Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

https://science.sciencemag.org/content/sci/267/5203/1449.full.pdf

The Fas Death Factor

DURING mammalian development, many cells are programmed to die1,2 most mediated by apoptosis3. The Fas antigen4 coded by the structural gene for mouse lymphoproliferation mutation (lpr)5,6, is a cell surface protein belonging to the tumour necrosis factor/nerve growth factor receptor family7,8, and mediates apoptosis7. The Fas antigen messenger RNA is expressed in the thymus, liver, heart, lung and ovary8. We prepared a monoclonal antibody against mouse Fas antigen, which immunoprecipitated the antigen (Mr 45K) and had cytolytic activity against cell lines expressing mouse Fas antigen. We report here that staining of mouse thymocytes with the antibody indicated that thymocytes from the wild-type and lprcg mice expressed the Fas antigen, whereas little expression of the Fas antigen was found in lpr mice. Intraperitoneal administration of the anti-Fas antibody into mice rapidly killed the wild-type mice but neither lpr nor lprcg mice. Biochemical, histological and electron microscope analyses indicated severe damage of the liver by apoptosis. These findings suggest that the Fas antigen is important in programmed cell death in the liver, and may be involved in fulminant hepatitis in some cases.

Lethal effect of the anti-Fas antibody in mice

The Fas ligand (FasL), a member of the tumor necrosis factor family, induces apoptosis in Fas–bearing cells. The membrane–bound human FasL was found to be converted to a soluble form (sFasL) by the action of a matrix metalloproteinase–like enzyme. Two neutralizing monoclonal anti–human FasL antibodies were identified, and an enzyme–linked immunosorbent assay (ELISA) for sFasL in human sera was established. Sera from healthy persons did not contain a detectable level of sFasL, whereas those from patients with large granular lymphocytic (LCL) leukemia and natural killer (NK) cell lymphoma did. These malignant cells constitutively expressed FasL, whereas peripheral NK cells from healthy persons expressed FasL only on activation. These results suggested that the systemic tissue damage seen in most patients with LGL leukemia and NK–type lymphoma is due to sFasL produced by these malignant cells. Neutralizing anti–FasL antibodies or matrix metalloproteinase inhibitors may be of use in modulating such tissue damage.

Fas ligand in human serum

Publisher Summary This chapter discusses the Fas /Fas ligand system and its physiological role. The chapter discusses the identification of a natural Fas ligand in a cytotoxic T-lymphocyte (CTL) cell line and proves that it is a member of the tumor necrosis factor (TNF) family. The Fas antigen is expressed on the surface of various mammalian cells. It is a member of the TNF/nerve growth factor (NGF) receptor family and transduces the apoptotic signal. The molecular analysis of the Fas gene has indicated that it is the structural gene for the mouse lymphoproliferation mutation. Fas ligand is a death factor, and Fas is its receptor. These results indicate that just as growth factor and its receptor regulate cell proliferation, cell death or apoptosis is regulated by a death factor and its receptor. Currently, the kinds of signaling molecules involved in Fas-mediated apoptosis are unknown. Fas may activate a similar signal transducer or utilize a completely different set of molecules. Because over-expression of the bcl-2 oncogene product partially inhibits Fas-mediated apoptosis, bcl-2 should interact somewhere in the signal-transducing pathway activated by the Fas system. The elucidation of the apoptotic signal transduction mechanism mediated by Fas may reveal a novel mechanism. The gain-of-function mutation of the growth factor system causes cellular transformation, whereas the loss-of-function mutation of the Fas system causes lymphadenopathy. In this regard, Fas and the Fas ligand may be considered as tumor suppressor genes. The loss-of-function mutation in the growth factor system causes the disappearance or dysfunction of specific cells. As pointed out above, it is possible that abnormal activation (gain of function mutation) of the Fas or Fas ligand causes fulminant hepatitis or other diseases such as CTL-mediated autoimmune diseases.

JW Ellwart

Papers

Expression of the APO-1 antigen in Burkitt lymphoma cell lines correlates with a shift towards a lymphoblastoid phenotype.