Contribution of Fas to diabetes development

Abstract

Fas (Tnfrsf6, Apo-1, CD95) is a death receptor involved in apoptosis induced in many cell types. Fas have been shown to be expressed by insulin-producing beta cells in mice and humans. However, the importance of Fas in the development of autoimmune diabetes remains controversial. To further evaluate the importance of Fas in pathogenesis of diabetes, we generated NOD mice (nonobese diabetic mice developing spontaneous autoimmune diabetes) with beta cell-specific expression of a dominant-negative point mutation in a death domain of Fas, known as lpr cg or Fas cg . Spontaneous diabetes was significantly delayed in NOD mice expressing Fas cg , and the effect depended on the expression level of the transgene. However, Fas cg -bearing mice were still sensitive to diabetes transferred by splenocytes from overtly diabetic NOD mice. At the same time, Fas cg expression did neutralize the accelerating effect of transgenic Fas-ligand expressed by the same beta cells. Thus, both Fas-dependent and -independent mechanisms are involved in beta cell destruction, but interference with the Fas pathway early in disease development may retard or prevent diabetes progression.

Fas Deficiency Prevents Type 1 Diabetes by Inducing Hyporesponsiveness in Islet β-Cell−Reactive T-Cells

“…Savinov et al (12), on the other hand, have shown that Fas is involved in ␤-cell death in a model where diabetes is accelerated by FasL expression on ␤-cells. However, it is not clear how/whether this system translates to the normal context.…”

“…More recently, in vivo treatment of mice with an anti-FasL antibody (11) or in whom a dominant-negative Fas mutation has been introduced (12) seems to suggest that Fas may contribute to the early stages of the disease. On the other hand, inactivation of the Fas gene, specifically in ␤-cells, has not prevented disease in a model where T-cells expressing a transgeneencoded T-cell receptor (TCR) specific for influenza hemagglutinin (HA) mediate diabetes in mice that express the HA peptide in ␤-cells (13).…”

Hepatic Insulin Gene Therapy in Insulin-Dependent Diabetes Mellitus

“…Autoimmune destruction of b-cells is for the most part due to induction of apoptosis (28,29) by cytokines such as interleukin (IL)-1b, tumor necrosis factor (TNF)-a, and interferon (INF)-c , which are secreted in the vicinity of the islets by activated T-lymphocytes (9,10). Overexpression of antiapoptotic genes by in vivo gene delivery into prediabetic animals could increase b-cell resistance to these cytokines.…”

Pathogenic Mechanisms in Type 1 Diabetes: The Islet is Both Target and Driver of Disease

“…Transgenic NOD mice, expressing dominant negative Fasassociated death domain (FADD), had limited protection ( Table 1). FADD is a component of the Fas signaling pathway that only occurs in beta-cells and transgenic mice containing a beta-cell-specific disruption of Fas [101,102]. Similarly, islets deficient in Fas expression were not protected in CD4 T cell-induced diabetes, suggesting beta-cell destruction occurs in the absence of a functional Fas pathway [103,104].…”