Defective Function of Fas in Patients With Type 1 Diabetes Associated With Other Autoimmune Diseases

Defective Function of Fas in Patients With Type 1 Diabetes Associated With Other Autoimmune Diseases Simona DeFranco 1 , Sara Bonissoni 1 , Franco Cerutti 2 , Gianni Bona 1 , Flavia Bottarel 1 , Francesco Cadario 1 , Alfredo Brusco 3 , Giuseppe Loffredo 4 , Ivana Rabbone 2 , Andrea Corrias 5 , Claudio Pignata 6 , Ugo Ramenghi 2 and Umberto Dianzani 1 1 Department of Medical Science, A. Avogadro University of Eastern Piedmont, Novara 2 Departments of Pediatrics and 3 Genetics, University of Turin, Turin 4 Department of Pediatric Hematology, Pausilipon Hospital, Naples 5 Department of Endocrinology, Regina Margherita Hospital, Turin 6 Department of Pediatrics, Federico II University of Naples, Naples, Italy Abstract 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. ALPS, autoimmune/