BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors

Sevdali, Eirini; Block, Violeta; Lataretu, Marie; Li, Huiying; Smulski, Cristian R.; Briem, Jana-Susann; Heitz, Yannic; Fischer, Bernh.; Ramirez, Neftali-Jose; Grimbacher, Bodo; Jäck, Hans‐Martin; Voll, Reinhard; Hölzer, Martin; Schneider, Pascal; Eibel, Hermann

doi:10.1016/j.celrep.2022.111019

Cited by 7 publications

(6 citation statements)

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“…BAFF-R is expressed in B cells and embodies different functions in B cells. BAFFR is a binding factor of BAFF on B cells, and the combination of both is an important regulator of B cell survival [32]. The binding of BAFFR-BAFF can activate the signaling pathways such as NF-KB1/2,PI3K,and Akt/ERK [33][34].…”

Section: Discussionmentioning

confidence: 99%

Causal role of immune cells in ovarian dysfunction :a mendelian randomization study

Weng,

Ling,

Dai

et al. 2024

Preprint

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Background At present, the etiology and mechanism of ovarian dysfunction are still unclear.Recent studies have indicated a potential correlation between immunity and ovarian dysfunction. However, the causal relationship between the immune cells and ovarian dysfunction still remains uncertain. For this aiticle,we aimed to figure out whether changes of immune cell composition contribute to ovarian dysfunction in this article. Methods Comprehensive two-sample Mendelian randomization analysis was performed to determine the causal role between immune cell compostitions and ovarian dysfunction in this study. The immune cell data are derived from the latest GWAS blood cell shape summary statistical data from the GWAS Catalog, and ovarian dysfunction data were obtained from the IEU Open GWAS. A total of 942 cases and 18,228 controls were included. A variety of analytical methods, including inverse variance weighting, weighted median, and MR-Egggera etc, were utilized to explore the link between immune cells and ovarian dysfunction. The Cochran's Q statistics were used to evaluate the heterogeneity of instrumental variables. The MR-Egger and MR pleiotropic residuals and outlier tests were utilized to detect the horizontal pleiotropy. The funnel plots and scatter plots visually assess heterogeneity and robustness. Results Our findings suggest that the presence of 36 immune phenotypes had a significant causal effect on ovarian dysfunction. Among them, 18 immunophenotypes were positively associated with ovarian dysfunction, including 7 in the B cell panel, 9 in the T cell panel, 1 in the monocyte cell panel and 1 in the NK cell panel; 28 immunophenotypes were negatively associated with ovarian dysfunction, including 11 in the B cell panel, 14 in the T cell panel, and in the monocyte cell panel. Conclusion Our study has demonstrated the close connection between immune cells and ovarian dysfunction by genetic background analysis. Further research is necessary to evaluate the potential of these immunophenotypes as early predictors of ovarian dysfunction, as well as possibility of new preventive strategies and new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Causal role of immune cells in ovarian dysfunction :a mendelian randomization study

Weng,

Ling,

Dai

et al. 2024

Preprint

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“…Two of the main pathways mediating survival signals downstream of BCR are NF-κB signaling (e.g., anti-apoptotic genes upregulation) and PI3K/AKT signaling (e.g., via its downstream effector transcriptional factor FOXO1) [ 86 , 87 , 88 , 89 ]. In naïve B cells, both CD79a and CD79b are required to physically interact with B-cell activating factor receptor (BAFFR), whose ligand, the B-cell activating factor (BAFF), initiates pro-survival PI3K/AKT signaling upon binding to BAFFR [ 90 ]. BCR signaling, combined with co-stimulation from CD40, BAFFR, and TLRs, regulates antibody-mediated immune responses requiring class switch recombination [ 21 ].…”

Section: The Cd79a/cd79b Heterodimer Is Critically Important For Bcr ...mentioning

confidence: 99%

“…Direct interactions of CD79a and CD79b with TLR9 lead to MYD88 recruitment and hence NF-κB signaling upregulation via the MYD88-TLR9-BCR supercomplex [ 49 ]. In addition to NF-κB signaling, ligand binding to BAFFR (which could be either attached or located closely to CD79a and CD79b) upregulates also PI3K/AKT as another critical BCR downstream pathway [ 90 ]. Furthermore, CD79b, along with other proteins involved in proximal BCR signaling (SYK and BTK), interacts with TRAF3 (a negative regulator of BCR signaling).…”

Section: Bcr Signaling Is Regulated At the Level Of Cd79a/cd79b Heter...mentioning

confidence: 99%

“…In addition to the My-T-BCR supercomplex, CD79a/CD79b maintains pro-survival PI3K/AKT signaling via interaction with BCR co-receptors BAFFR and CD19 in B-cell NHL [ 76 , 90 ]. The pro-survival signal comes from BAFF-dependent Lyn-mediated activation of PI3K/AKT [ 90 ]. A similar PI3K-dependent pro-survival signal is sustained by CD79b through CD19 activation.…”

Section: Cd79a and Cd79b Are Important Regulators Of Proximal And Dis...mentioning

confidence: 99%

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B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells

Tkachenko,

Kupcova,

Havranek

2023

IJMS

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B-cell receptor (BCR) is a B cell hallmark surface complex regulating multiple cellular processes in normal as well as malignant B cells. Igα (CD79a)/Igβ (CD79b) are essential components of BCR that are indispensable for its functionality, signal initiation, and signal transduction. CD79a/CD79b-mediated BCR signaling is required for the survival of normal as well as malignant B cells via a wide signaling network. Recent studies identified the great complexity of this signaling network and revealed the emerging role of CD79a/CD79b in signal integration. In this review, we have focused on functional features of CD79a/CD79b, summarized signaling consequences of CD79a/CD79b post-translational modifications, and highlighted specifics of CD79a/CD79b interactions within BCR and related signaling cascades. We have reviewed the complex role of CD79a/CD79b in multiple aspects of normal B cell biology and how is the normal BCR signaling affected by lymphoid neoplasms associated CD79A/CD79B mutations. We have also summarized important unresolved questions and highlighted issues that remain to be explored for better understanding of CD79a/CD79b-mediated signal transduction and the eventual identification of additional therapeutically targetable BCR signaling vulnerabilities.

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“…The BAFFR activates the noncanonical NF-κB pathway but can also induce the canonical NF-κB signaling through crosstalk with the BCR, involving CD79A/B, SYK, and BTK ( Figure 2 ) [ 224 , 225 ]. Interestingly, BAFF activates PI3K/AKT only in naive B cells [ 226 ]. BAFF-induced PI3K/AKT signaling requires direct interactions between BAFFR and BCR components CD79A/B and is enhanced by the AKT coactivator TCL1A.…”

Section: Other Signaling Pathways Implicated 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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BAFFR activates PI3K/AKT signaling in human naive but not in switched memory B cells through direct interactions with B cell antigen receptors

Cited by 7 publications

References 97 publications

Causal role of immune cells in ovarian dysfunction :a mendelian randomization study

Causal role of immune cells in ovarian dysfunction :a mendelian randomization study

B-Cell Receptor Signaling and Beyond: The Role of Igα (CD79a)/Igβ (CD79b) in Normal and Malignant B Cells

Aberrant B Cell Signaling in Autoimmune Diseases

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