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Immunol."],"abstract":"<jats:p>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 (<jats:italic>TNFRSF13B<\/jats:italic>), encoding TACI. Mutations in <jats:italic>TNFRSF13B<\/jats:italic> 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 na\u00efve B cells from CVID patients harboring the C104R mutation in <jats:italic>TNFRSF13B<\/jats:italic> and compared them to their healthy relatives with the same mutation. In addition, the proteome of stimulated na\u00efve B cells was investigated. For functional validation, intracellular protein concentrations were measured by flow cytometry. Our analysis revealed 8% less accessible chromatin in unstimulated na\u00efve 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-\u03baB TF families. Validation experiments supported dysregulation of the NF-\u03baB and MAPK pathways. In steady state, na\u00efve 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 na\u00efve B cells from TACI mutation carriers.<\/jats:p>","DOI":"10.3389\/fimmu.2022.938240","type":"journal-article","created":{"date-parts":[[2022,8,16]],"date-time":"2022-08-16T05:07:28Z","timestamp":1660626448000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Multi-omics analysis of na\u00efve B cells of patients harboring the C104R mutation in TACI"],"prefix":"10.3389","volume":"13","author":[{"given":"Neftali","family":"Ramirez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Posadas-Cantera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niko","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres Caballero 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