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

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.

• Authors: S DeFranco, S Bonissoni, F Cerutti, G Bona, F Bottarel, F Cadario, A Brusco, G Loffredo, I Rabbone, A Corrias, C Pignata, U Ramenghi, U Dianzani
• Journal: Diabetes (Diabetes) Vol. 50 Issue 3 Pg. 483-8 (Mar 2001) ISSN: 0012-1797 [Print] United States
• PMID: 11246866 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• fas Receptor

Topics

• Adolescent
• Adult
• Antibodies, Monoclonal (pharmacology)
• Autoimmune Diseases (complications)
• Cell Death (drug effects, physiology)
• Cell Line
• Child
• Diabetes Mellitus, Type 1 (complications, genetics, physiopathology)
• Drug Resistance
• Female
• Humans
• Male
• Mutation
• Reference Values
• T-Lymphocytes (immunology, physiology)
• Thyroiditis (physiopathology)
• fas Receptor (analysis, genetics, immunology, physiology)