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

Abstract

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 autoreactive T cells. Continued autoimmune activity leads to the destruction of pancreatic β-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 β-cells. In this Perspective, we discuss various processes that lead to the generation of neoepitopes in pancreatic β-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 β-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 β-cell proteins.

Figure 1

Mechanisms of neoepitope formation. The formation of neoepitopes arises as a consequence of various types of insults that generate ER stress, ROS, and/or inflammatory cytokines in the affected tissue. These stresses elicit posttranscriptional (including alternative splicing and DRiP) and posttranslational (both enzymatic and nonenzymatic) processes that lead to the generation and release of neoepitopes with altered immunogenicity that can be presented to autoreactive T cells by APCs or recognized by autoreactive B cells, which have escaped negative selection in the thymus and bone marrow. These autoreactive cells become activated and carry out autoimmune effector functions, perhaps leading to additional inflammation, further release of self-epitopes, and an expansion and acceleration of autoimmunity. DC, dendritic cell.

Figure 2

Roles for neoepitopes in T1D pathogenesis. Neoepitopes can be envisioned to play a role at multiple stages of T1D pathogenesis. A: Genetic risk may confer an impaired response, increasing neoepitope formation. B: Environmental insults may cause neoepitope formation. C: Early autoimmunity may include neoepitope responses in addition to responses to insulin and GAD65. D: Progression to dysglycemia is likely to include the emergence of new classes of neoepitope responses. E: Neoepitope responses are clearly present as part of ongoing autoimmunity that is present during established T1D. Aab, autoantibody; Ins, insulin; Neo, neoepitope.