Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance

Prior to the onset of type 1 diabetes, there is progressive loss of immune self-tolerance, evidenced by the accumulation of islet autoantibodies and emergence of auto-reactive T cells. Continued autoimmune activity leads to the destruction of pancreatic beta-cells and loss of insulin secretion. Studies of samples from patients with type 1 diabetes and of murine disease models have generated important insights about genetic and environmental factors that contribute to susceptibility and immune pathways that are important for pathogenesis. However, important unanswered questions remain regarding the events that surround the initial loss of tolerance and subsequent failure of regulatory mechanisms to arrest autoimmunity and preserve functional beta-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic beta-cells, their recognition by autoreactive T cells and antibodies, and potential roles for such responses in the pathology of disease. Emerging evidence supports the relevance of neoepitopes generated through processes that are mechanistically linked with beta-cell stress. Together, these observations support a paradigm in which neoepitope generation leads to the activation of pathogenic immune cells that initiate a feed-forward loop that can amplify the antigenic repertoire toward pancreatic beta-cell proteins.