Defective function of Fas in patients with type 1 diabetes associated with other 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-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.
DeFranco
S
S
Department of Medical Science, A. Avogadro University of Eastern Piedmont, Novara, Italy.
Bonissoni
S
S
Cerutti
F
F
Bona
G
G
Bottarel
F
F
Cadario
F
F
Brusco
A
A
Loffredo
G
G
Rabbone
I
I
Corrias
A
A
Pignata
C
C
Ramenghi
U
U
Dianzani
U
U
D000293:Adolescent; D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000150:complications*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000235:genetics / Q000503:physiopathology*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology; D013966:Thyroiditis / Q000503:physiopathology; D019014:fas Receptor / Q000032:analysis / Q000235:genetics / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D019014:fas Receptor