Inflammatory β-Cell Stress and Immune Surveillance in Type 1 Diabetes.

Abstract

Recent years have seen increased recognition for the role of β-cell stress as a contributing factor to the autoimmune destruction process that ultimately results in symptomatic type 1 diabetes (T1D). Preclinical studies have discovered a variety of stress responses in the β-cell that occur at presymptomatic stages and contribute to disease progression, but unifying explanations of how these mechanisms operate to promote disease progression remain incomplete. We propose that stressed β-cells transition into β-cells expressing inflammatory molecules that provoke an immune response to restore homeostasis by coordinating islet repair and the removal of stressed cells. However, when immune surveillance fails, stressed β-cells accumulate and contribute to autoimmunity. Therapies directed toward stressed β-cells to either curb their inflammatory signaling or to eliminate them (essentially doing the job of the failed immune surveillance) are moving from animal models into the clinic with promising initial results, although the understanding of how the immune response is coordinated by stressed β-cells is not clear. In this article, we discuss β-cell stress responses implicated in T1D pathogenesis based on evidence from humans and highlight existing knowledge gaps in their mechanisms. Future work in this field is poised to target T1D by simultaneously targeting stressed β-cells and the failed immune response to halt the progression of autoimmunity and prevent β-cell destruction.