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Autor
Allende, Luis M 1 Alsina, Laia 1 Andrieux, Geoffroy 1 Arpesella, Leonardo 1 Bakardjieva, Marina 1 Benes, Vladimir 1 Boerries, Melanie 1 Böhler, Chiara 1 Carsetti, Rita 1 Catala, Albert 1 Díez, Paula 1 Ehl, Stephan 1 Fernández García, Jonatan 1 Fuentes, Manuel 1 García Valiente, Rodrigo 1 Gonzalez-Granado, Luis I 1 Janowska, Iga 1 Kalina, Tomas 1 Lorenzetti, Raquel 1 Magerus, Aude 1
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Pracoviště
B Cell Unit Immunology Research Area ... 1 CIBSS Centre for Integrative Biologic... 1 Center for Chronic Immunodeficiency U... 1 Center for Pediatrics and Adolescent ... 1 Clinical Immunology and Primary Immun... 1 Department of Hematology Institut de ... 1 Department of Immunobiology Faculty o... 1 Department of Immunology Hospital Uni... 1 Department of Immunology Leiden Unive... 1 Department of Immunology University H... 1 Department of Medicine and General Cy... 1 Department of Paediatric Haematology ... 1 Department of Paediatric Infectious D... 1 Department of Pathology University Me... 1 Department of Rheumatology and Clinic... 1 Department of Rheumatology and Immuno... 1 Division of Clinical and Experimental... 1 Division of Molecular Immunology Depa... 1 Division of Rheumatology and Clinical... 1 Faculty of Biology University of Frei... 1
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Autor
Allende, Luis M 1 Alsina, Laia 1 Andrieux, Geoffroy 1 Arpesella, Leonardo 1 Bakardjieva, Marina 1 Benes, Vladimir 1 Boerries, Melanie 1 Böhler, Chiara 1 Carsetti, Rita 1 Catala, Albert 1 Díez, Paula 1 Ehl, Stephan 1 Fernández García, Jonatan 1 Fuentes, Manuel 1 García Valiente, Rodrigo 1 Gonzalez-Granado, Luis I 1 Janowska, Iga 1 Kalina, Tomas 1 Lorenzetti, Raquel 1 Magerus, Aude 1
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Pracoviště
B Cell Unit Immunology Research Area ... 1 CIBSS Centre for Integrative Biologic... 1 Center for Chronic Immunodeficiency U... 1 Center for Pediatrics and Adolescent ... 1 Clinical Immunology and Primary Immun... 1 Department of Hematology Institut de ... 1 Department of Immunobiology Faculty o... 1 Department of Immunology Hospital Uni... 1 Department of Immunology Leiden Unive... 1 Department of Immunology University H... 1 Department of Medicine and General Cy... 1 Department of Paediatric Haematology ... 1 Department of Paediatric Infectious D... 1 Department of Pathology University Me... 1 Department of Rheumatology and Clinic... 1 Department of Rheumatology and Immuno... 1 Division of Clinical and Experimental... 1 Division of Molecular Immunology Depa... 1 Division of Rheumatology and Clinical... 1 Faculty of Biology University of Frei... 1
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- Staniek, Julian
- Kalina, Tomas
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Andrieux, Geoffroy
Autor Andrieux, Geoffroy ORCID Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Consortium (DKTK), partner site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Boerries, Melanie
Autor Boerries, Melanie ORCID Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany German Cancer Consortium (DKTK), partner site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Janowska, Iga
- Fuentes, Manuel
- Díez, Paula
- Bakardjieva, Marina
- Stancikova, Jitka
- Raabe, Jan
Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.
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