Fas (CD95) triggers programmed cell death and is involved in cell-mediated cytotoxicity and in shutting off the immune response. Inherited loss-of-function mutations hitting the Fas system cause the autoimmune/lymphoproliferative syndrome (ALPS). We have recently shown that ALPS patients' families display increased frequency of common autoimmune diseases, including type 1 diabetes. This work evaluates Fas function in type 1 diabetic patients without typical ALPS. Cell death induced by anti-Fas monoclonal antibody was investigated in T-cells from 13 patients with type 1 diabetes alone and 19 patients with type 1 diabetes plus other autoimmune diseases (IDDM-P). Moreover, we analyzed 19 patients with thyroiditis alone (TYR), because most IDDM-P patients displayed thyroiditis. Frequency of resistance to Fas-induced cell death was significantly higher in patients with IDDM-P (73%) than in type 1 diabetic (23%) or TYR (16%) patients or in normal control subjects (3%). The defect was specific because resistance to methyl-prednisolone-induced 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-resistant IDDM-P patients. Analysis of the families of two Fas-resistant patients showing that several members were Fas-resistant suggests that the defect has a genetic component. Moreover, somatic fusion of T-cells from Fas-resistant subjects and the Fas-sensitive HUT78 cell line generates Fas-resistant hybrid cells, which suggests that the Fas resistance is due to molecules exerting a dominant-negative effect on a normal Fas system. These data suggest that Fas defects may be a genetic factor involved in the development of polyreactive type 1 diabetes.

Two newborns affected by diabetes mellitus, 1 transient (case 1) and the other permanent (case 2), have been followed-up to the second year of life. Evolution towards resolution or persistence of the disease was studied using clinical and laboratory parameters. Spontaneous resolution occured in case 1 at the age of 4 months. Until this age no difference in clinical course and insulin-requirement, was found. Case 2 is still insulin dependent at the age of 19 month.During the follow-up serum fructosamine was constantly normal in case 1 and elevated in case 2. Basal C-peptide values of case 1 were not detectable at birth but already reached normal range, one month before clinical resolution. On the contrary in case 2, C-peptide values were severely reduced during the whole follow-up period.In our experience serum fructosamine and C-peptide evaluation may represent prognostic parameters of spontaneous resolution and may differentiate transient neonatal diabetes from permanent.