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Published on: June 16, 2011
Defective function of Fas in patients with type 1 diabetes associated with other autoimmune diseases
S DeFranco1, S Bonissoni, F Cerutti
1Department of Medical Science, A. Avogadro University of Eastern Piedmont, Novara, 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.
Insights
Fas (CD95) receptor defects impair T-cell death in patients with type 1 diabetes and other autoimmune diseases. This resistance to programmed cell death, potentially genetic, suggests a role for Fas dysfunction in polyautoimmunity.
Area of Science:
- Immunology
- Genetics
- Cell Biology
Background:
- The Fas receptor (CD95) is crucial for programmed cell death, immune regulation, and preventing autoimmunity.
- Inherited Fas dysfunction causes autoimmune/lymphoproliferative syndrome (ALPS).
- Previous research indicated increased autoimmune disease prevalence in ALPS families, including type 1 diabetes.
Purpose of the Study:
- To investigate Fas-mediated cell death in type 1 diabetes patients without ALPS.
- To determine if Fas dysfunction is associated with type 1 diabetes and other autoimmune conditions.
Main Methods:
- Assessed T-cell susceptibility to Fas-induced cell death using anti-Fas monoclonal antibody in patients with type 1 diabetes, type 1 diabetes plus other autoimmune diseases (IDDM-P), and thyroiditis (TYR).
- Evaluated resistance to methyl-prednisolone-induced cell death to confirm specificity.
- Analyzed Fas expression levels and screened for Fas mutations in resistant patients.
- Conducted family studies and somatic cell fusion experiments to explore the genetic basis and mechanism of Fas resistance.
Main Results:
- Significantly higher frequency of Fas-induced cell death resistance observed in IDDM-P patients (73%) compared to type 1 diabetes alone (23%), TYR patients (16%), and controls (3%).
- Fas expression and Fas gene mutations were normal in resistant patients, ruling out simple loss-of-function mutations.
- Family analyses and cell fusion experiments suggested a dominant-negative genetic component contributing to Fas resistance.
- Resistance to methyl-prednisolone-induced cell death was not significantly increased, indicating specificity of the Fas defect.
Conclusions:
- Fas dysfunction, characterized by resistance to Fas-induced cell death, is prevalent in patients with type 1 diabetes and co-occurring autoimmune diseases.
- This Fas defect appears to have a genetic basis, potentially involving dominant-negative mechanisms.
- Fas pathway defects may represent a significant genetic risk factor for developing polyreactive autoimmune diseases, including type 1 diabetes.
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