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Straus, S.E. et al. The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98, 194−200

University of Freiburg, Freiburg, Baden-Württemberg, Germany
Blood (Impact Factor: 10.43). 07/2001; 98(1):194-200. DOI: 10.1182/blood.V98.1.194
Source: PubMed

ABSTRACT Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3(+)CD4(-)CD8(-) T-cell-receptor alpha/beta cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P <.001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.

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Available from: Elaine S Jaffe, Aug 19, 2015
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    • "Activation of Fas by its physiological ligand, FasL, has been proved to definitely trigger cell apoptosis (Nagata, 1997; Krammer, 2000). FasL-Fas signaling pathway plays a critical role in immune system function, such as killing virus-infected or damaged cells and tumor suppression (Straus et al., 2001). Execution of Fas apoptosis-inducing function relies on the assembly of an intracellular death-inducing signaling complex (DISC), which involves the aspartate-specific cysteine protease, Caspase-8, its adaptor/activator, Fas-associated death domain (FADD), and its modulator, (FADD)-like interleukin 1b-converting enzyme inhibitory protein (Kischkel et al., 1995; Boldin et al., 1995; Chinnaiyan et al., 1995; Boldin et al., 1996; Muzio et al., 1996; Irmler et al., 1997). "
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    • "The discovery that certain spontaneous mutant mouse strains that develop lymphadenopathy and SLE (systemic lupus erythematosus)-like autoimmune disease carry homozygous defects in the genes encoding FAS (Fas lpr/lpr or Fas lprcg / lprcg ) (Watanabe-Fukunaga et al., 1992) or FASL (Fasl gld/gld ) (Takahashi et al., 1994) and the realization that a large fraction of human ALPS (autoimmune lymphoproliferative syndrome) patients have heterozygous inherited mutations in the FAS gene (Drappa et al., 1996; Fisher et al., 1995; Rieux-Laucat et al., 1995) demonstrated that FASL- FAS signaling plays a critical role in the control of the immune system. ALPS patients (Straus et al., 2001) as well as the FAS-or FASL-deficient mice (Davidson et al., 1998) have an abnormally increased predisposition to lymphoma development, demonstrating that FASL- FAS signaling is also critical for tumor suppression, at least within the lymphoid compartment. FASL expressed on activated T lymphocytes or natural killer (NK) contributes to their ability to kill target cells, such as virus infected or damaged cells (Trambas and Griffiths, 2003). "
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    ABSTRACT: FAS belongs to the subgroup of the tumor necrosis factor receptor (TNF-R) family that contains an intracellular "death domain" and triggers apoptosis. Its physiological ligand FASL is a member of the TNF cytokine family. Studies with mutant mice and cells from human patients have shown that FAS plays critical roles in the immune system, including the killing of pathogen-infected cells and the death of obsolete and potentially dangerous lymphocytes. Fas thereby functions as a guardian against autoimmunity and tumor development. FAS triggers apoptosis through FADD-mediated recruitment and activation of caspase-8. In certain cells such as hepatocytes, albeit not lymphocytes, FAS-induced apoptosis requires amplification through proteolytic activation of the proapoptotic BCL-2 family member BID. Curiously, several components of the FAS signaling machinery have been implicated in nonapoptotic processes, including cellular activation, differentiation, and proliferation. This review describes current understanding of Fas-induced apoptosis signaling and proposes experimental strategies for future advances.
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    • "CD40L/ CD40 T/B interaction can induce class-switch and further affinity maturation of immunoglobulins with autoimmune specificity [115]. Development of lymphoma has also been reported in patients with ALPS and their relatives [116] [117] [118]. Deregulated expression of Fas pathway may contribute to tumorigenesis and tumor escape from endogenous growth control. "
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    ABSTRACT: The immune system has evolved sophisticated mechanisms controlling the development of responses to dangerous antigens while avoiding unnecessary attacks to innocuous, commensal or self antigens. The risk of autoimmunity is continuously checked and balanced against the risk of succumbing to exogenous infectious agents. It is therefore of paramount importance to understand the molecular events linking the breakdown of tolerance and the development of immunodeficiency. Apoptotic mechanisms are used to regulate the development of thymocytes, the shaping of T cell repertoire, its selection and the coordinate events leading to immune responses in the periphery. Moreover, they are at the heart of the homeostatic controls restoring T cell numbers and establishing T cell memory. T lymphocytes shift continuously from survival to death signals to ensure immune responsiveness without incurring in autoimmune damage. In this review we shall consider some key facts on the relationship of lymphopenia to autoreactivity, the mechanisms controlling positive and negative selection in the thymus, the role of apoptosis in selected primary immunodeficiency states and in systemic and organ-specific autoimmunity, with examples from human diseases and their animal models.
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