Faculty Opinions recommendation of A novel homozygous Fas ligand mutation leads to early protein truncation, abrogation of death receptor and reverse signaling and a severe form of the autoimmune lymphoproliferative syndrome.

2017 ◽  
Author(s):  
David Teachey
Keyword(s):  
Fas Ligand ◽  
Death Receptor ◽  
Severe Form ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Reverse Signaling ◽  
Early Protein ◽  
Lymphoproliferative Syndrome ◽  
Protein Truncation

scholarly journals Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation

2013 ◽  
Vol 131 (2) ◽  
pp. 486-490 ◽  
Author(s):  
Aude Magerus-Chatinet ◽  
Marie-Claude Stolzenberg ◽  
Nina Lanzarotti ◽  
Bénédicte Neven ◽  
Cécile Daussy ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

scholarly journals Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

Blood ◽  
2020 ◽  
Vol 136 (17) ◽  
pp. 1933-1945
Author(s):  
Emese Molnár ◽  
Nesrine Radwan ◽  
Gábor Kovács ◽  
Hajnalka Andrikovics ◽  
Frances Henriquez ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Molecular Genetic ◽  
Group Identification ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Functional Test ◽  
Enzyme Linked Immunosorbent Assay ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunodeficiency caused by mutations in genes affecting the extrinsic apoptotic pathway (FAS, FASL, CASP10). This study evaluated the clinical manifestations, laboratory findings, and molecular genetic results of 215 patients referred as possibly having ALPS. Double-negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by fluorescence-activated cell sorting; interleukin 10 (IL-10) and IL-18 and soluble FAS ligand (sFASL) were measured by enzyme-linked immunosorbent assay. Genetic analysis was performed by next-generation sequencing. Clinical background data were collected from patients’ records. Patients were categorized into definite, suspected, or unlikely ALPS groups, and laboratory parameters were compared among these groups. Of 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient populations showed higher DNT percentages than unlikely ALPS and had higher rates of lymphoproliferation. Definite ALPS patients had a significantly more abnormal in vitro apoptosis function, with lower annexin, than patients with suspected ALPS (P = .002) and patients not meeting ALPS criteria (P < .001). The combination of elevated DNTs and an abnormal in vitro apoptosis functional test was the most useful in identifying all types of ALPS patients; the combination of an abnormal in vitro apoptosis functional test and elevated sFASLs was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test, and DNTs are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASLs and abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

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

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1306-1312 ◽  
Author(s):  
Manuel Del-Rey ◽  
Jesus Ruiz-Contreras ◽  
Alberto Bosque ◽  
Sara Calleja ◽  
Jose Gomez-Rial ◽  
...  
Keyword(s):  
T Cell ◽  
Gene Mutation ◽  
Fas Ligand ◽  
Clinical Manifestations ◽  
Lymphoproliferative Disease ◽  
Jurkat Cells ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Activation Induced Cell Death ◽  
Fasl Gene ◽  
Lymphoproliferative Syndrome

Abstract Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferation and autoimmune clinical manifestations and is generally caused by defective Fas-mediated apoptosis. This report describes the first homozygous FASL gene mutation in a woman with clinical and immunologic features of ALPS. T-cell blasts from the patient did not induce FasL-mediated apoptosis on Fas-transfected murine L1210 or on Jurkat cells, and activation-induced cell death was impaired. Furthermore, Fas-dependent cytotoxicity was drastically reduced in COS cells transfected with the mutant FasL. In addition, FasL expression on T-cell blasts from the patient was similar to that observed in a healthy control, despite its bearing the high-producer genotype –844C/C in the FASL promoter. Sequencing of the patient's FASL gene revealed a new mutation in exon 4 (A247E). The location of A247E in the FasL extracellular domain and the conservation of the protein sequence of that region recorded in 8 species different from humans support the essential role of FasL COOH terminal domain in Fas/FasL binding. These findings provide evidence that inherited nonlethal FASL abnormalities cause an uncommon apoptosis defect producing lymphoproliferative disease, and they highlight the need for a review of the current ALPS classification to include a new ALPS type Ic subgroup.

The Autoimmune Lymphoproliferative Syndrome with Defective FAS or FAS-Ligand Functions

2018 ◽  
Vol 38 (5) ◽  
pp. 558-568 ◽  
Author(s):  
Frédéric Rieux-Laucat ◽  
Aude Magérus-Chatinet ◽  
Bénédicte Neven
Keyword(s):  
Fas Ligand ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

scholarly journals Erratum to: A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats

2017 ◽  
Vol 28 (3-4) ◽  
pp. 152-154 ◽  
Author(s):  
Danielle Aberdein ◽  
◽  
John S. Munday ◽  
Barbara Gandolfi ◽  
Keren E. Dittmer ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

A FAS-ligand variant associated with autoimmune lymphoproliferative syndrome in cats

2016 ◽  
Vol 28 (1-2) ◽  
pp. 47-55 ◽  
Author(s):  
Danielle Aberdein ◽  
◽  
John S. Munday ◽  
Barbara Gandolfi ◽  
Keren E. Dittmer ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphoproliferative Syndrome

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

Haematologica ◽  
2015 ◽  
Vol 100 (9) ◽  
pp. 1189-1198 ◽  
Author(s):  
S. Nabhani ◽  
S. Ginzel ◽  
H. Miskin ◽  
S. Revel-Vilk ◽  
D. Harlev ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Ligand Expression ◽  
Lymphoproliferative Syndrome

scholarly journals Clinical, Immunologic, and Genetic Features of an Autoimmune Lymphoproliferative Syndrome Associated With Abnormal Lymphocyte Apoptosis

Blood ◽  
1997 ◽  
Vol 89 (4) ◽  
pp. 1341-1348 ◽  
Author(s):  
Michael C. Sneller ◽  
Jin Wang ◽  
Janet K. Dale ◽  
Warren Strober ◽  
Lindsay A. Middelton ◽  
...  
Keyword(s):  
Fas Ligand ◽  
Cell Receptor ◽  
Clinical Syndrome ◽  
In Vitro Assays ◽  
Autoimmune Lymphoproliferative Syndrome ◽  
Lymphocyte Apoptosis ◽  
Clinical Genetic ◽  
Activated Lymphocytes ◽  
Lymphoproliferative Syndrome

Abstract Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4−CD8− T cells that express the α/β T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.

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