Defective expression of CD95 (FAS/APO-1) molecule suggests apoptosis impairment of T and B cells in HLA-B8, DR3-positive individuals

Giorgio Stassi, Matilde Todaro, Ruggero De Maria, Giuseppina Candore, Diego Cigna, Calogero Caruso, Aldo Galluzzo, Carla Giordano

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)39-45
Number of pages7
JournalHuman Immunology
Volume55
Issue number1
DOIs
Publication statusPublished - Jun 1997

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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