|
 |
|
|||||||
|
|||||||||
© 2001 by the American Diabetes Association, Inc.
Defective Function of Fas in Patients With Type 1 Diabetes Associated With Other Autoimmune Diseases
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
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.
Abbreviations: ALPS, autoimmune/lymphoproliferative syndrome; DN, double negative; FACS, fluorescence-activated cell sorter; FasL, Fas ligand; FCS, fetal calf serum; FITC, fluorescein isothiocyanate; IDDM-P, type 1 diabetes plus other autoimmune diseases; IL, interleukin; mAb, monoclonal antibody; PDN, methyl-prednisolone; PE, phycoerythrin; PHA, phytohemagglutinin; SSCP, single-strand conformation polymorphism; TNF, tumor necrosis factor; TYR, thyroiditis alone
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  E. Orilieri, G. Cappellano, R. Clementi, A. Cometa, M. Ferretti, E. Cerutti, F. Cadario, M. Martinetti, D. Larizza, V. Calcaterra, et al. Variations of the Perforin Gene in Patients With Type 1 Diabetes Diabetes, April 1, 2008; 57(4): 1078 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Teachey, C. S. Manno, K. M. Axsom, T. Andrews, J. K. Choi, B. H. Greenbaum, J. M. McMann, K. E. Sullivan, S. F. Travis, and S. A. Grupp Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS) Blood, March 15, 2005; 105(6): 2443 - 2448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Vendrame, C. Santangelo, R. Misasi, S. Dionisi, C. Gizzi, M. Realacci, D. Grassetti, U. Di Mario, and F. Dotta Defective lymphocyte caspase-3 expression in type 1 diabetes mellitus Eur. J. Endocrinol., January 1, 2005; 152(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |