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B cell development and allelic exclusion in IgβΔC IgHEL transgenic mice. In the B220 vs. CD43 and B220 vs. IgM plots, numbers indicate percentages of lymphocytes as determined by forward vs. side scatter parameters. In the IgD vs. IgM plots, numbers indicate percentages of B220⁺ cells in the boxed region. For H chain allelic exclusion, dot plots show B cells gated on B220⁺IgM⁺ cells stained with IgMa and IgMb, and the numbers indicate the percentage of B220⁺IgM⁺ cells in each quadrant. B220 vs. IgM staining in the spleen (Spl) and peritoneal cavity (Per) is shown.
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The B cell receptor (BCR) regulates B cell development and function through immunoglobulin (Ig)alpha and Ig beta, a pair of membrane-bound Ig superfamily proteins, each of which contains a single cytoplasmic immunoreceptor tyrosine activation motif (ITAM). To determine the function of Ig beta, we produced mice that carry a deletion of the cytoplasm...
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We describe the phenotypic and functional properties of B lineage cells developing in fetal liver organ cultures (FLOC) of mouse embryos at day 14 or 15 of gestation which contain pro/pre-B-I cells. FLOC B cell development proceeds to mature IgM+, IgD+ and CD23+ lipopolysaccharide-reactive B cells within a culture period of 5-6 days. The phenotypes...
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... They participate in multiple immunological processes including affinity maturation of antibodies, antigen presentation, immunological memory, and regulatory cytokine production [22,26,70]. B cells express surface BCR that is pivotal for their function and survival [71,72]. The BCR is composed of membrane immunoglobulin (mIg) molecules that are associated with immunoglobulin alpha (Igα)/Igβ (also named CD79a/CD79b) heterodimers, facilitating intracellular signaling [73,74]. ...
Human germinal center (GC)-associated lymphoma (HGAL) is a multi-domain adaptor protein expressed in GC B lymphocytes, T follicular helper (Tfh) cells and lymphomas derived from these cells. HGAL expression is an independent predictor of longer survival of diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (HL) patients. HGAL regulates B cell receptor (BCR) signaling and immunological synapse formation by binding to either the downstream effectors [e.g., spleen tyrosine kinase (Syk)] or other signaling regulators [e.g., growth factor receptor-bound protein 2 (Grb2)]. HGAL regulates the cytoskeleton that reshapes B cell morphology during BCR signaling and cell motility by at least two molecular mechanisms: enhanced Ras homolog gene family member A (RhoA) signaling and inhibition of myosin-actin translocation. These effects on the cytoskeleton decrease lymphoma dissemination in animal models and contribute to decreased lymphoma dissemination in patients. The latter may contribute to the association of HGAL protein expression with longer survival of patients with DLBCL and HL tumors. The ability to regulate multiple and distinct functions simultaneously in B cells implies that the HGAL protein level is tightly regulated. It was demonstrated that HGAL can be regulated by PR/SET domain 1 (PRDM1)/B lymphocyte-induced maturation protein-1 (BLIMP1) and interleukin-4 (IL-4) at the transcription level, by microRNA-155 (miR-155) at the post-transcriptional level, and by F-box protein 10 (FBXO10) at the post-translational level. Constitutive enforced expression of HGAL at physiological levels leads to lymphoid hyperplasia and DLBCL in mice. Future studies need to focus on identifying HGAL interactome, dissecting its interaction network, and understanding HGAL spatiotemporal signaling in live cells in physiological conditions. Further, the recent demonstration of HGAL expression in Tfh cells requires the determination of its function in these cells. These studies will contribute to new insights into the biology of these cellular subsets and how immune dysregulation contributes to lymphomagenesis.
... There is a BAFF signal that is required for cell survival during differentiation, besides the BCR signal, that its downregulation results in the loss of more than 90% of mature B cells [90,91]. As mentioned, TACI acts as a negative regulator in the maturation process of B cells, yet BCMA has no role in this stage whereas its role is in the later stages of differentiation [60,[92][93][94]. ...
B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma cells of Multiple myeloma (MM) patients, as well as the normal population. BCMA is used as a biomarker for MM. Two members of the TNF superfamily proteins, including B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are closely related to BCMA and play an important role in plasma cell survival and progression of MM. Despite the maximum specificity of the monoclonal antibody technologies, introducing the tumor-specific antigen(s) is not applicable for all malignancies, such as MM that there plenty of relatively specific antigens such as GPCR5D, MUC1, SLAMF7 and etc., but higher expression of BCMA on these cells in comparison with normal ones can be regarded as a relatively exclusive marker. Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.
... 148 CD79B can also regulate BCR signal strength/duration, but this appears to be due to its role in BCR internalization. 149,150 The Wienands laboratory used the DT-40 chicken B cell model in an effort to define the mechanism by which SHIP-1 is recruited and activated following BCR stimulation. 81 Using a proteomics approach, they identified Dok-3 and Grb2 as key adaptor proteins that interact with SHIP-1 following BCR stimulation. ...
At least 20% of B cells in the periphery expresses an antigen receptor with a degree of self‐reactivity. If activated, these autoreactive B cells pose a risk as they can contribute to the development of autoimmune diseases. To prevent their activation, both B cell‐intrinsic and extrinsic tolerance mechanisms are in place in healthy individuals. In this review article, I will focus on B cell‐intrinsic mechanisms that prevent the activation of autoreactive B cells in the periphery. I will discuss how inhibitory signaling circuits are established in autoreactive B cells, focusing on the Lyn‐SHIP‐1‐SHP‐1 axis, how they contribute to peripheral immune tolerance, and how disruptions of these circuits can contribute to the development of autoimmunity.
... To investigate whether immunization with the recombinant proteins influences different stages of B cell development, we analyzed bone marrow B220 + B cells using the B cell markers IgM and IgD to detect mature (IgD + IgM − , IgD + IgM + ) and immature (IgD − IgM + ) B cells and the markers B220 and CD43 to identify pre-pro-B (CD43 + B220 + ), pre-B, and pro-B (CD43 − B220 + ) cells [40][41][42][43] . Notably, we found that mature (IgD + IgM − , IgD + IgM + ) and immature (IgD − IgM + ) B cells in the mouse bone marrow were considerably decreased after 2 immunization cycles of rNS1 and rDR4, but not rGST and rTACI (Fig. 4, *P < 0.05, vs. respective GST groups). ...
... Anti-CD21/CD35 and anti-CD23 Igs were used to identify spleen B cell subsets following previously described methods. Following previously described methods 33,34,[40][41][42][43] , we analyze spleen transitional T1, T2, and follicular and marginal zone, mature B cells, bone marrow mature (IgD + IgM -, IgD + IgM + ) and immature (IgD -IgM + ) B cells, and pre-pro-B (CD43 + B220 + ), pre-B and pro-B (CD43 -B220 + ) cells. A flow cytometer (FACSCalibur; BD Biosciences, San Jose, CA, USA) was used in this study as described [86][87][88] . ...
Dengue virus (DENV) infections may cause life-threatening dengue hemorrhagic fever (DHF). Suppressed protective immunity was shown in these patients. Although several hypotheses have been formulated, the mechanism of DENV-induced immunosuppression remains unclear. Previously, we found that cross-reactive antibodies against tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 1 (death receptor 4 [DR4]) were elicited in DHF patients, and that anti-DR4 autoantibody fractions were elicited by nonstructural protein 1 (NS1) immunizations in experimental mice. In this study, we found that anti-DR4 antibodies could suppress B lymphocyte function in vitro and in vivo. Treatment with the anti-DR4 immunoglobulin (Ig) induced caspase-dependent cell death in immortalized B lymphocyte Raji cells in vitro. Anti-DR4 Igs elicited by NS1 and DR4 immunizations markedly suppressed mouse spleen transitional T2 B (IgM+IgD+), bone marrow pre-pro-B (B220+CD43+), pre-B (B220+CD43−), and mature B cell (B220+IgD+) subsets in mice. Furthermore, functional analysis revealed that the pre-elicitation of anti-NS1 and anti-DR4 Ig titers suppressed subsequently neutralizing antibody production by immunization with DENV envelop protein. Our data suggest that the elicitation of anti-DR4 titers through DENV NS1 immunization plays a suppressive role in humoral immunity in mice.
... The B-cell antigen receptor (BCR) consists of the membrane-bound immunoglobulin (mIg) comprising two heavy (H) and two light (L) chains and the signal-transducing Iga/Igb (CD79a/CD79b) heterodimer (Reth & Wienands, 1997). The cytoplasmic tails of Iga and Igb each contain an immunoreceptor tyrosine-based activation motif (ITAM) with two conserved tyrosines that are crucial for the development and maintenance of mature B cells (Reth, 1989;Torres et al, 1996;Kraus et al, 2001Kraus et al, , 2004Reichlin et al, 2001). Upon antigen ligation and opening of the BCR, the spleen tyrosine kinase (Syk) phosphorylates and interacts with the ITAM tyrosines of Iga and Igb (Rolli et al, 2002). ...
... The expression of a pre-BCR and a BCR is required for B-cell development and the maintenance of mature B cells. Mice with a deletion of any one of the H chain, Iga, or Igb genes display a developmental block at the pro-B-cell stage (Kitamura et al, 1991;Gong & Nussenzweig, 1996;Torres et al, 1996;Minegishi et al, 1999;Reichlin et al, 2001;Meffre & Nussenzweig, 2002;Pelanda et al, 2002). The deletion of the H chain gene or the mutation of the ITAM tyrosines of Iga in mature B-cell results in apoptosis and disappearance of B cells from the periphery in a few days (Lam et al, 1997;Kraus et al, 2004). ...
Expression of the B-cell antigen receptor (BCR) is essential not only for the development but also for the maintenance of mature B cells. Similarly, many B-cell lymphomas, including Burkitt lymphoma (BL), require continuous BCR signaling for their tumor growth. This growth is driven by immunoreceptor tyrosine-based activation motif (ITAM) and PI3 kinase (PI3K) signaling. Here, we employ CRISPR/Cas9 to delete BCR and B-cell co-receptor genes in the human BL cell line Ramos. We find that Ramos B cells require the expression of the BCR signaling component Igβ (CD79b), and the co-receptor CD19, for their fitness and competitive growth in culture. Furthermore, we show that in the absence of any other BCR component, Igβ can be expressed on the B-cell surface, where it is found in close proximity to CD19 and signals in an ITAM-dependent manner. These data suggest that Igβ and CD19 are part of an alternative B-cell signaling module that use continuous ITAM/PI3K signaling to promote the survival of B lymphoma and normal B cells.
... The B-cell antigen receptor (BCR) consists of the membrane-bound immunoglobulin (mIg) comprising two heavy (H) and two light (L) chains and the signal-transducing Iga/Igb (CD79a/CD79b) heterodimer (Reth & Wienands, 1997). The cytoplasmic tails of Iga and Igb each contain an immunoreceptor tyrosine-based activation motif (ITAM) with two conserved tyrosines that are crucial for the development and maintenance of mature B cells (Reth, 1989;Torres et al, 1996;Kraus et al, 2001Kraus et al, , 2004Reichlin et al, 2001). Upon antigen ligation and opening of the BCR, the spleen tyrosine kinase (Syk) phosphorylates and interacts with the ITAM tyrosines of Iga and Igb (Rolli et al, 2002). ...
... The expression of a pre-BCR and a BCR is required for B-cell development and the maintenance of mature B cells. Mice with a deletion of any one of the H chain, Iga, or Igb genes display a developmental block at the pro-B-cell stage (Kitamura et al, 1991;Gong & Nussenzweig, 1996;Torres et al, 1996;Minegishi et al, 1999;Reichlin et al, 2001;Meffre & Nussenzweig, 2002;Pelanda et al, 2002). The deletion of the H chain gene or the mutation of the ITAM tyrosines of Iga in mature B-cell results in apoptosis and disappearance of B cells from the periphery in a few days (Lam et al, 1997;Kraus et al, 2004). ...
... We found that HSCs, CLPs, and CMPs exhibited Type I and II Xist RNA patterns, similar to fibroblasts, which are typically 80-90% Type I (Fig 1B and 1C and S3 Fig). Next, we examined CLP-derived B cell progenitors in the bone marrow, (Fig 1A), including pro-B cells (B220 lo , AA4.1 + , CD19 + , CD43 + ), pre-B cells (B220 lo , AA4.1 + , CD19 + , CD43 -, CD23 -, IgM -), and immature B cells (B220 lo , AA4.1 + , CD19 + , CD43 -, CD23 +/-, IgM + ) from female mice [40,41] (S1B Fig), and then performed Xist RNA FISH. Remarkably, we found that pro-B cells completely lacked any Xist RNA signals (Fig 1B and 1C and S3 Fig). ...
Author summary
Females are predisposed to develop various autoimmune disorders, and the genetic basis for this susceptibility is the X-chromosome. X-linked genes are dosage compensated between sexes by X-chromosome Inactivation (XCI) during embryogenesis and maintained into adulthood. Here we show that the chromatin of the inactive X loses epigenetic modifications during B cell lineage development. We found that female mature B cells, which are the pathogenic cells in autoimmunity, have a dynamic two-step mechanism of maintaining XCI during stimulation. The transcription factor YY1, which regulates DNA looping during V(D)J recombination in B cells, is necessary for relocalizing Xist RNA back to the inactive X in activated B cells. YY1 deletion ex vivo in mature B cells impairs heterochromatin mark enrichment on the inactive X, and results in increased X-linked gene expression. We demonstrate that the DNA binding domain of YY1 is sufficient for localizing Xist RNA to the inactive X during B cell stimulation. Our study indicates that Xist RNA localization is critical for maintaining XCI in female lymphocytes. We propose that chromatin changes on the Xi during B cell development and the dynamic nature of YY1-dependent XCI maintenance in mature B cells predisposes X-linked immunity genes to reactivation.
... Such an assertion is further supported by studies examining mice expressing transgenic BCRs specific for self-antigens showing that signals mediated by the BCR are central to the multiple checkpoint decisions that arise during B cell ontogeny (Table 1; Fig. 2). Another critical point is related to the avidity of the BCR for self-antigens that dictates B cell development [7] from the early pre-B to the mature B cell stages [45,46]. As a whole, a consensus point of view is to consider that the strength of BCR signaling is a critical determinant of B cell-positive selection and the elimination of potentially autoreactive B cells. ...
Maintenance of self-tolerance of auto-reactive lymphocytes is a fundamental mechanism to prevent the onset of autoimmune diseases. Deciphering the mechanisms involved in the deregulations leading to tolerance disruption and autoimmunity is still a major area of interest to identify new therapeutic targets and options. Ca(2+) signaling plays a major role in B cell normal development and is therefore finely tuned by B cell receptor (BCR)-dependent and independent pathways. Developmental changes in the characteristics of BCR-dependent Ca(2+) signals as well as the modulation of basal intracellular concentration ([Ca(2+)]i) contribute strongly to self-tolerance maintaining mechanisms responsible for the physical or functional elimination of autoreactive B cells such as clonal deletion, receptor editing, and anergy. Implication of Ca(2+) signals in B tolerance mechanisms mainly occurs through the specific activation of transcriptional programs depending on the amplitude, shape, and duration of Ca(2+) signals. A large number of studies reported Ca(2+) signaling defects in autoimmune pathology such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and primary Sjӧgren's syndrome (pSS). However, the precise nature of the molecular events responsible for these deregulations is not fully understood. Moreover, the demonstration of a direct correlation between Ca(2+) signaling defects and tolerance disruption is still lacking. The recent identification of proteins involved in B cell Ca(2+) signals such as ORAI, stromal interaction molecule and transient receptor potential is opening new horizons for understanding Ca(2+) signaling defects observed in autoimmune diseases and for proposing potentially new therapeutic solutions. This review aims to present an overview of the developmental evolution of BCR dependent Ca(2+) signaling and to place this signaling pathway in the context of mechanisms involved in tolerance maintenance and breakdown.
... Dysfunctions of many signalling molecules involved in these checkpoints are known to disrupt B cell development and maturation 1,2 . In the bone marrow, the successful formation of the pre-B cell receptor (BCR) and the BCR provide signals for mediating developmental transitions 3,4 . Immature BCR-bearing B cells exit the bone marrow as transitional B cells and undergo further maturation in the periphery, possibly in the spleen 5 , via later transitional stages, first to precursors and thence to the mature functional stages of both marginal zone (MZ) and classical follicular B cells 6,7 . ...
... Bruton's tyrosine kinase (Btk) is a Tec family kinase selectively expressed in the hematopoietic lineage in the myeloid and B lymphocyte compartments 14 , and Btk deficiency in the X-linked immune-deficient (Xid) mouse strain leads to reduction of peripheral mature, particularly follicular B cell numbers 15,16 . These data have been interpreted to indicate that BCR signalling is critical for maturation and/or maintenance of peripheral B cells 11,[17][18][19] , as has also been shown by more direct manipulations of the BCR 4,17 . However, while Btk is clearly involved in signalling from the BCR 3,20 , Btk deficiency still allows some BCR-mediated signalling [21][22][23][24] , and Btk is also involved in signalling downstream of other cell-surface molecules on both B and non-B cells [25][26][27][28][29][30][31] . ...
X-linked immune-deficient (Xid) mice, carrying a mutation in Bruton’s tyrosine kinase (Btk), have multiple B cell lineage differentiation defects. We now show that, while Xid mice showed only mild reduction in the frequency of the late transitional (T2) stage of peripheral B cells, the defect became severe when the Xid genotype was combined with either a CD40-null, a TCRbeta-null or an MHC class II (MHCII)-null genotype. Purified Xid T1 and T2 B cells survived poorly in vitro compared to wild-type (WT) cells. BAFF rescued WT but not Xid T1 and T2 B cells from death in culture, while CD40 ligation equivalently rescued both. Xid transitional B cells ex vivo showed low levels of the p100 protein substrate for non-canonical NF-kappaB signalling. In vitro, CD40 ligation induced equivalent activation of the canonical but not of the non-canonical NF-kappaB pathway in Xid and WT T1 and T2 B cells. CD40 ligation efficiently rescued p100-null T1 B cells from neglect-induced death in vitro. These data indicate that CD40-mediated signals, likely from CD4 T cells, can mediate peripheral transitional B cell maturation independent of Btk and the non-canonical NF-kappaB pathway, and thus contribute to the understanding of the complexities of peripheral B cell maturation.
... Following phosphorylation, protein kinases and adaptor molecules are recruited to the ITAM motifs and transmit signals downstream. The cytoplasmic tails of Igα/Igβ are therefore crucial for IgM BCR signal transduction, as evidenced Correspondence: Prof. Ari Waisman e-mail: waisman@uni-mainz.de by gene targeting experiments where the cytoplasmic tails of these molecules are deleted or the ITAM motifs mutated [4][5][6]. Those transduced signals eventually determine the survival of progenitor as well as mature B cells [7][8][9]. ...
... During B-cell development and antigen response, signals from B-cell receptors play a key role in the checkpoint selection and peripheral maintenance that takes place with the cooperation of membrane-bound Ig and the signal-transducing Igα/Igβ heterodimer [5,8,20]. Our previous work suggested that in comparison to IgM-expressing B cells, B cells that express IgG1 as their BCR are less dependent on Igα [14]. ...
... The importance of Igα and Igβ for B-cell development has been shown through the simultaneous truncation of them both, which leads to a complete arrest of B-cell development in the BM so that only pro-B cells, but no mature stages of B cells can be detected [5]. ...
The function of the IgM B-cell receptor (BCR) is dependent on intact signaling of the co-receptors Igα and Igβ, both of which contain a cytoplasmic tail bearing an immunoreceptor tyrosine-based activation motif (ITAM). We have previously demonstrated that the cytoplasmic tail of the IgG1 BCR can partially compensate for the loss of the signaling moiety of Igα. Here, we show that unlike Igα, Igβ signaling is indispensable for the development and function of IgG1 expressing B cells. Deletion of the cytoplasmic signaling tail of Igβ compromised the survival and proliferation not only of IgM(+) B cells but also of IgG1 expressing B cells. In the absence of the signaling tail of Igβ, the transcription levels of the anti-apoptotic gene bcl-xl and the cell-cycle gene ccnd2 were reduced, consistent with the observed defects in survival and proliferation. These results demonstrate functional differences between Igα and Igβ in the transduction of IgG1 BCR signal. This article is protected by copyright. All rights reserved.
