A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome

Rey, Manuel; Ruiz–Contreras, Jesús; Bosque, Alberto; Calleja, Sara; Gómez-Rial, José; Roldán, Ernesto; Morales, Pablo; Serrano, Antonio; Anel, Alberto; Paz-Artal, Estela; Allende, Luis M.

doi:10.1182/blood-2006-04-015776

Cited by 114 publications

(81 citation statements)

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“…Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both (3,8,9). Mutations in the Fas ligand gene (FASLG) in ALPS (ALPS-FASLG) have only been reported in five patients, two of them with the autosomal dominant form (10,11) and three with the autosomal recessive form of the disease (12)(13)(14). Cases with clinical and immunological features of ALPS with unknown genetic defects are referred to as ALPS-U (15).…”

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Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation

et al. 2015

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Background: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells, and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG). Methods: ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays. results: This report describes the cases of a patient who presented a severe form of ALPS-FASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity, and AICD in T-cell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing Epstein-Barr virus (EBV)-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients. conclusion: Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T-and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy. c linically, patients with autoimmune lymphoproliferative syndrome (ALPS) have nonmalignant lymphadenopathies, splenomegaly, autoimmune cytopenias, and susceptibility to malignancy (1-5). Immunological features of ALPS consist of an expanded population of double-negative (DN) T-cells (TcRαβ+CD4-CD8-), while elevated levels of circulating plasma biomarkers, including IL-10, IL-18, soluble Fas ligand (sFasL), and vitamin B12, have also been described (6,7). ALPS patients are classified according to the underlying genetic defect (Mendelian inheritance in man (MIM) no. 601859). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both (3,8,9). Mutations in the Fas ligand gene (FASLG) in ALPS (ALPS-FASLG) have only been reported in five patients, two of them with the autosomal dominant form (10,11) and three with the autosomal recessive form of the disease (12)(13)(14). Cases with clinical and immunological features of ALPS with unknown genetic defects are referred to as ALPS-U (15). In addition, the demonstration of an apoptosis defect is critical for the diagnosis of ALPS. Specifically, activation-induced cell death (AICD), a homeostatic mechanism involved in the termination of the adaptive immune response by extrinsic or intrinsic cell death pathways, is impaired in ALPS-FASLG patients (12,13,16) (see Supplementary Table S1 online).This report describes the cases of two Moroccan brothers (P1 and P2), born to consanguineous parents, who presented a severe form of ALPS caused by a novel homozygous FASLG mutati...

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Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation

et al. 2015

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“…6,[8][9][10][11] Homozygous or compound heterozygous FAS mutations result in a clinically more severe phenotype. Less frequently, FASLG mutations (ALPS-FASLG) [12][13][14][15][16] or CASP10 mutations (ALPS-CASP10) 17 have been detected. Similar symptoms are caused by mutations in CASP8 (caspase-8 deficiency state), KRAS or NRAS (RASassociated ALPS-like disease).…”

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Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nFor instance, forced expression of the Fas regulating miR146a caused an immune disorder similar to ALPS in transgenic mice. 22 One factor known to regulate expression of both Fas and FasL is interleukin-12 (IL12). [23][24][25][26][27][28][29][30] This cytokine mediates its effects via binding to a heterodimeric receptor composed of the IL12 receptors β1 (IL12RB1) and β2 (IL12RB2) and subsequent activation of JAK/STAT signaling. 31 The IL12 receptor is mainly expressed on T lymphocytes and natural killer (NK) cells. IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor. Phagocytic cells release both IL12 and IL23 in response to non-viral infections to induce the secretion of interferon (IFN)g by T and NK cells. This in turn stimulates phagocytes to eliminate intracellular pathogens and activation of IFNg−secreting T helper cells. The IL12 signaling pathway is known to regulate FasL expression on activated T cells and knockout of IL12RB2 predisposes mice to spontaneous autoimmunity, lymphoproliferation and B-cell malignancies. 36 In the present study we identified a patient with a classical ALPS phenotype that was associated with a truncating nonsense mutation in IL12RB1 and loss of IL12/IL23-mediated signaling. Methods Study cohorts and DNA isolationTwenty-six ALPS patients, relatives and healthy controls were enrolled in the study. Written informed consent was obtained from all participants. Experiments were approved by the Ethical Review Boards of Hadassah, the Israeli Ministry of Health and the local Ethics committee of the University of Düsseldorf. Mononuclear cells were derived from peripheral blood by Ficoll (Biochrom, Berlin, Germany) density centrifugation. DNT cells were magnetically selected employing the double-negative T-cell isolation kit (Miltenyi, Bergisch-Gladbach, Germany). Genomic DNA was isolated from whole blood or DNT cells using the DNA blood kit (Qiagen, Hilden, Germany). Whole-exome sequencing and data analysisAfter exclusion of mutations in known ALPS-associated genes by targeted Sanger sequencing (Online Supplementary Methods, Online Supplementary Table S1) whole-exome sequencing was carried out as described elsewhere. 37 In brief, sequencing libraries of 350 bp fragments were generated from sheared genomic DNA. Exome capture was performed using the SeqCap EZ Exome Library 2.0 kit (Roche/Nimblegen, Madison, WI, USA). One hundred base-pair, single-read sequencing was performed on a HiSeq2000 (Illumina, San Diego, CA, USA).Sequencing data were aligned against the human reference genome hg19 (GRCh37, statistics provided in Online Supplementary Table S2) and converted using Samtools. 38 Variation calls were obtained employing GATK, HapMap, OmniArray and dbSNP134 datasets (The Broad Institu...

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“…9,10 In addition, germline mutations in the genes coding for Fas L, caspase 10, and caspase 8 and somatic mutations in NRAS and KRAS have been identified in a small number of patients with ALPS and related disorders. [11][12][13][14][15][16] The classification and diagnostic criteria for ALPS were revised recently. 17 The majority of ALPS-FAS-related mutations are located in the Fas intracellular domain (ICD) and within its death domain (DD) in particular.…”

Section: Introductionmentioning

confidence: 99%

A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation

Neven

Magérus-Chatinet

Florkin

et al. 2011

Blood

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A homozygous Fas ligand gene mutation in a patient causes a new type of autoimmune lymphoproliferative syndrome

Cited by 114 publications

References 34 publications

Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation

Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation

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