APS3v refers to the occurrence of AITD + T1D in the same individual. A unique HLA-DR pocket predisposes to APS3v. Both islet & thyroid peptides were presented to T-cells by the APS3v-DR pocket. Flexible APS3v HLA-DR pocket triggers autoimmune T-cell responses in AITD + T1D. The unique APS3v HLA-DR pocket is thus an attractive drug target.