT8-reactive CD8+ T cells which recognized a single ZnT8186–194 (VAANIVLTV) epitope. This ZnT8186–194-reactive fraction accounted for 50–53% of total ZnT8-specific CD8+ T cells. Another ZnT8153–161 (VVTGVLVYL) sequence was recognized in 20–25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognized by type 2 diabetic and healthy subjects (7–12% for ZnT8186–194 and 0% for ZnT8153–161).
Conclusions/interpretation
ZnT8-reactive CD8+ T cells are predominantly directed against the ZnT8186–194 epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8186–194 may point to common environmental triggers precipitating beta-cell autoimmunity.
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