Dysregulated PI3K Signaling in B Cells of CVID Patients

Harder, Ina; Münchhalfen, Matthias; Andrieux, Geoffroy; Boerries, Melanie; Grimbacher, Bodo; Eibel, Hermann; Maccari, Maria Elena; Ehl, Stephan; Wienands, Jürgen; Jellusova, Julia; Warnatz, Klaus; Keller, Baerbel

doi:10.3390/cells11030464

Cited by 8 publications

(5 citation statements)

References 74 publications

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“…Our findings verify observations reported decades ago, describing absent or reduced expression of MYC in B cells from CVID patients ( 67 ). A recent report showed a reduction of E2F signaling in naïve and CD21low B cells from CVID patients, further pointing towards a CVID-associated alteration ( 45 ) and possibly accounting for the reduced B-cell survival in patients. The increased interferon-α and -γ response in stimulated naïve B cells from TACI mutation carriers provides another cause for autoimmune manifestation: It was shown that the enhanced interferon signature in naïve B cells from SLE patients drives autoimmunity ( 51 , 68 ).…”

Section: Discussionmentioning

confidence: 94%

“…The most downregulated pathways were interferon-α response, followed by pathways influencing cell metabolism (fatty acid metabolism, protein secretion, and oxidative phosphorylation). Recent studies have determined alterations in these pathways in CVID patients ( 43 – 45 ). In CSM B cells, we found the same dysregulated pathways and more ( Supplementary Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

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

Ramirez

Posadas-Cantera²,

Langer³

et al. 2022

Front. Immunol.

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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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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

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

Ramirez

Posadas-Cantera²,

Langer³

et al. 2022

Front. Immunol.

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“…In CD11c+ ABCs from Xist cKO High mice, upregulated autosomal genes were enriched for genes involved in lymphocyte activation, including Bcl3 (important for antigen-specific autoantibody formation) 73 , Bmpr1a (upregulated in some memory B cell subsets) 74 , Cxcr4 (plays a role in B cell homeostasis and trafficking) 75 , and Fas (upregulated in ABCs from patients with SLE) 41 . In CD11c+ ABCs from pristane-treated Xist cKO mice, upregulated autosomal genes were enriched for genes involved in immune processes, including Pik3r6 (mediates signaling pathways that regulate proliferation, class-switch recombination, and plasma cell differentiation) 76 , Sh3kbp1 (poises B cells to respond to BCR stimulation) 77 , and Zbtb20 (involved in plasma cell differentiation via Irf4) 78 . Unlike ABCs, upregulated autosomal genes in GL7+ B cells were enriched for genes involved in DNA replication and mitotic cell processes, including Tipin 79 , Ska2 80 Recent work has demonstrated that Xist RNA itself can contribute to the development of femalebiased autoimmune disease.…”

Section: Discussionmentioning

confidence: 99%

XistDeletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes

Lovell,

Jiwrajka,

Amerman

et al. 2024

Preprint

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Systemic lupus erythematosus (SLE) is an autoimmune disease preferentially observed in females. X-linked gene expression in XX females is normalized to that of XY males by X-Chromosome Inactivation (XCI). However, B cells from female SLE patients and mouse models of SLE exhibit mislocalization of Xist RNA, a critical regulator of XCI, and aberrant expression of X-linked genes, suggesting that impairment of XCI may contribute to disease. Here, we find that a subset of female mice harboring a conditional deletion of Xist in B cells ('Xist cKO') spontaneously develop SLE phenotypes, including expanded activated B cell subsets, disease-specific autoantibodies, and glomerulonephritis. Moreover, pristane-induced SLE-like disease is more severe in Xist cKO mice. Activated B cells from Xist cKO mice with SLE phenotypes have increased expression of proinflammatory X-linked genes implicated in SLE. Together, this work indicates that impaired XCI maintenance in B cells directly contributes to the female-bias of SLE.

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“…Balanced regulation of PI3K activity is critical, since patients with activated PI3Kδ syndrome (APDS) due to a PI3K gain-of-function mutation present with immunodeficiency and lymphoproliferation. Conversely, a subgroup of patients with common variable immunodeficiency (CVID) display disturbed BCR-activated PI3K signaling, particularly in ABCs [ 177 ].…”

Section: B Cell Receptor Signaling In Autoimmunitymentioning

confidence: 99%

Aberrant B Cell Signaling in Autoimmune Diseases

Corneth

Neys

Hendriks

2022

Cells

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Aberrant B cell signaling plays a critical in role in various systemic and organ-specific autoimmune diseases. This is supported by genetic evidence by many functional studies in B cells from patients or specific animal models and by the observed efficacy of small-molecule inhibitors. In this review, we first discuss key signal transduction pathways downstream of the B cell receptor (BCR) that ensure that autoreactive B cells are removed from the repertoire or functionally silenced. We provide an overview of aberrant BCR signaling that is associated with inappropriate B cell repertoire selection and activation or survival of peripheral B cell populations and plasma cells, finally leading to autoantibody formation. Next to BCR signaling, abnormalities in other signal transduction pathways have been implicated in autoimmune disease. These include reduced activity of several phosphates that are downstream of co-inhibitory receptors on B cells and increased levels of BAFF and APRIL, which support survival of B cells and plasma cells. Importantly, pathogenic synergy of the BCR and Toll-like receptors (TLR), which can be activated by endogenous ligands, such as self-nucleic acids, has been shown to enhance autoimmunity. Finally, we will briefly discuss therapeutic strategies for autoimmune disease based on interfering with signal transduction in B cells.

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Dysregulated PI3K Signaling in B Cells of CVID Patients

Cited by 8 publications

References 74 publications

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

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

XistDeletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes

Aberrant B Cell Signaling in Autoimmune Diseases

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