Dataset Information

Multi-omics Analysis of naive B cells of patients harboring the C104R mutation in TACI

ABSTRACT: 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. 10% 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-B TF families. Validation experiments supported dysregulation of the NF-B 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 was detected. Using a multi-omics approach, our findings provide valuable insights into the impaired biology of naïve B cells from TACI mutation carriers.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood

SUBMITTER: Matteo Pecoraro

LAB HEAD: Bodo Grimbacher

PROVIDER: PXD035459 | Pride | 2022-10-14

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20200303_MaPe_NeRa_SA_BG_FR006_1_TACI_sB_Pro.raw	Raw
	20200303_MaPe_NeRa_SA_BG_FR052_1_ND_sB_Pro.raw	Raw
	20200312_MaPe_NeRa_SA_BG_FR038_1_TACI_sB_Pro.raw	Raw
	20200318_MaPe_NeRa_SA_BG_FR029_1_TACI_sB_Pro.raw	Raw
	20200327_MaPe_NeRa_SA_BG_FR044_1_TACI_sB_Pro.raw	Raw

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

Ramirez Neftali N Posadas-Cantera Sara S Langer Niko N de Oteyza Andres Caballero Garcia ACG Proietti Michele M Keller Baerbel B Zhao Fangwen F Gernedl Victoria V Pecoraro Matteo M Eibel Hermann H Warnatz Klaus K Ballestar Esteban E Geiger Roger R Bossen Claudia C Grimbacher Bodo B

Frontiers in immunology 20220816

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 (<i>TNFRSF13B</i>), encoding TACI. Mutations in <i>TNFRSF13B</i> alone may not be sufficient for the development of CVID, as 1% of the healthy population carry these mutations. The common hypo ...[more]

PMID: 36072607

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