B Cell Receptor and BAFF Receptor Signaling Regulation of B Cell Homeostasis

Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2009; 183(6):3561-7. DOI: 10.4049/jimmunol.0800933
Source: PubMed


B lymphocyte homeostasis depends on tonic and induced BCR signaling and receptors sensitive to trophic factors, such as B cell-activating factor receptor (BAFF-R or BR3) during development and maintenance. This review will discuss growing evidence suggesting that the signaling mechanisms that maintain B cell survival and metabolic fitness during selection at transitional stages and survival after maturation rely on cross-talk between BCR and BR3 signaling. Recent findings have also begun to unravel the molecular mechanisms underlying this crosstalk. In this review I also propose a model for regulating the amplitude of BCR signaling by a signal amplification loop downstream of the BCR involving Btk and NF-kappaB that may facilitate BCR-dependent B cell survival as well as its functional coupling to BR3 for the growth and survival of B lymphocytes.

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Available from: Wasif Noor Khan, Mar 13, 2015
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    • "The three cell-surface receptors are BAFF receptor (BAFF-R), B cell maturation antigen (BCMA) and transmembrane activator , calcium modulator and cyclophilin ligand interactor (TACI) respectively . BAFF-R binds to BAFF, BCMA binds to BAFF with weaker affinity and a proliferation-inducing ligand (APRIL), and TACI binds to BAFF and APRIL [11] [12] [13]. Earlier studies suggest that BAFF-R may be the primary BAFF binding receptor responsible for B-cell development and survival [14]. "
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    ABSTRACT: B cell activating factor (BAFF), which belongs to the tumor necrosis factor (TNF) family, is testified to play a critical role in B cell survival, proliferation, maturation and immunoglobulin secretion. In the present study, the cDNA of open reading frame (ORF) in African ostrich (Struthio camelus) BAFF (designated OsBAFF) was cloned by reverse transcription-PCR (RT-PCR). The OsBAFF gene encodes a 288-amino acid protein containing a predicted transmembrane domain and a putative furin protease cleavage site like BAFFs from chicken (cBAFF), quail (qBAFF), duck (dBAFF), goose (gBAFF) and dove (doBAFF). RT-PCR analysis showed that the OsBAFF gene is strongly expressed in the bursa of Fabricius, thymus, spleen, and bone marrow. The soluble OsBAFF had been cloned into pET28a. SDS-PAGE and Western blotting analysis confirmed that the soluble fusion protein His-OsBAFF was efficiently expressed in Escherichia coli Rosset (DE3). In vitro, purified OsBAFF was not only able to promote the survival of African ostrich bursal lymphocytes, but also able to co-stimulate proliferation of mouse splenic B cells. The expression of OsBAFF in lymphocyte cells was higher than the control after LPS stimulation. These findings indicated that OsBAFF plays an important role in survival and proliferation of African ostrich bursal lymphocytes, which may provide valuable information for research into the immune system of African ostrich and OsBAFF may serve as a potential immunologic factor for enhancing immunological efficacy in African ostrich and any other birds. Copyright © 2015 Elsevier B.V. All rights reserved.
    International immunopharmacology 08/2015; 28(1):686-694. DOI:10.1016/j.intimp.2015.07.043 · 2.47 Impact Factor
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    • "Numerous studies have shown that elevated activating signals or decreased inhibitory potential can lead to the development of autoreactive B cells [34]–[37]. It is also known that elevated level of BAFF, or dual BCR and TLR signals may potentiate the risk for autoimmunity [12], [38]. We have recently reported that both BAFF-R and TLR9 can collaborate with BCR to protect B-cells from Fas-induced programmed death [39]. "
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    ABSTRACT: B cell development and activation are regulated by combined signals mediated by the B cell receptor (BCR), receptors for the B-cell activating factor of the tumor necrosis factor family (BAFF-R) and the innate receptor, Toll-like receptor 9 (TLR9). However, the underlying mechanisms by which these signals cooperate in human B cells remain unclear. Our aim was to elucidate the key signaling molecules at the crossroads of BCR, BAFF-R and TLR9 mediated pathways and to follow the functional consequences of costimulation.Therefore we stimulated purified human B cells by combinations of anti-Ig, B-cell activating factor of the tumor necrosis factor family (BAFF) and the TLR9 agonist, CpG oligodeoxynucleotide. Phosphorylation status of various signaling molecules, B cell proliferation, cytokine secretion, plasma blast generation and the frequency of IgG producing cells were investigated. We have found that BCR induced signals cooperate with BAFF-R- and TLR9-mediated signals at different levels of cell activation. BCR and BAFF- as well as TLR9 and BAFF-mediated signals cooperate at NFκB activation, while BCR and TLR9 synergistically costimulate mitogen activated protein kinases (MAPKs), ERK, JNK and p38. We show here for the first time that the MAP3K7 (TGF beta activated kinase, TAK1) is responsible for the synergistic costimulation of B cells by BCR and TLR9, resulting in an enhanced cell proliferation, plasma blast generation, cytokine and antibody production. Specific inhibitor of TAK1 as well as knocking down TAK1 by siRNA abrogates the synergistic signals. We conclude that TAK1 is a key regulator of receptor crosstalk between BCR and TLR9, thus plays a critical role in B cell development and activation.
    PLoS ONE 05/2014; 9(5):e96381. DOI:10.1371/journal.pone.0096381 · 3.23 Impact Factor
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    • "Thus, BLyS levels dictate homeostatic ''space'' for pre-immune B-2 cells by governing both the proportion and quality of TR B cells that complete differentiation , as well as the lifespan of mature B cells themselves, thereby controlling the overall size and composition of FO and MZ B cell populations. These observations also suggest that BCR and BR3 signals are integrated and non-redundant, since the absence of either signaling arm severely curtails peripheral B cell maturation and maintenance (reviewed in [46] [47]). The molecular mechanisms of interplay between BCR and BR3 signaling pathways appear complex [32] [48] [49], but likely involve cross-talk between downstream signaling and transcriptional regulatory systems including non-classical NF-kB, PI3-Kinase, and Syk [32,49–52]. "
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    ABSTRACT: BLyS family members govern selection and survival of cells in the preimmune B cell compartment, and emerging evidence suggests similar roles in antigen-experienced B cell pools. We review the features of this family, with particular emphasis on recent findings of how BLyS influences affinity maturation in germinal centers, which lie at the intersection of the pre-immune and antigen-experienced B cell compartments. We propose a model whereby tolerogenic selection at the transitional stage and affinity maturation in the germinal center employ the same BLyS driven mechanism.
    Cytokine & growth factor reviews 04/2014; 25(2). DOI:10.1016/j.cytogfr.2014.01.001 · 5.36 Impact Factor
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