CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding and Signaling Responses

2021 ◽  
Author(s):  
Violeta Block ◽  
Eirini Sevdali ◽  
Mike Recher ◽  
Hassan Abolhassani ◽  
Lennart Hammarstrom ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
Ectodomain Shedding ◽  
Cellular Functions ◽  
Single Nucleotide Variants ◽  
B Cell Activating Factor ◽  
Human B Cells ◽  
Receptor Component ◽  
Primary Amino

Abstract Purpose B cell activating factor (BAFF) binding to BAFF-receptor(BAFFR) activates essential cellular functions required forthe survival of mature, human B cells. Thus,deletion ofthe BAFFR gene blocks the development of B cells at the transition from immature to mature B cells resulting in B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants changing the primary amino acid sequence of BAFFR gene exist. Some of these variants were foundin patients suffering from immunodeficiency, autoimmunity, or B cell lymphomas. However, it remains unclearto which extent such variants disturb the activity of BAFFR. Methods Since individual differences and genetic/environmental modifiers change the expression and activity of BAFFR, we developed a cellular system that allows the unbiased analysis of BAFFR variants P21R, A52T, G64V, Dup92-95, P146S, and H159Y regarding oligomerization, signaling, and ectodomain shedding.Results Here we show that several of these variants impair BAFFR oligomerization, direct interactions between BAFFR and the B cell receptor component CD79B, BAFFR ectodomain shedding and the activation of AKT and ERK1/2. Conclusion All of these variants are pathogenic and have the potential to contribute to the development of primary antibody deficiencies, autoimmunity and lymphoma, but they most likely do not cause B lymphopenia and agammaglobulinemia like complete BAFFR deficiency.

scholarly journals B-cell-activating factor inhibits CD20-mediated and B-cell receptor-mediated apoptosis in human B cells

Immunology ◽  
2008 ◽  
Vol 125 (4) ◽  
pp. 570-590 ◽  
Author(s):  
Yohei Saito ◽  
Yoshitaka Miyagawa ◽  
Keiko Onda ◽  
Hideki Nakajima ◽  
Ban Sato ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Activating Factor ◽  
Human B Cells

scholarly journals Rewiring of B cell receptor signaling by Epstein–Barr virus LMP2A

2020 ◽  
Vol 117 (42) ◽  
pp. 26318-26327
Author(s):  
Kamonwan Fish ◽  
Federico Comoglio ◽  
Arthur L. Shaffer ◽  
Yanlong Ji ◽  
Kuan-Ting Pan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Barr Virus ◽  
Human B Cells ◽  
Bcr Signaling ◽  
Epstein Barr

Epstein–Barr virus (EBV) infects human B cells and reprograms them to allow virus replication and persistence. One key viral factor in this process is latent membrane protein 2A (LMP2A), which has been described as a B cell receptor (BCR) mimic promoting malignant transformation. However, how LMP2A signaling contributes to tumorigenesis remains elusive. By comparing LMP2A and BCR signaling in primary human B cells using phosphoproteomics and transcriptome profiling, we identified molecular mechanisms through which LMP2A affects B cell biology. Consistent with the literature, we found that LMP2A mimics a subset of BCR signaling events, including tyrosine phosphorylation of the kinase SYK, the calcium initiation complex consisting of BLNK, BTK, and PLCγ2, and its downstream transcription factor NFAT. However, the majority of LMP2A-induced signaling events markedly differed from those induced by BCR stimulation. These included differential phosphorylation of kinases, phosphatases, adaptor proteins, transcription factors such as nuclear factor κB (NF-κB) and TCF3, as well as widespread changes in the transcriptional output of LMP2A-expressing B cells. LMP2A affected apoptosis and cell-cycle checkpoints by dysregulating the expression of apoptosis regulators such as BCl-xL and the tumor suppressor retinoblastoma-associated protein 1 (RB1). LMP2A cooperated with MYC and mutant cyclin D3, two oncogenic drivers of Burkitt lymphoma, to promote proliferation and survival of primary human B cells by counteracting MYC-induced apoptosis and by inhibiting RB1 function, thereby promoting cell-cycle progression. Our results indicate that LMP2A is not a pure BCR mimic but rather rewires intracellular signaling in EBV-infected B cells that optimizes cell survival and proliferation, setting the stage for oncogenic transformation.

ZAP-70 Expression in Human B cells: Analysis of Normal Cells and Acute Lymphoblastic Leukemia (ALL) Cells with Pro/Pre B Phenotype.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4443-4443
Author(s):  
Marta Crespo ◽  
Neus Villamor ◽  
Eva Gine ◽  
Dolors Colomer ◽  
Teresa Marafioti ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Protein Tyrosine Kinase ◽  
Lymphoblastic Leukemia ◽  
Human Lymphocytes ◽  
Critical Role ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Qrt Pcr ◽  
Human B Cells

Abstract ZAP-70 is a protein tyrosine kinase of the Syk/ZAP-70 family that plays a critical role in the signal transduction from the T-cell receptor. In human lymphocytes, ZAP-70 gene has been reported to be expressed in T and NK derived cells, and in IgVH unmutated B-chronic lymphocytic leukemia cells. More recently, ZAP-70 expression has been shown to be required for the development of pro-B cells to pre-B cells in mice. To ascertain the expression of ZAP-70 gene in human immature B-cell stages, we analyzed ZAP-70 protein and/or mRNA in normal human B cells at different stages of B cell maturation, including pro/pre-B cells and tumoral cells from 20 B-ALL. ZAP-70 expression was assessed by flow cytometry (FC), immunofluorescence (IF), and/or by quantitative real time RT-PCR (QRT-PCR). In normal bone marrow, ZAP-70 expression was found only in T and in immature B cells (CD19+/CD10+/CD20 −). Moreover, T cells -but no mature B cells- from normal tonsil expressed ZAP-70, as assessed by QRT-PCR and IF. In B-ALLs, a high ZAP-70 expression by FC was observed in 9/13 cases (mean, 82.6%, range 60–99%), whereas in 4 cases ZAP-70 was barely detectable (mean, 13%). By QRT-PCR, 10/16 B-ALLs showed levels of expression similar to ZAP-70 non-expressing cell lines and normal B-cells, whereas in the remaining cases ZAP-70 expression was 3–4 times higher than in normal mature B-cells. Taken together, a high expression of ZAP-70 was found in 11/21 (52%) B-ALLs. No relationship was observed between the level of ZAP-70 expression and the B-ALL maturation status. In conclusion, among normal B cell subsets ZAP-70 expression is restricted to B-cells with pro/pre phenotype. In addition, ZAP-70 is expressed in 52% of B-ALLs, probably as a reflection of their B-cell origin.

Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcγRIIb with Fc-engineered antibodies

2008 ◽  
Vol 45 (15) ◽  
pp. 3926-3933 ◽  
Author(s):  
Seung Y. Chu ◽  
Igor Vostiar ◽  
Sher Karki ◽  
Gregory L. Moore ◽  
Greg A. Lazar ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Human B Cells

scholarly journals B cell receptor triggering sensitizes human B cells to TRAIL-induced apoptosis

2010 ◽  
Vol 88 (5) ◽  
pp. 937-945 ◽  
Author(s):  
Andre Ortlieb Guerreiro-Cacais ◽  
Jelena Levitskaya ◽  
Victor Levitsky
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Human B Cells ◽  
Induced Apoptosis

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4537-4543 ◽  
Author(s):  
Hélène Gary-Gouy ◽  
Julie Harriague ◽  
Georges Bismuth ◽  
Cornelia Platzer ◽  
Christian Schmitt ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Human Peripheral Blood ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Negative Regulator ◽  
B Cell Tolerance ◽  
Human B Cells ◽  
B Cell Survival

CD5 is a negative regulator of B-cell receptor (BCR) signaling that is up-regulated after BCR stimulation and likely contributes to B-cell tolerance in vivo. However, CD5 is constitutively expressed on the B-1 subset of B cells. Contrary to CD5− B-2 B cells, B-1 B cells are long-lived because of autocrine interleukin-10 (IL-10) production through unknown mechanisms. We demonstrate herein a direct relationship between CD5 expression and IL-10 production. Human peripheral blood CD5+ B cells produce more IL-10 than CD5− B cells after BCR activation. Introducing CD5 into CD5− B cells induces the production of IL-10 by activating its promoter and the synthesis of its mRNA. The cytoplasmic domain of CD5 is sufficient for this process. CD5 also protects normal human B cells from apoptosis after BCR stimulation while reducing the BCR-induced Ca2+ response. We conclude that CD5 supports the survival of B cells by stimulating IL-10 production and by concurrently exerting negative feedback on BCR-induced signaling events that can promote cell death.

scholarly journals B Cell Receptor Engagement and T Cell Contact Inducebcl-6Somatic Hypermutation in Human B Cells: Identity with Ig Hypermutation

2000 ◽  
Vol 165 (2) ◽  
pp. 830-839 ◽  
Author(s):  
Hong Zan ◽  
Zongdong Li ◽  
Kozaburo Yamaji ◽  
Patricia Dramitinos ◽  
Andrea Cerutti ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cell Contact ◽  
Human B Cells
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