Autoimmune-Mediated Beta-Cell Death & Dysfunction: Potential Role of Signaling through the Fas Receptor

Type 1 diabetes mellitus (T1DM) is an endocrine disorder that continues to afflict a growing proportion of the U.S. population. Characterized by an autoimmune attack on the pancreatic [beta] cells that leads to their destruction, T1DM develops from absolute insulin deficiency resulting in chronic hyperglycemia. Although the disease requires lifelong insulin therapy and confers enhanced risk for long-term complications, the mechanism of [beta] cell death remains unclear. Fas receptor signaling is critical among cells of hematopoietic origin for its role in immune homeostasis and mediation of target cell death. Fas receptor-ligand interactions might also have a role in [beta] cell death leading to the development of T1DM; pro-inflammatory cytokines released from islet leukocytes can induce Fas receptor to the [beta] cell surface, and systemic loss-of-function mutations in Fas receptor and Fas ligand (FasL) abrogate disease in spontaneous diabetes-prone mice. However, systemic deficiency in Fas and FasL causes an alteration in the T cell repertoire that prevents diabetes, and thus cannot be attributed to absence of Fas [beta] cell signaling. Moreover, the use of distinct Fas mutations and transgenic models that produce dissimilar mechanisms of [beta] cell death leads to conflicting results reported in the scientific literature. Recent evidence using transgenic mouse models of diabetes has indicated a role for Fas in the insulitic phase but not the effector phase of [beta] cell death, while other studies have suggested that alteration of the T cell repertoire by Fas signaling is a causal factor in the autoimmune [beta] cell attack. Furthermore, ectopically-expressed FasL is a potential therapeutic tool for protection of islet transplants by its known ability to provide immune privilege in some tissues. This literature review collectively presents the diverse roles for Fas signaling in [beta] cell death and provides insight into why conflicting conclusions regarding Fas signaling currently exist. Thus, the goal of this literature review is to enable investigators interested in Fas-mediated signaling in the pancreatic [beta] cell to choose an appropriate model system for study design that ideally will translate to therapeutic interventions for T1DM.