scholarly journals Gene Dose–Dependent Maturation and Receptor Editing of B Cells Expressing Immunoglobulin (Ig)g1 or Igm/Igg1 Tail Antigen Receptors

2000 ◽  
Vol 191 (6) ◽  
pp. 1031-1044 ◽  
Author(s):  
Sarah L. Pogue ◽  
Christopher C. Goodnow
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Copy Number ◽  
Memory B Cells ◽  
Mouse Strains ◽  
Allelic Exclusion ◽  
Antigen Receptors ◽  
Cytoplasmic Domains ◽  
Transgene Copy Number

Conserved differences between the transmembrane and cytoplasmic domains of membrane immunoglobulin (Ig)M and IgG may alter the function of antigen receptors on naive versus memory B cells. Here, we compare the ability of these domains to signal B cell allelic exclusion and maturation in transgenic mice. A lysozyme-binding antibody was expressed in parallel sets of mice as IgM, IgG1, or a chimeric receptor with IgM extracellular domains and transmembrane/cytoplasmic domains of IgG1. Like IgM, the IgG1 or chimeric IgM/G receptors triggered heavy chain allelic exclusion and supported development of mature CD21+ B cells. Many of the IgG or IgM/G B cells became CD21high and downregulated their IgG and IgM/G receptors spontaneously, resembling memory B cells and B cells with mutations that exaggerate B cell antigen receptor signaling. Unlike IgM-transgenic mice, “edited” B cells that carry non–hen egg lysozyme binding receptors preferentially accumulated in IgG and IgM/G mice. This was most extreme in lines with the highest transgene copy number and diminished in variant offspring with fewer copies. The sensitivity of B cell maturation to transgene copy number conferred by the IgG transmembrane and cytoplasmic domains may explain the diverse phenotypes found in other IgG-transgenic mouse strains and may reflect exaggerated signaling.

IRF-4/MUM-1 Expression Is a Critical Switch in the Generation of Plasma Cells Versus Memory B-Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 337-337 ◽  
Author(s):  
Ulf Klein ◽  
Stefano Casola ◽  
Giorgio Cattoretti ◽  
Qiong Shen ◽  
Marie Lia ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Plasma Cells ◽  
Large Fraction ◽  
Variable Region ◽  
Memory B Cells ◽  
Critical Event ◽  
Tumor Subtypes

Abstract Most types of human B-cell lymphomas harbor somatically mutated Ig variable region genes, reflecting their origin from cells that have undergone the germinal center (GC) reaction of T-dependent immune responses. The lymphomas exhibit diverse phenotypes and clinical behaviors, likely as a consequence of differences both in the mechanisms of transformation and in the specific target cell. We have recently identified two distinct subsets of GC B-cells that may represent late stages of the GC-reaction and may be the precursors of plasma cells and memory B-cells. The corresponding subsets are characterized by downregulation of the GC-marker BCL6 and the alternative expression of IRF-4/MUM-1 or nuclear c-Rel. These two subsets seem to reflect distinct cellular programs which are altered during B-lymphomagenesis in various tumor subtypes which co-express BCL6, IRF-4 and nuclear c-Rel, an event never observed in normal B-cells. In order to gain insights into the physiologic role of IRF-4/MUM-1 and nuclear c-Rel in GC-development, we are ablating their expression specifically in mouse GC B-cells. Transgenic mice were generated that carry an IRF-4/MUM-1 null allele and a conditional IRF-4/MUM-1 allele which, following Cre-mediated deletion of the loxP-flanked promotor region and exons 1 and 2, expresses eGFP, thus allowing to track the development of the IRF-4/MUM-1 deficient cells at the single cell level. IRF-4/MUM-1fl/- mice were crossed with transgenic mice that express the Cre-recombinase specifically in B-cells undergoing class-switch to IgG1, an event occurring in a large fraction of GC B-cells. Upon immunization with sheep red blood cells or nitrophenyl-(NP)-KLH, mice unable to express IRF-4/MUM-1 in late GC B-cells (IRF-4/MUM-1fl/-/Cγ 1Cre/+), in contrast to control mice (IRF-4/MUM-1fl/+/Cγ 1Cre/+), did not develop plasma cells (IgG1+CD138+) in the peripheral lymphoid organs, blood, and bone marrow. On the other hand, the generation of memory B-cells appears normal since antigen-specific B-cells were present in the spleen (eGFP+B220+PNA-IgG1+) and blood (eGFP+B220+CD38+IgG1+). These results suggest that the IRF-4/MUM-1 gene product is required for the development of antigen-selected GC B-cells into plasma cells. We suggest that the expression of IRF-4/MUM-1 in a GC centrocyte is the critical event in the commitment of B-cells to differentiate into a plasma cell versus a memory B-cell, and are currently testing the role of nuclear c-Rel in the same process.

BAFFR Activates PI3K/AKT Signaling in Human Naive But Not in Switched Memory B Cells Through Direct Interactions with B Cell Antigen Receptors

2021 ◽  
Author(s):  
Eirini Sevdali ◽  
Violeta Block ◽  
Marie Lataretu ◽  
Huiying Li ◽  
Cristian R. Smulski ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Akt Signaling ◽  
Memory B Cells ◽  
Antigen Receptors ◽  
Cell Antigen

scholarly journals The cytoplasmic domains of immunoglobulin (Ig) alpha and Ig beta can independently induce the precursor B cell transition and allelic exclusion.

1995 ◽  
Vol 182 (5) ◽  
pp. 1389-1394 ◽  
Author(s):  
F Papavasiliou ◽  
M Jankovic ◽  
H Suh ◽  
M C Nussenzweig
Keyword(s):  
B Cells ◽  
B Cell ◽  
Allelic Exclusion ◽  
Sufficient Information ◽  
Cytoplasmic Domains ◽  
Independent Events ◽  
Membrane Immunoglobulin ◽  
Redundant Functions ◽  
Regulatory Functions ◽  
Cell Transition

In mature B cells, signals transduced through membrane immunoglobulin (Ig) produce cellular activation, yet the same receptor can also mediate deletion and silencing of autoreactive B cells. In addition, Ig expression during the antigen-independent phase of B cell development regulates the precursor B (pre-B) cell transition and allelic exclusion. To account for the diverse regulatory functions induced by membrane Ig, it has been proposed that individual receptor components have independent physiologic activities. Here we establish a role for Ig alpha in the pre-B cell transition and allelic exclusion. We find that the cytoplasmic domain of Ig alpha contains sufficient information to trigger both of these antigen-independent events. Direct comparisons of the cytoplasmic domains of Ig alpha and Ig beta show that the two are indistinguishable in the induction of the pre-B cell transition and allelic exclusion. Our experiments suggest that, despite the reported differences in certain biochemical assays, Ig alpha and Ig beta have redundant functions in the developing B cell.

scholarly journals Recall of B cell memory depends on relative locations of prime and boost

2021 ◽  
Author(s):  
Masayuki Kuraoka ◽  
Chen-Hao Yeh ◽  
Goran Bajic ◽  
Ryutaro Kotaki ◽  
Shengli Song ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Centers ◽  
Cross Reactivity ◽  
Memory B Cells ◽  
Antigen Receptors ◽  
Vaccination Strategies ◽  
B Cell Memory ◽  
Homologous Antigen ◽  
Heterologous Antigens

Re-entry of memory B cells to recall germinal centers (GCs) is essential for updating their B-cell antigen receptors (BCRs). Using single B-cell culture and fate-mapping, we have characterized BCR repertoires in recall GCs following boost immunizations at sites local or distal to the priming. Local boosts with homologous antigen recruit to recall GCs progeny of primary GC B cells more efficiently than do distal boosts. Recall GCs following local boosts contain significantly more B cells with elevated levels of Ig mutations and higher avidity BCRs. This local preference is unaffected by blockade of CD40:CD154 interaction that terminate active, primary GC responses. Local boosts with heterologous antigens elicit secondary GCs with B-cell populations enriched for cross-reactivity to the priming and boosting antigens; in contrast, cross-reactive GC B cells are rare following distal boosts. Our findings indicate the importance of locality in humoral immunity and inform serial vaccination strategies for evolving viruses.

scholarly journals CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation.

1996 ◽  
Vol 183 (4) ◽  
pp. 1707-1718 ◽  
Author(s):  
K F Byth ◽  
L A Conroy ◽  
S Howlett ◽  
A J Smith ◽  
J May ◽  
...  
Keyword(s):  
Signal Transduction ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Development ◽  
Cell Development ◽  
Cross Linking ◽  
Thymocyte Development ◽  
Double Positive

The CD45 transmembrane glycoprotein has been shown to be a protein phosphotyrosine phosphatase and to be important in signal transduction in T and B lymphocytes. We have employed gene targeting to create a strain of transgenic mice that completely lacks expression of all isoforms of CD45. The spleens from CD45-null mice contain approximately twice the number of B cells and one fifth the number of T cells found in normal controls. The increase in B cell numbers is due to the specific expansion of two B cell subpopulations that express high levels of immunoglobulin (IgM) staining. T cell development is significantly inhibited in CD45-null animals at two distinct stages. The efficiency of the development of CD4-CD8- thymocytes into CD4+ CD8+ thymocytes is reduced by twofold, subsequently the frequency of successful maturation of the double positive population into mature, single positive thymocytes is reduced by a further four- to fivefold. In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture. In contrast, apoptosis can be induced normally in CD45-null thymocytes by non-TCR-mediated signals. Since both positive and negative selection require signals through the TCR complex, these findings suggest that CD45 is an important regulator of signal transduction via the TCR complex at multiple stages of T cell development. CD45 is absolutely required for the transmission of mitogenic signals via IgM and IgD. By contrast, CD45-null B cells proliferate as well as wild-type cells to CD40-mediated signals. The proliferation of B cells in response to CD38 cross-linking is significantly reduced but not abolished by the CD45-null mutation. We conclude that CD45 is not required at any stage during the generation of mature peripheral B cells, however its loss reveals a previously unrecognized role for CD45 in the regulation of certain subpopulations of B cells.

scholarly journals Ras Mediates Effector Pathways Responsible for Pre-B Cell Survival, Which Is Essential for the Developmental Progression to the Late Pre-B Cell Stage

2000 ◽  
Vol 192 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Hitoshi Nagaoka ◽  
Yoshimasa Takahashi ◽  
Reiko Hayashi ◽  
Tohru Nakamura ◽  
Kumiko Ishii ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Antigen Receptors ◽  
Cell Stage ◽  
Light Chain Gene ◽  
B Cell Survival ◽  
Effector Pathways

Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21ras in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21Asn-17 Ha-ras was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21ras activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21ras activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.

scholarly journals OVERLAP STIMULATION OF PRIMARY AND SECONDARY B CELLS BY CROSS-REACTING DETERMINANTS

1973 ◽  
Vol 138 (5) ◽  
pp. 1276-1281 ◽  
Author(s):  
N. R. Klinman ◽  
J. L Press ◽  
G. P. Segal
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Receptors ◽  
Cell Stimulation ◽  
Stimulation Of

Experiments were carried out to test the validity of the hypothesis that postulated differences in the nature of the antigen receptors of primary and secondary B cells should be reflected in a greater specificity in primary B-cell stimulation (2). Enumeration of clonal precursors stimulated by either DNP-Hy, TNP-Hy, or a mixture of both antigens confirmed this hypothesis. Since the sum of primary B cells stimulated by DNP-Hy and TNP-Hy is approximately equal to the number stimulated by a mixture of both, overlap stimulation of primary B cells by these antigens could be considered negligible. In contrast, the stimulation of B cells from mice previously immunized with DNP-Hy showed extensive overlap of stimulation by DNP-Hy and TNP-Hy. Thus secondary B cells appear less fastidious in their affinity requirements for stimulation than primary B cells.

scholarly journals Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells

2021 ◽  
Author(s):  
Sarah Wilmore ◽  
Karly-Rai Rogers-Broadway ◽  
Joe Taylor ◽  
Elizabeth Lemm ◽  
Rachel Fell ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Translation ◽  
Cell Receptor ◽  
Memory B Cells ◽  
B Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Mrna Levels ◽  
Mrna Stabilization

AbstractSignaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1/2 and AKT phosphorylation). Analysis of normal naïve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of MYC mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of MYC mRNA in anti-IgM treated cells. This was mediated by MYC mRNA stabilization and was not observed for MCL1 mRNA. Following drug wash-out, MYC mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized MYC mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and/or MCL1.

scholarly journals Characterization of B-cell Receptor Heavy Chain Complementarity-determining Region 3 Repertoire Based on the Differences of Symbiotic Microorganisms in the Gut of Mice

2021 ◽  
Author(s):  
Jun Li ◽  
Yurong Pan ◽  
Qingqing Ma ◽  
Long Ma ◽  
Bin Shi ◽  
...  
Keyword(s):  
Small Intestine ◽  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Intestinal Microflora ◽  
Cell Receptor ◽  
Memory B Cells ◽  
B Cell Receptor ◽  
Positive Effects ◽  
Significant Difference

Abstract Background Colonization of gut microorganism is related to maturation of B cells in peripheral immune organs. This study aims to investigate the effect of intestinal microflora in Germ-free (GF), Specific Pathogen-free (SPF) and Clean (CL) BALB/C mice to small intestine total B-cell and memory B-cell receptor (BCR) complementary-determining region 3 (CDR3) repertoire. Results The composition and characteristics of intestinal microflora were analyzed by 16S rDNA sequencing. Genomic DNA extracted from small intestine tissue and memory B-cells of GF, SPF and CL mice were conducted via high-throughput DNA sequencing methods. As expected, significant differences of gut microflora diversity were observed in the three mice groups. CL group showed the most diversity, followed by SPF group, and GF group had the lowest diversity. Moreover, anormogenesis of intestinal lymphoid tissue were observed in GF mice. Diversity of the BCR heavy chain CDR3 repertoire in memory B cells were significant difference among three groups, but not in total B cells. The nucleotide polymorphism, usage frequency of gene segments (V, D, J, V–J gene segments) and amino acid of total B cells and memory B cells CDR3 were comparable among three mice groups, and there was significant difference between CL and GF mice groups. Conclusions The results of this study advocate that the colonization of intestinal microorganisms affect the diversity of B cells CDR3 repertoire. Elucidating mechanism of microbiome participated in the function of intestinal mucosal immune system may have positive effects on human health, and it requires further investigation.

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