In Vitro Evaluation of the Apoptosis Function in Human Activated T Cells

Magérus-Chatinet, Aude; Rieux-Laucat, Frédéric

doi:10.1007/978-1-4939-6780-3_4

Cited by 6 publications

(1 citation statement)

References 18 publications

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“…This assays allow to evaluate the capacity of the activated T lymphocytes to enter apoptosis: 1) after induction by an agonist of the death receptor FAS or by an agonist of the death receptor TRAIL, allowing the assessment of the extrinsic apoptosis pathway; 2) after re-activation of the cells by stimulating the TCR, which induces the expression of membrane FAS-L, leading to AICD (activation induced cell death); or 3) after deprivation of interleukin-2, leading to ACAD (activated cell autonomous death) involving the intrinsic pathway of apoptosis, also called the mitochondrial pathway. This test has been described in detail in a methods journal [ 32 ].…”

Section: To Humansmentioning

confidence: 99%

The genetic landscape of the FAS pathway deficiencies

2021

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Dysfunction of the FAS-FASLG pathway causes a lymphoproliferative disorder with autoimmunity called Autoimmune lymphoproliferative syndrome (ALPS) mainly caused by FAS mutations. The goal of this review is to describe the genetic bases of the autoimmune lymphoproliferative syndrome and to underline their genetic complexity with the contribution of both germline and somatic events accounting for the variable clinical penetrance of the FAS mutations. Starting from the cohort of patients studied in the French cohort (>165 cases), we also reviewed the literature cases in order to depict a full description of the mutations affecting the FAS-FASLG pathway involved in the outcome of this rare non-malignant and non-infectious pediatric lymphoproliferative disease. We also discussed the variable clinical penetrance associated with mutations affecting the extracellular domain of the protein. Such non-penetrant germline mutations are frequently associated with an additional somatic event impacting the second allele of FAS . Moreover, the uncomplete clinical penetrance associated with mutations affecting the intracellular domain of FAS, in patient lacking additional FAS somatic event, suggested a potential digenic inheritance with a FAS mutation accompanied by a genetic modifier possibly impacting another player of the lymphocytes homeostasis (affecting the survival, activation or apoptosis of the peripheral leukocytes).

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Section: To Humansmentioning

confidence: 99%

The genetic landscape of the FAS pathway deficiencies

2021

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Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Pellé,

Moreno,

Lorenz

et al. 2024

Journal of Allergy and Clinical Immunology

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Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

Consonni,

Moreno,

Vinuales Colell

et al. 2024

Cell Death Dis

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Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.

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In Vitro Evaluation of the Apoptosis Function in Human Activated T Cells

Cited by 6 publications

References 18 publications

The genetic landscape of the FAS pathway deficiencies

The genetic landscape of the FAS pathway deficiencies

Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome

Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

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