The development of lymphomas in families with autoimmune lymphoproliferative syndrome (ALPS) with germline Fas mutations and defective lymphocyte apoptosis

University of Freiburg, Freiburg, Baden-Württemberg, Germany
Blood (Impact Factor: 10.45). 07/2001; 98(1):194-200. DOI: 10.1182/blood.V98.1.194
Source: PubMed


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
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    • "Autoimmune lymphoproliferative syndrome (ALPS) is another genetic lymphoproliferative disease and is characterized by lymphadenomegaly and/or splenomegaly, due to polyclonal accumulation of lymphocytes, and peripheral expansion of CD4/CD8 double-negative (DN) T cells [5–10]. In addition, patients often display autoimmune manifestations that predominantly involve blood cells and are predisposed to lymphomas in adulthood [11]. ALPS is due to defective function of the Fas/Apo-1 (CD95) death receptor, inducing apoptosis of the Fas-expressing cell upon binding with Fas ligand (FasL) [12,13]. "
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    ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is caused by genetic defects decreasing Fas function and is characterized by lymphadenopathy/splenomegaly and expansion of CD4/CD8 double-negative T cells. This latter expansion is absent in the ALPS variant named Dianzani Autoimmune/lymphoproliferative Disease (DALD). In addition to the causative mutations, the genetic background influences ALPS and DALD development. We previously suggested a disease-modifying role for the perforin gene involved in familial hemophagocytic lymphohistiocytosis (FHL). The UNC13D gene codes for Munc13-4, which is involved in perforin secretion and FHL development, and thus, another candidate for a disease-modifying role in ALPS and DALD. In this work, we sequenced UNC13D in 21 ALPS and 20 DALD patients and compared these results with sequences obtained from 61 healthy subjects and 38 multiple sclerosis (MS) patients. We detected four rare missense variations in three heterozygous ALPS patients carrying p.Cys112Ser, p.Val781Ile, and a haplotype comprising both p.Ile848Leu and p.Ala995Pro. Transfection of the mutant cDNAs into HMC-1 cells showed that they decreased granule exocytosis, compared to the wild-type construct. An additional rare missense variation, p.Pro271Ser, was detected in a healthy subject, but this variation did not decrease Munc13-4 function. These data suggest that rare loss-of-function variations of UND13D are risk factors for ALPS development.
    Full-text · Article · Jul 2013 · PLoS ONE
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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). "

    Full-text · Article · Jun 2013 · Neuroscience
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    • "Decreased expression of Fas was shown in tumor cells from hepatocellular carcinoma, colon cancer or melanoma [76]. Moreover, mutations or deletions in genes encoding Fas and TRAIL-R1-R2 were noticed in some cancer cells and involved in some familial forms of cancers [76, 77]. Many studies have suggested that tumor cells could escape from the immune system by expressing FasL and inducing apoptosis in activated Fas+ CTL. "
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