Defective expression of the apoptosis-inducing CD95 (Fas/APO-1) molecule on T and B cells in IDDM.
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.
Giordano
C
C
Laboratory of Immunology, Institute of Clinical Medicine, Palermo, Italy.
De Maria
R
R
Stassi
G
G
Todaro
M
M
Richiusa
P
P
Giordano
M
M
Testi
R
R
Galluzzo
A
A
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D001786:Blood Glucose / Q000378:metabolism; D017252:CD3 Complex / Q000502:physiology; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015309:Glucose Clamp Technique; D006801:Humans; D008297:Male; D051379:Mice; D012016:Reference Values; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis*
D015703:Antigens, CD; D001786:Blood Glucose; D017252:CD3 Complex; D019014:fas Receptor