Project description:Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. Here the authors perform single cell omics analyses in CVID discordant monozygotic twins and show epigenetic and transcriptional alterations associated with activation in memory B cells.
Project description:To elucidate the role of duodenal microenvironment in Common variable immunodeficiency pathogenesis (CVID), we sought to explore the transcriptome regulation in duodenal biopsies.
Project description:We performed a comparison of transcriptome between follicular CD8 T cells (CXCR5+CD8+CD3+) from 3 lymph nodes of patients with common variable immunodeficiency (CVID) and 3 tonsils of healthy donors, discovering 67 differentially expressed genes that show immunoregulatory potential of CVID follicular CD8 T cells.
Project description:Identification of IVIg regulated genes in human peripheral blood monocytes from Common Variable Immunodeficiency patients (CVID) [CD14+]
Project 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. 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.
Project description:Identification of IVIg regulated genes in human peripheral blood mononuclear cells from Common Variable Immunodeficiency patients (CVID) [PMBC]
