Defective function of Fas in patients with type 1 diabetes associated withother autoimmune diseases

Fas (CD95) triggers programmed cell death and is involved in cell-mediated cytotoxicity and in shutting off the immune response, Inherited loss-of-fun ction mutations hitting the Fas system cause the autoimmune/lymphoprolifera tive syndrome (ALPS). We have recently shown that ALPS patients' families d isplay increased frequency of common autoimmune diseases, including type I diabetes. This work evaluates Fas function in type 1 diabetic patients with out typical ALPS, Cell death induced by anti-Fas monoclonal antibody was in vestigated in T-cells from 13 patients with type 1 diabetes alone and 19 pa tients with type 1 diabetes plus other autoimmune diseases (IDDM-P). Moreov er, we analyzed 19 patients with thyroiditis alone (TYR), because most IDDM -P patients displayed thyroiditis, Frequency of resistance to Fas-induced c ell death was significantly higher in patients with IDDM-P (73%) than in ty pe 1 diabetic (23%) or TYR (16%) patients or in normal control subjects (3% ). The defect was specific because resistance to methyl-prednisolonle-induc ed cell death was not significantly increased in any group. Fas was always expressed at normal levels, and no Fas mutations were detected in four Fas- resistamt IDDM-P patients. Analysis of the families of two Fas-resistant pa tients showing that several members ware Fas-resistant suggests that the de fect has at genetic component. Moreover, somatic fusion of T-cells from Fas -resistant subjects and the Fas-sensitive HUT78 cell line generates Fas-res istant hybrid cells, which suggests that the Fas resistance is due to molec ules exerting a dominant-negative effect on a normal Fas system. These data suggest that Fas defects may be a genetic factor involved in the developme nt of polyreactive type 1 diabetes.