scholarly journals The immunoglobulin allotype contributed by peritoneal cavity B cells dominates in SCID mice reconstituted with allotype-disparate mixtures of splenic and peritoneal cavity B cells.

1990 ◽  
Vol 172 (2) ◽  
pp. 475-485 ◽  
Author(s):  
J E Riggs ◽  
R S Stowers ◽  
D E Mosier
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peritoneal Cavity ◽  
B Lymphocyte ◽  
Feedback Inhibition ◽  
Cell Lineage ◽  
Scid Mice ◽  
Term Survival ◽  
Regulatory Interactions ◽  
Immunoglobulin Allotype

We have studied potential regulatory interactions between mature B lymphocyte populations by analysis of C.B-17 severe combined immunodeficient (SCID) mice reconstituted simultaneously with immunoglobulin allotype-congenic mixtures of spleen (SP) and peritoneal cavity (PerC) B cells. We have previously shown that the independent transfer of B cells from these sources leads to the long-term survival of donor B cells and reconstitution of immunoglobulin levels in SCID mice (Riggs, J.E., D.L. Robertson, R.S. Stowers, and D.E. Mosier, manuscript submitted for publication). SP and PerC B cells differ in numerous respects, with the PerC having higher proportions of large, activated B cells that express the IgM greater than IgD phenotype and greater numbers of CD5 B cells. The injection of equal numbers of B cells from SP and PerC into SCID recipients (e.g., BALB/c SP + C.B-17 Per C----SCID) has led to the following observations: (a) serum IgM allotypes in B cell chimeras revealed strict dominance by the allotype contributed by the PerC B cells; (b) this dominance was not due to regulatory T cells; (c) B cells of the unexpressed (i.e., SP) allotype were present in the chimera in the spleen but not the peritoneal cavity; and (d) immunization with TI and TD antigens failed to elicit the SP IgM allotype, whereas secondary TD antigen immunization elicited low levels of the SP IgG2a allotype. Additional experiments demonstrated concurrent expression of IgM allotypes derived from both SP and PerC B cells in recipients that: (a) received a 10-fold excess of SP B cells; (b) received SP B cells before PerC B cell transfer; or (c) received SP B cells intravenously and PerC B cells intraperitoneally. We conclude that the establishment of IgM synthesis by PerC B cells leads to a feedback inhibition of subsequent IgM synthesis by SP B cells, and that the frequency of B cells that can lead to this effect is substantially higher in peritoneal cavity than in spleen. These data provide further confirmation of regulatory interactions between B cells in the absence of T lymphocytes, but confound the interpretation of experiments supporting the existence of a separate CD5+ B cell lineage.

scholarly journals Blimp-1-Dependent Repression of Pax-5 Is Required for Differentiation of B Cells to Immunoglobulin M-Secreting Plasma Cells

2002 ◽  
Vol 22 (13) ◽  
pp. 4771-4780 ◽  
Author(s):  
Kuo-I Lin ◽  
Cristina Angelin-Duclos ◽  
Tracy C. Kuo ◽  
Kathryn Calame
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Critical Role ◽  
Cell Lineage ◽  
Immunoglobulin M ◽  
Dependent Manner ◽  
Plasmacytic Differentiation

ABSTRACT B-cell lineage-specific activator protein (BSAP), encoded by the Pax-5 gene, is critical for B-cell lineage commitment and B-cell development but is not expressed in terminally differentiated B cells. We demonstrate a direct connection between BSAP and B-lymphocyte-induced maturation protein 1 (Blimp-1), a transcriptional repressor that is sufficient to drive plasmacytic differentiation. Blimp-1 binds a site on the Pax-5 promoter in vitro and in vivo and represses the Pax-5 promoter in a binding-site-dependent manner. By ectopically expressing Blimp-1 or a competitive inhibitor of Blimp-1, we show that Blimp-1 is both necessary and sufficient to repress Pax-5 during plasmacytic differentiation of primary splenic B cells. Blimp-1-dependent repression of Pax-5 is sufficient to regulate BSAP targets CD19 and J chain and is necessary but not sufficient to induce XBP-1. We further show that repression of Pax-5 is required for Blimp-1 to drive differentiation of splenocytes to immunoglobulin M-secreting cells. Thus, repression of Pax-5 plays a critical role in the Blimp-1-dependent program of plasmacytic differentiation.

scholarly journals Inhibition of immunoglobulin gene rearrangement by the expression of a lambda 2 transgene.

1989 ◽  
Vol 169 (6) ◽  
pp. 1911-1929 ◽  
Author(s):  
J Hagman ◽  
D Lo ◽  
L T Doglio ◽  
J Hackett ◽  
C M Rudin ◽  
...  
Keyword(s):  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Gene Rearrangement ◽  
Feedback Inhibition ◽  
Cell Lineage ◽  
Serum Levels ◽  
Lymphoid Cells ◽  
Immunoglobulin Gene ◽  
Cell Stage

The rearrangement of Ig genes is known to be regulated by the production of H and kappa L chains. To determine whether lambda L chains have a similar effect, transgenic mice were produced with a lambda 2 gene. It was necessary to include the H chain enhancer, since a lambda gene without the added enhancer did not result in transgene expression. The lambda 2 transgene with the H enhancer was expressed in lymphoid cells only. The majority of the B cells of newborn transgenic mice produced lambda, whereas kappa + cells were reduced. Concomitantly, serum levels of kappa and kappa mRNA were diminished. By 2 wk after birth the proportion of kappa-expressing cells was dramatically increased. Adults had reduced proportions of B cells that produced lambda only, but the levels of lambda were still higher than in normal littermates. Also, kappa + cells were still lower than in normal mice. Analysis of hybridomas revealed that reduction of kappa gene rearrangement was the basis for the decreased frequency of kappa + cells. Furthermore, many cells also contained an unrearranged H chain allele. It was concluded that feedback inhibition by the lambda 2 together with endogenous H protein may have inhibited recombinase activity in early pre-B cells, leading to inhibition of both H chain and kappa gene rearrangement. Thus, lambda 2 can replace kappa in a feedback complex. The levels of serum lambda 1 and, to a lesser degree, of spleen lambda 1 mRNA were reduced in the lambda 2 transgenic mice. However, the proportion of hybridomas with endogenous lambda gene rearrangement was at least as high as in normal mice. It was therefore concluded that the suppression of functional lambda 1 may be a consequence of decreased selection of endogenous lambda-producing cells because of the excess of transgenic lambda. The escape of kappa-producing cells from feedback inhibition may be the result of several mechanisms that operate to varying degrees, among them: (a) kappa rearrangement during a period in which the recombinase is still active after appearance of a lambda 2/mu stop signal; (b) a B cell lineage that is not feedback inhibited at the pre-B cell stage; (c) subthreshold levels of transgenic lambda 2 in some pre-B cells; and (d) loss of the lambda 2 transgenes in rare pre-B cells.

scholarly journals Rearrangement and selection of VH11 in the Ly-1 B cell lineage.

1990 ◽  
Vol 172 (1) ◽  
pp. 371-374 ◽  
Author(s):  
C E Carmack ◽  
S A Shinton ◽  
K Hayakawa ◽  
R R Hardy
Keyword(s):  
Polymerase Chain Reaction ◽  
B Cells ◽  
B Cell ◽  
Peritoneal Cavity ◽  
Cell Lineage ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Vh Genes ◽  
Self Antigen ◽  
Selection Of

One of the predominant VH genes utilized to encode the anti-BrMRBC specificity is a member of the small VH11 family rearranged to JH1. Using the polymerase chain reaction (PCR) we have determined that the frequency of B cells with a VH11 rearrangement is 10-20 times higher in Ly-1 B than in Ly-1- "conventional" B cells regardless of location (spleen or peritoneal cavity). Conventional B cells rearrange this gene at comparable levels in pre-B cells and in mature B cells utilizing all JH gene segments. In contrast, the increased levels of VH11 rearrangement in Ly-1 B are restricted to JH1 (and some JH2) and therefore appear to be the result of selection. Furthermore, most peritoneal Ly-1 B cells with VH11 rearrangements fall in a fraction stained by anti-BrMRBC antibody, likely bearing multivalent natural (likely self) antigen constitutively bound to their surface Ig receptors. Thus, we suggest that autoantigens are largely responsible for the accumulation of autoantibody specificities in the Ly-1 B cell lineage with time, whereas they do not exert this effect in the conventional B cells.

scholarly journals Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells.

1992 ◽  
Vol 176 (5) ◽  
pp. 1343-1353 ◽  
Author(s):  
L Reininger ◽  
T Radaszkiewicz ◽  
M Kosco ◽  
F Melchers ◽  
A G Rolink
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Cell Lines ◽  
B Lymphocyte ◽  
Fetal Liver ◽  
Elevated Serum ◽  
Scid Mice ◽  
Cell Hyperplasia

Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL-7) were established from fetal liver of (NZB x NZW)F1 mice. They express the B lineage-specific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+ B cells that can then be stimulated by lipopolysaccharide to become IgM-secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x NZW)F1-derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100-300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB x NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression.

scholarly journals B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB.

1996 ◽  
Vol 16 (6) ◽  
pp. 2898-2905 ◽  
Author(s):  
Y Zhuang ◽  
P Cheng ◽  
H Weintraub
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Cell Lineage ◽  
Lymphocyte Development ◽  
Normal Numbers ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
B Lymphocyte Development ◽  
Essential Function

B-lymphocyte development requires the basic helix-loop-helix proteins encoded by the E2A gene. In this study, the control mechanism of E2A was further explored by disruption of the E2A-related genes, E2-2 and HEB. In contrast to E2A, E2-2 and HEB are not essential for the establishment of the B-cell lineage. However, both E2-2 and HEB are required for the generation of the normal numbers of pro-B cells in mouse embryos. Breeding tests among mice carrying different mutations revealed that E2-2 and HEB interact with E2A in many developmental processes including generation of B cells. Specifically, mice transheterozygous for any two mutations of these three genes produced fewer pro-B cells than the singly heterozygous littermates. This study indicates that B-cell development is dependent not only on an essential function provided by the E2A gene but also on a combined dosage set by E2A, E2-2, and HEB.

scholarly journals Long-Term Survival and Gradual Recovery of B Cells in Patients (Pts) with Refractory Large B Cell Lymphoma (LBCL) Treated with Axicabtagene Ciloleucel (Axi-Cel)

2021 ◽  
Vol 27 (3) ◽  
pp. S404-S405
Author(s):  
Caron A. Jacobson ◽  
Frederick L. Locke ◽  
Armin Ghobadi ◽  
David B. Miklos ◽  
Lazaros J. Lekakis ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Term Survival ◽  
Long Term Survival ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Scope of action of the immunoglobulin mutator system

Genome ◽  
1989 ◽  
Vol 31 (1) ◽  
pp. 118-121 ◽  
Author(s):  
Matthias R. Wabl ◽  
Hans-Martin Jäck ◽  
R. C. von Borstel ◽  
Charles M. Steinberg
Keyword(s):  
B Cell ◽  
Mutation Rate ◽  
Heavy Chain ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Spontaneous Mutation ◽  
Cell Lineage ◽  
Variable Region ◽  
High Rate ◽  
Spontaneous Mutation Rate

The authors have developed a method to measure the rate of spontaneous mutations taking place in IgH, the gene encoding the immunoglobulin heavy chain. When an amber chain-termination codon mutates to a sense codon, translation of the polypeptide chain will be completed, and mutant cells producing the heavy chain can be detected with a fluorescent labelled antibody. The protocol used is the compartmentalization test which minimizes any effect of selection. In subclones of the pre-B lymphocyte line 18–81, the spontaneous mutation rate in the part of IgH encoding the variable region is somewhat greater than 10−5 mutations per base pair per generation. This supports the hypothesis that hypermutation is not dependent on cell stimulation by an antigen. In a hybrid between a cell of this line and a myeloma (which represents the terminal stage of the B-cell lineage), the mutation rate was too low to be determined by this test, less than 10−9. When the same loss to gain procedure system was used with an opal chain-terminating codon in the part of IgH encoding the constant region (Cμ), a high rate of reversion by deletion was found. Long (more than one exon) and short (less than one exon) deletions occurred at rates of 1.7 × 10−5 and 1.4 × 10−7 per generation, respectively. It is thought that the high rate of deletion is not related to somatic hypermutation but rather to DNA rearrangement during the heavy-chain class switch, which is occurring in these pre-B cell lines. The point mutation rate was too low to be detected above the background of deletion mutants, less than 5 × 10−8. The immunoglobulin mutator system works weakly, if at all, on two other, nonimmunoglobulin, genes tested: B2m (β2 microglobulin) and the gene for ouabain resistance.Key words: pre-B lymphocyte, B lymphocyte, spontaneous mutation rate, compartmentalization test, deletion mutation, hypermutation.

scholarly journals Ligand-independent Signaling Functions for the B Lymphocyte Antigen Receptor and Their Role in Positive Selection during B Lymphopoiesis

2001 ◽  
Vol 194 (11) ◽  
pp. 1583-1596 ◽  
Author(s):  
Gregory Bannish ◽  
Ezequiel M. Fuentes-Pananá ◽  
John C. Cambier ◽  
Warren S. Pear ◽  
John G. Monroe
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Antigen Receptor ◽  
Cell Development ◽  
B Cell Development ◽  
B Lymphopoiesis ◽  
Biologically Relevant ◽  
Developmental Progression

Signal transduction through the B cell antigen receptor (BCR) is determined by a balance of positive and negative regulators. This balance is shifted by aggregation that results from binding to extracellular ligand. Aggregation of the BCR is necessary for eliciting negative selection or activation by BCR-expressing B cells. However, ligand-independent signaling through intermediate and mature forms of the BCR has been postulated to regulate B cell development and peripheral homeostasis. To address the importance of ligand-independent BCR signaling functions and their regulation during B cell development, we have designed a model that allows us to isolate the basal signaling functions of immunoglobulin (Ig)α/Igβ-containing BCR complexes from those that are dependent upon ligand-mediated aggregation. In vivo, we find that basal signaling is sufficient to facilitate pro-B → pre-B cell transition and to generate immature/mature peripheral B cells. The ability to generate basal signals and to drive developmental progression were both dependent on plasma membrane association of Igα/Igβ complexes and intact immunoregulatory tyrosine activation motifs (ITAM), thereby establishing a correlation between these processes. We believe that these studies are the first to directly demonstrate biologically relevant basal signaling through the BCR where the ability to interact with both conventional as well as nonconventional extracellular ligands is eliminated.

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4342-4346 ◽  
Author(s):  
Claudiu V. Cotta ◽  
Zheng Zhang ◽  
Hyung-Gyoon Kim ◽  
Christopher A. Klug
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Nk Cell ◽  
Cell Lineage ◽  
Blood Analysis ◽  
Hematopoietic Stem ◽  
Peripheral Blood Analysis

Abstract Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

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