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Defective function of the Fas apoptotic pathway in type 1 diabetes mellitus correlates with age at onset.

Authors: De Franco, S  Chiocchetti, A  Ferretti, M  Castelli, L  Cadario, F  Cerutti, F  Rabbone, I  Indelicato, M  Mazzarino, C  Chessa, M  Bona, G  Dianzani, U 
Citation: De Franco S, etal., Int J Immunopathol Pharmacol. 2007 Jul-Sep;20(3):567-76.
Pubmed: (View Article at PubMed) PMID:17880769

The Fas death receptor triggers lymphocyte apoptosis through an extrinsic and an intrinsic pathway involving caspase-8 and -9 respectively. Inherited defects of Fas function are displayed by a proportion of patients with Type 1 diabetes mellitus (T1DM) especially those with a second autoimmunity (T1DM-p). This study assesses activation of both pathways in Fas-resistant (FasR) patients to localize the defect. 21/28 (75 percent) T1DM-p, 14/50 (38 percent) T1DM, and 7/150 (5 percent) controls were FasR. Analysis of the 35 FasR patients and 20 Fas-sensitive (FasS) controls showed that caspase-9 activity was lower in T1DM-p and T1DM than in controls, whereas caspase-8 activity was lower in T1DM-p than in T1DM and the controls. Single patient analysis showed that 16/35 patients displayed defective activity of one (FasR1), whereas 19 displayed normal activity of both caspases (FasR2). Ages at onset of diabetes mellitus in T1DM and the second autoimmune disease in T1DM-p were lower in FasR than in FasS patients. All FasR1 patients developed diabetes mellitus before the age of 9 years, whereas a later onset was displayed by 26% FasR2 and 53% FasS patients. These data show that defective Fas function may involve both the extrinsic and intrinsic pathway in T1DM and severity correlates with the precocity of the autoimmune attack and its tissue polyreactivity.


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RGD Object Information
RGD ID: 2311245
Created: 2009-06-30
Species: All species
Last Modified: 2009-06-30
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.