title: Defective expression of CD95 (FAS/APO-1) molecule suggests apoptosis impairment of T and B cells in HLA-B8, DR3-positive individuals.
abstract: Activation-induced apoptosis is one of the primary control mechanisms for the negative selection of an immune response, leading to maintenance of immune homeostasis and selective T cell deletion. The interaction between the surface molecule Fas and its ligand (FasL) has been proposed as a primary mechanism initiating T cell apoptosis. The T cell receptor modulates the expression and function of these molecules. Defects in the Fas/FasL apoptosis pathway have been shown to result in autoimmune disease in humans and in murine models. Because subjects carrying the HLA-B8, DR3 haplotype show a number of immune dysfunctions, including membrano-proliferative glomerulonephritis, systemic lupus erythematosus, Graves' disease, and others, we investigated Fas expression on T and B cells, and sensitivity to Fas-mediated apoptosis of activated T cells, to determine whether abnormalities of the Fas pathway might be associated with the development of autoimmune diseases in this group of individuals. Our findings show that B cells and resting T cells from HLA-B8+, DR3+ subjects express markedly reduced levels of Fas compared with those isolated from HLA-B8-, DR3+ individuals. Reduced levels of Fas were also evident on the surface of T cells from HLA-B8+, DR3+ subjects activated in vitro by stimulation with OKT3 and phytohemoagglutinin. Cycling T cells from these subjects, evaluated for apoptotic nuclei by flow cytometry after incubation with a cytolytic anti-Fas mAb, showed a significantly lower percentage of Fas-mediated apoptosis than did those from HLA-B8-, DR3- individuals. Normal levels of apoptosis were restored after exposure to a synthetic ceramide analog (C2). Further elucidation of the interaction of these molecules in autoimmune diseases may lead to better understanding of the pathogenesis of these disorders.
authors.affiliation: Laboratory of Immunology, University of Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.forename: M
authors.initials: M
authors.lastname: Todaro
authors.forename: R
authors.initials: R
authors.lastname: De Maria
authors.forename: G
authors.initials: G
authors.lastname: Candore
authors.forename: D
authors.initials: D
authors.lastname: Cigna
authors.forename: C
authors.initials: C
authors.lastname: Caruso
authors.forename: A
authors.initials: A
authors.lastname: Galluzzo
authors.forename: C
authors.initials: C
authors.lastname: Giordano
mesh_terms: D018941:Antigens, CD19 / Q000032:analysis; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D005434:Flow Cytometry; D015795:HLA-B8 Antigen / Q000032:analysis*; D015803:HLA-DR3 Antigen / Q000032:analysis*; D006650:Histocompatibility Testing; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019014:fas Receptor / Q000096:biosynthesis*
chemical_list: D018941:Antigens, CD19; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D015795:HLA-B8 Antigen; D015803:HLA-DR3 Antigen; D018950:Lipopolysaccharide Receptors; D019014:fas Receptor