The role of Fas and related death receptors in autoimmune and other disease states,☆☆,

https://doi.org/10.1016/S0091-6749(99)70412-4Get rights and content

Abstract

The Fas receptor, also known as APO-1 or CD95, has emerged as a key initiator of apoptotic programmed cell death in a variety of cell types. CD4+ T cells are unique in their ability to commit “suicide” by stimulating their own Fas receptors with secreted or membrane-bound Fas ligand. This takes place in the setting of repeated stimulation with T-cell antigens and is thought to be a mechanism for controlling the expansion of T cells during viral infections and autoimmune disease states. T cells can also trigger apoptosis in B cells, macrophages, and other cell types through Fas ligand. These interactions negatively regulate the immune system but can also contribute to immunopathology, as occurs in Fas-mediated damage of target tissues in hepatitis and other organ-specific autoimmune diseases. The dual role of Fas in the immune response complicates the understanding of its role in disease states and may limit its potential as a therapeutic target. Despite the many roles of Fas in immunoregulation, findings in experimental mouse strains and human patients with genetic deficiencies in the Fas pathway have shown that the main result of disrupting this pathway in vivo is systemic autoimmunity and a predisposition toward lymphoid malignancies. The role of Fas in various cell types and the lessons we have learned from Fas-deficient patients with the autoimmune lymphoproliferative syndrome will be discussed. (J Allergy Clin Immunol 1999;103:729-38.)

Section snippets

Fas/CD95: A death receptor in the TNF-receptor superfamily

The Fas receptor was first identified by antibodies that induced rapid cell death. Treatment of susceptible cells with these antibodies induced all the hallmarks of apoptosis (ie, programmed cell death), a process originally defined in cells dying during normal development or after induction with chemotherapeutic agents, glucocorticoids, or γ-irradiation.1 Unlike cells dying by necrosis, in which the intracellular contents of the cell are released into the environment after membrane rupture,

THE ROLE OF FAS/FAS LIGAND INTERACTIONS IN AUTOIMMUNE AND OTHER DISEASE STATES

The role of the Fas receptor in regulating the human immune response and in the evolution of clinical disease is being actively investigated. The recent identification of the autoimmune lymphoproliferative syndrome (ALPS) as a disorder of defective lymphocyte apoptosis provides definitive evidence that directly links Fas receptor dysfunction with specific clinical and laboratory findings. Altered Fas or Fas ligand function may contribute to other human autoimmune, infectious, and malignant

THE FAS/FAS LIGAND SYSTEM IN DIAGNOSIS AND THERAPY

The interest in the Fas pathway, together with the availability of tests for soluble Fas and soluble Fas ligand, have stimulated investigation into the potential utility of these assays in a large array of human disorders. Overall, it appears that soluble Fas and Fas ligand are increased in clinical states of immune activation. As such, these tests do not appear to provide significant advantage over a variety of other nonspecific markers of immune activation. However, in certain circumstances,

Acknowledgements

We thank Dr Michael Lenardo for discussion and critique of the manuscript and Drs Stephen Straus and Elaine Jaffe for the CT scan and pathology source material.

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    Drs Siegel and Fleisher prepared this manuscript in their private capacity, and no official endorsement or support by the National Institutes of Health should be inferred.

    ☆☆

    Reprint requests: Thomas A. Fleisher, MD, Bldg 10, Rm 2C306, 10 Center Dr, MSC 1508, Bethesda, MD 20892-1508.

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