A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS

Maccari, Maria Elena; Fuchs, Sebastian; Küry, Patrick; Andrieux, Geoffroy; Völkl, Simon; Bengsch, Bertram; Lorenz, Myriam Ricarda; Heeg, Maximilian; Rohr, Jan; Jägle, Sabine; Castro, Carla; Groß, Miriam; Warthorst, Ursula; König, Christoph; Fuchs, Ilka; Speckmann, Carsten; Thalhammer, Julian; Kapp, Friedrich; Seidel, Markus G.; Dückers, Gregor; Schönberger, Stefan; Schütz, Christian; Führer, Marita; Kobbe, Robin; Holzinger, Dirk; Klemann, Christian; Smíšek, Petr; Owens, Stephen; Horneff, Gerd; Kolb, R; Naumann-Bartsch, Nora; Miano, Maurizio; Staniek, Julian; Rizzi, Marta; Kalina, Tomáš; Schneider, Pascal; Erxleben, Anika; Backofen, Rolf; Ekici, Arif B.; Niemeyer, Charlotte M.; Warnatz, Klaus; Grimbacher, Bodo; Eibel, Hermann; Mackensen, Andréas; Frei, Andreas P.; Schwarz, Klaus; Boerries, Melanie; Ehl, Stephan; Rensing‐Ehl, Anne

doi:10.1084/jem.20192191

Cited by 29 publications

(26 citation statements)

References 60 publications

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“…Over the past 10–15 years, improvements in genomic technologies have led to the description of a number of monogenic disorders mimicking ALPS. These rare conditions, defined as CVID or ALPS-like phenotypes, clinically resemble ALPS and, therefore, are often misdiagnosed, highlighting the urgent need to revise the NIH ALPS diagnostic criteria based on increased knowledge of the pathogenic mechanisms and biomarkers of such disorders ( 23 – 25 , 34 , 35 ). Therefore, an earlier genetic diagnosis should be performed in all patients with immune dysregulation to define a more precise therapeutic strategy and to make a proper assessment in case of stem cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

et al. 2021

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Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.

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Section: Discussionmentioning

confidence: 99%

Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

et al. 2021

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“…In patients with ALPS, CD4 and CD8 T cells exhibit abnormal phenotypes reminiscent of terminally differentiated exhausted T cells seen in conditions where T cells are chronically stimulated. This phenotype, also observed in their DN T cells, along with evidence that links the TCR repertoire in CD8 + and DN T cells, suggests that self-antigen encounter drives CD8 to DN T cell conversion in ALPS and emphasizes the importance of Fas in keeping in check self-reactive CD8 T cells ( 56 , 57 ).…”

Section: Discussionmentioning

confidence: 79%

Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens

et al. 2021

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Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.

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“…Fas-associated death domain-containing protein (FADD) is an adaptor protein that is responsible for relaying apoptotic signals initiated by Fas [14]. FADD has 2 functional domains: the death domain (DD) and the death effector domain (DED) [15].…”

Section: Resultsmentioning

confidence: 99%

FADD Deficiency Mimicking ALPS-FAS: An Expanding Phenotype.

Setia

Bargir

Shanmukhaiah

et al. 2021

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Autoimmune lymphoproliferative syndrome (ALPS) is caused due to defects in the Fas-mediated apoptotic pathway. This disease is characterised by chronic non -malignant lymphoproliferation, autoimmune cytopenias and accumulation of double-negative T cells. FAS is the most commonly affected gene observed in patients with ALPS. There is a paucity of data in other ALPS associated genes. Mutations in the FADD gene is extremely rare, and to date, only five patients with a homozygous mutation in exon 2 and one patient with a compound heterozygous mutation are reported. The clinical spectrum of FADD includes neurological dysfunction, recurrent bacterial and viral infections and liver dysfunction. Here we report two patients with novel FADD mutation with clinical phenotype like ALPS-FAS. This article provides an expanding phenotype of FADD deficiency where patients can solely present with lymphoproliferation and autoimmunity without any features of febrile episodes or neurodevelopmental delay. We identified a novel homozygous FADD mutation by targeted Next-generation sequencing (NGS). We performed a comprehensive immune evaluation along with biomarker estimation, mTOR activity on DNTs and apoptosis assay. We describe two siblings born to third-degree consanguineous marriage with homozygous FADD mutation. The index patient P1 presented with lymphoproliferation, autoimmune manifestations in the form of Evans phenotype, lymphocytosis and elevated DNTs, whereas P2 only had mild lymphoproliferation with no autoimmune manifestations. The mutation in our patients lies in exon 2 of the FADD gene, encoding the death domain. The death domain (DD) of FADD protein interacts directly with the death domains of Fas, and mutation at this site disrupts binding to Fas and abolishes apoptosis. FADD deficiency should also be considered in patients presenting with lymphoproliferation and autoimmunity since they can mimic clinical features of ALPS-FAS.

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A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS

Cited by 29 publications

References 60 publications

Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure

Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens

FADD Deficiency Mimicking ALPS-FAS: An Expanding Phenotype.

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