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Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI

Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 1...

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Autores principales: Ramirez, Neftali, Posadas-Cantera, Sara, Langer, Niko, de Oteyza, Andres Caballero Garcia, Proietti, Michele, Keller, Baerbel, Zhao, Fangwen, Gernedl, Victoria, Pecoraro, Matteo, Eibel, Hermann, Warnatz, Klaus, Ballestar, Esteban, Geiger, Roger, Bossen, Claudia, Grimbacher, Bodo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9443529/
https://www.ncbi.nlm.nih.gov/pubmed/36072607
http://dx.doi.org/10.3389/fimmu.2022.938240
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author Ramirez, Neftali
Posadas-Cantera, Sara
Langer, Niko
de Oteyza, Andres Caballero Garcia
Proietti, Michele
Keller, Baerbel
Zhao, Fangwen
Gernedl, Victoria
Pecoraro, Matteo
Eibel, Hermann
Warnatz, Klaus
Ballestar, Esteban
Geiger, Roger
Bossen, Claudia
Grimbacher, Bodo
author_facet Ramirez, Neftali
Posadas-Cantera, Sara
Langer, Niko
de Oteyza, Andres Caballero Garcia
Proietti, Michele
Keller, Baerbel
Zhao, Fangwen
Gernedl, Victoria
Pecoraro, Matteo
Eibel, Hermann
Warnatz, Klaus
Ballestar, Esteban
Geiger, Roger
Bossen, Claudia
Grimbacher, Bodo
author_sort Ramirez, Neftali
collection PubMed
description Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding TACI. Mutations in TNFRSF13B alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in TNFRSF13B and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.
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spelling pubmed-94435292022-09-06 Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI Ramirez, Neftali Posadas-Cantera, Sara Langer, Niko de Oteyza, Andres Caballero Garcia Proietti, Michele Keller, Baerbel Zhao, Fangwen Gernedl, Victoria Pecoraro, Matteo Eibel, Hermann Warnatz, Klaus Ballestar, Esteban Geiger, Roger Bossen, Claudia Grimbacher, Bodo Front Immunol Immunology Common variable immunodeficiency (CVID) is the most prevalent form of symptomatic primary immunodeficiency in humans. The genetic cause of CVID is still unknown in about 70% of cases. Ten percent of CVID patients carry heterozygous mutations in the tumor necrosis factor receptor superfamily member 13B gene (TNFRSF13B), encoding TACI. Mutations in TNFRSF13B alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypothesis is that TACI mutations are not fully penetrant and additional factors contribute to the development of CVID. To determine these additional factors, we investigated the perturbations of transcription factor (TF) binding and the transcriptome profiles in unstimulated and CD40L/IL21-stimulated naïve B cells from CVID patients harboring the C104R mutation in TNFRSF13B and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated naïve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated naïve B cells and 25% less accessible chromatin in class-switched memory B cells from affected and unaffected TACI mutation carriers compared to healthy donors. The most enriched TF binding motifs in TACI mutation carriers involved members from the ETS, IRF, and NF-κB TF families. Validation experiments supported dysregulation of the NF-κB and MAPK pathways. In steady state, naïve B cells had increased cell death pathways and reduced cell metabolism pathways, while after stimulation, enhanced immune responses and decreased cell survival were detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers. Frontiers Media S.A. 2022-08-16 /pmc/articles/PMC9443529/ /pubmed/36072607 http://dx.doi.org/10.3389/fimmu.2022.938240 Text en Copyright © 2022 Ramirez, Posadas-Cantera, Langer, de Oteyza, Proietti, Keller, Zhao, Gernedl, Pecoraro, Eibel, Warnatz, Ballestar, Geiger, Bossen and Grimbacher https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Ramirez, Neftali
Posadas-Cantera, Sara
Langer, Niko
de Oteyza, Andres Caballero Garcia
Proietti, Michele
Keller, Baerbel
Zhao, Fangwen
Gernedl, Victoria
Pecoraro, Matteo
Eibel, Hermann
Warnatz, Klaus
Ballestar, Esteban
Geiger, Roger
Bossen, Claudia
Grimbacher, Bodo
Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title_full Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title_fullStr Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title_full_unstemmed Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title_short Multi-omics analysis of naïve B cells of patients harboring the C104R mutation in TACI
title_sort multi-omics analysis of naïve b cells of patients harboring the c104r mutation in taci
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9443529/
https://www.ncbi.nlm.nih.gov/pubmed/36072607
http://dx.doi.org/10.3389/fimmu.2022.938240
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