Summary
Triggering of CD95 (Fas/APO-1) cell surface receptors regulates the elimination of autoreactive T and B lymphocytes through a mechanism of cell suicide called apoptosis. Three different mutations involving CD95 or its ligand are responsible for induction of autoimmunity in susceptible mouse strains. To determine whether a defect involving the CD95 receptor is associated with human insulin-dependent diabetes mellitus (IDDM), we have studied the expression of CD95 on peripheral blood mononuclear cells from IDDM patients at different stages of the disease. Three-colour flow cytometry and mean fluorescence analysis showed that T and B lymphocytes from newly diagnosed IDDM and patients with long-standing disease, and subjects at high risk of developing the disease were highly defective in CD95 expression (p<0.001), whereas monocytes from all the groups studied expressed normal amounts of CD95 molecules on their cell surface. T-cell subset analysis showed that the impairment of CD95 expression in IDDM patients and high-risk subjects involved both CD3+ CD4+ (p<0.001) and CD3+ CD8+ cells (p range: <0.01–0.001), suggesting that this alteration concerns both helper and cytotoxic T cells. Moreover, after activation in vitro with anti-CD3 monoclonal antibody, T cells from newly diagnosed IDDM patients maintained a reduced CD95 expression during the entire cell culture period (24–72 h) in comparison to the control population (p<0.001). In conclusion, we found a reduced expression of the apoptosis-inducing CD95 receptor on T and B lymphocytes of individuals with clinical and preclinical IDDM. We hypothesize that this defective expression may impair the capacity of autoreactive lymphocytes to undergo CD95-mediated apoptosis, contributing to the lack of control on beta-cell specific B- and T-cell clones.
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Abbreviations
- MFI:
-
Mean fluorescence intensity
- mAb:
-
monoclonal antibody
- ICA:
-
islet cell autoantibody
- IAA:
-
insulin autoantibody
- PE:
-
phycoerythrin
- FITC:
-
fluorescein
- Per-CP:
-
peridinid chlorophyll protein
- PBMC:
-
peripheral blood mononuclear cells
- AICD:
-
activation-induced cell death
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Giordano, C., De Maria, R., Stassi, G. et al. Defective expression of the apoptosis-inducing CD95 (Fas/APO-1) molecule on T and B cells in IDDM. Diabetologia 38, 1449–1454 (1995). https://doi.org/10.1007/BF00400606
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DOI: https://doi.org/10.1007/BF00400606