Atypical presentation of autoimmune lymphoproliferative syndrome due to CASP10 mutation

Tripodi, Serena Ilaria; Mazza, Cinzia; Moratto, Daniele; Ramenghi, Ugo; Caorsi, Roberta; Gattorno, Marco; Badolato, Raffaele

doi:10.1016/j.imlet.2016.07.001

Cited by 15 publications

(11 citation statements)

References 11 publications

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“…Noteworthy, mutations in caspase-10 (70) or caspase-8 (71), both downstream of Fas and TRAIL-R signaling, result in immune dysregulation with features of autoimmune lymphoproliferative syndrome. Moreover, caspase-8 deficiency (71) is associated with defects in B and T cell activation and immunodeficiency whereas caspase-10 deficiency is associated with susceptibility to infections (72) and arthritis (73), pointing to a dual role of caspases in inducing both apoptotic and non-apoptotic signaling. Indeed, the real contribution of TRAIL and TRAIL-R expression in autoimmune disease is still unclear, as the available data are controversial.…”

Section: Discussionmentioning

confidence: 99%

TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes

et al. 2019

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The maintenance of B cell homeostasis requires a tight control of B cell generation, survival, activation, and maturation. In lymphocytes upon activation, increased sensitivity to apoptotic signals helps controlling differentiation and proliferation. The death receptor Fas is important in this context because genetic Fas mutations in humans lead to an autoimmune lymphoproliferative syndrome that is similar to lymphoproliferation observed in Fas-deficient mice. In contrast, the physiological role of TNF-related apoptosis-inducing ligand receptors (TRAIL-Rs) in humans has been poorly studied so far. Indeed, most studies have focused on tumor cell lines and on mouse models whose results are difficult to transpose to primary human B cells. In the present work, the expression of apoptosis-inducing TRAIL-R1 and TRAIL-R2 and of the decoy receptors TRAIL-R3 and TRAIL-R4 was systematically studied in all developmental stages of peripheral B cells isolated from the blood and secondary lymphoid organs. Expression of TRAIL-Rs is modulated along development, with highest levels observed in germinal center B cells. In addition, T-dependent and T-independent signals elicited induction of TRAIL-Rs with distinct kinetics, which differed among B cell subpopulations: switched memory cells rapidly upregulated TRAIL-R1 and -2 upon activation while naïve B cells only reached similar expression levels at later time points in culture. Increased expression of TRAIL-R1 and -2 coincided with a caspase-3-dependent sensitivity to TRAIL-induced apoptosis in activated B cells but not in freshly isolated resting B cells. Finally, both TRAIL-R1 and TRAIL-R2 could signal actively and both contributed to TRAIL-induced apoptosis. In conclusion, this study provides a systematic analysis of the expression of TRAIL-Rs in human primary B cells and of their capacity to signal and induce apoptosis. This dataset forms a basis to further study and understand the dysregulation of TRAIL-Rs and TRAIL expression observed in autoimmune diseases. Additionally, it will be important to foresee potential bystander immunomodulation when TRAIL-R agonists are used in cancer treatment.

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Section: Discussionmentioning

confidence: 99%

TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes

et al. 2019

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“…So far, two CASP10 mutations (I406L, L285F) have been described (Wang et al , ; Zhu et al , ) as pathogenic by exerting a dominant negative effect on the wild type protein. However, not all individuals carrying these mutations show overt disease or a typical phenotype (Tripodi et al , ). A similar condition has also been reported in patients with a pathogenic FAS mutation, indicating that clinical penetrance of ALPS genes is very heterogeneous (Cerutti et al , ).…”

Section: Introductionmentioning

confidence: 99%

FAS‐mediated apoptosis impairment in patients with ALPS/ALPS‐like phenotype carrying variants on CASP10 gene

et al. 2019

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Summary Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10‐mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS‐like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS‐ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS‐like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

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“…CASP10 variants were found in 5 patients (2 definite, 1 suspected, and 2 nonevaluable). CASP10 variant (c.1216A>T; p.Ile406Leu) has been previously published as pathogenic in ALPS, in vitro functional studies proved its pathogenicity, although its minor allele frequency (MAF: 0.4%) and in silico prediction programmes defined as benign variant (ACMG categorisation: likely benign)33 . CASP10 p.variants, had an elevated percentage of DNT (n=2), but a normal in vitro lymphocyte apoptosis functional test and sFASL.…”

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confidence: 99%

Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

Molnár

Radwan

Kovàcs

et al. 2020

Blood

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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 possible ALPS. Double negative T-cell (DNT) percentage and in vitro apoptosis functional tests were evaluated by FACS; interleukin 10 and 18 (IL-10, -18) and soluble FAS ligand (sFASL) were measured by ELISA. Genetic analysis was performed by next generation sequencing. Clinical background data were collected from patients' records. Patients were categorised into definite, suspected and unlikely ALPS, and laboratory parameters were compared among these groups. From 215 patients, 38 met the criteria for definite ALPS and 17 for suspected ALPS. The definite and suspected ALPS patient population showed higher DNT 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=0.002) and patients not meeting the ALPS criteria (P<0.001). The combination of elevated DNT and an abnormal in vitro apoptosis functional test was the most useful to identify all types of ALPS patients; the combination of abnormal in vitro apoptosis functional test and elevated sFASL was a predictive marker for ALPS-FAS group identification. Lymphoproliferation, apoptosis functional test and DNT are the most sensitive markers; elevated IL-10 and IL-18 are additional indicators for ALPS. The combination of elevated sFASL and an abnormal apoptosis function was the most valuable prognosticator for patients with FAS mutations.

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Atypical presentation of autoimmune lymphoproliferative syndrome due to CASP10 mutation

Cited by 15 publications

References 11 publications

TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes

TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes

FAS‐mediated apoptosis impairment in patients with ALPS/ALPS‐like phenotype carrying variants on CASP10 gene

Key diagnostic markers for autoimmune lymphoproliferative syndrome with molecular genetic diagnosis

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