Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Maccari, Maria Elena; Schneider, Pascal; Smulski, Cristian R.; Meinhardt, Andrea; Pinto, Fernando; González‐Granado, Luis Ignacio; Schuetz, Catharina; Sica, Mauricio P.; Groß, Miriam; Fuchs, Ilka; Küry, Patrick; Heeg, Maximilian; Vocat, Tatjana; Willen, Laure; Thomas, Caroline; Hühn, Regina; Magérus, Aude; Lorenz, Myriam Ricarda; Schwarz, Klaus; Rieux‐Laucat, Frédéric; Ehl, Stephan; Rensing‐Ehl, Anne

doi:10.1016/j.jaci.2022.11.028

Cited by 11 publications

(10 citation statements)

References 53 publications

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“…5C). Notably, similar to previously described DNA co-transfection studies [29], both tandem molecules (FasL WT-A247E and FasLWT-G277S ) were cytotoxic very similar to FasL WT-WT in Jurkat cells and tumor cells (Fig. 4C, D).…”

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationssupporting

confidence: 87%

“…A recent study has shown that, unlike homozygous mutations, patients with described heterozygous ALPS mutations maintained intact FasL cytotoxicity and were resistant to haploinsufficiency [29]. Considering that the FasL E247 and FasL S277 mutants did not effectively interact with Fas (Fig.…”

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 94%

“…A key marker of ALPS is a high proportion of CD4 − CD8 − TCRαβ+ T cells, called doublenegative T cells, and increased plasma concentrations of soluble Fas-ligand with limited cytotoxicity potential to eliminate T cells. Several homozygous missense mutations [18,29] in FasL, such as G277S [30], A247E [31], R156G [32], etc., have been attributed to APLS. When tested, unlike PPCR interface FasL mutants (PPCR IFMs), such as E163A, E271A, the described FasL mutations in ALPS patients [such as G277S, A247E, R156G] partially activated cell death of both tumor and Jurkat cells (Fig.…”

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 99%

“…We also asked if Fas PPCR IFMs with the ability to trimerize normally will negatively affect the cytotoxic function of FasL WT heterologously. As described, 1:1 DNA co-transfection conditions of WT and mutant FasL could generate technical variations [29]; we genetically ligated Histagged WT-FasL with mutants in tandem via G4S linkers (two ligand molecules next to each other as two separate units) and expressed using a CHO expression system (Fig. 5A, B).…”

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 99%

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Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Mondal,

Gaur,

Wamba

et al. 2023

Cell Death Differ

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Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.

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Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationssupporting

confidence: 87%

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 94%

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 99%

Section: Differential Fas Activation Profile Of Alps and Ppcr Mutationsmentioning

confidence: 99%

See 2 more Smart Citations

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Mondal,

Gaur,

Wamba

et al. 2023

Cell Death Differ

View full text Add to dashboard Cite

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“…FAS ligand deficiency (ALPS-FASLG) follows an autosomal-recessive inheritance and presents clinically like homozygous ALPS-FAS [ 44 – 46 ]. No convincing disease association of heterozygous FASLG mutations has so far been described [ 47 – 49 ]. FADD deficiency also follows an autosomal-recessive mode of inheritance, but the clinical phenotype of this disease is more complex.…”

Section: Introductionmentioning

confidence: 99%

Autoimmune lymphoproliferative immunodeficiencies (ALPID) in childhood: breakdown of immune homeostasis and immune dysregulation

Toskov,

Ehl

2023

Mol Cell Pediatr

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Many inborn errors of immunity (IEI) manifest with hallmarks of both immunodeficiency and immune dysregulation due to uncontrolled immune responses and impaired immune homeostasis. A subgroup of these disorders frequently presents with autoimmunity and lymphoproliferation (ALPID phenotype). After the initial description of the genetic basis of autoimmune lymphoproliferative syndrome (ALPS) more than 20 years ago, progress in genetics has helped to identify many more genetic conditions underlying this ALPID phenotype. Among these, the majority is caused by a group of autosomal-dominant conditions including CTLA-4 haploinsufficiency, STAT3 gain-of-function disease, activated PI3 kinase syndrome, and NF-κB1 haploinsufficiency. Even within a defined genetic condition, ALPID patients may present with staggering clinical heterogeneity, which makes diagnosis and management a challenge. In this review, we discuss the pathophysiology, clinical presentation, approaches to diagnosis, and conventional as well as targeted therapy of the most common ALPID conditions.

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Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

Xu,

Denton,

et al. 2024

J Clin Immunol

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Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children’s Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.

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Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Cited by 11 publications

References 53 publications

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer

Autoimmune lymphoproliferative immunodeficiencies (ALPID) in childhood: breakdown of immune homeostasis and immune dysregulation

Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

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