scholarly journals Antigen Receptor Engagement Turns off the V(D)J Recombination Machinery in Human Tonsil B Cells

1998 ◽  
Vol 188 (4) ◽  
pp. 765-772 ◽  
Author(s):  
Eric Meffre ◽  
Fotini Papavasiliou ◽  
Paul Cohen ◽  
Odette de Bouteiller ◽  
Diana Bell ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Light Chains ◽  
Immunoglobulin Gene ◽  
Antigen Receptors ◽  
Human Tonsil ◽  
Recombination Activating Gene ◽  
Cognate Antigen

The germinal center (GC) is an anatomic compartment found in peripheral lymphoid organs, wherein B cells undergo clonal expansion, somatic mutation, switch recombination, and reactivate immunoglobulin gene V(D)J recombination. As a result of somatic mutation, some GC B cells develop higher affinity antibodies, whereas others suffer mutations that decrease affinity, and still others may become self-reactive. It has been proposed that secondary V(D)J rearrangements in GCs might rescue B cells whose receptors are damaged by somatic mutations. Here we present evidence that mature human tonsil B cells coexpress conventional light chains and recombination associated genes, and that they extinguish recombination activating gene and terminal deoxynucleotidyl transferase expression when their receptors are cross-linked. Thus, the response of the recombinase to receptor engagement in peripheral B cells is the opposite of the response in developing B cells to the same stimulus. These observations suggest that receptor revision is a mechanism for receptor diversification that is turned off when antigen receptors are cross-linked by the cognate antigen.

scholarly journals Biallelic Germline Transcription at the κ Immunoglobulin Locus

2003 ◽  
Vol 197 (6) ◽  
pp. 743-750 ◽  
Author(s):  
Nandita Singh ◽  
Yehudit Bergman ◽  
Howard Cedar ◽  
Andrew Chess
Keyword(s):  
B Cells ◽  
Chromatin Structure ◽  
Replication Timing ◽  
Allelic Exclusion ◽  
Antigen Receptors ◽  
Germline Transcription ◽  
Immature B Cells ◽  
Recombination Activating Gene ◽  
Immunoglobulin Locus

Rearrangement of antigen receptor genes generates a vast array of antigen receptors on lymphocytes. The establishment of allelic exclusion in immunoglobulin genes requires differential treatment of the two sequence identical alleles. In the case of the κ immunoglobulin locus, changes in chromatin structure, methylation, and replication timing of the two alleles are all potentially involved in regulating rearrangement. Additionally, germline transcription of the κ locus which precedes rearrangement has been proposed to reflect an opening of the chromatin structure rendering it available for rearrangement. As the initial restriction of rearrangement to one allele is critical to the establishment of allelic exclusion, a key question is whether or not germline transcription at the κ locus is monoallelic or biallelic. We have used a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay and an RNA–fluorescence in situ hybridization (FISH) to show that germline transcription of the κ locus is biallelic in wild-type immature B cells and in recombination activating gene (RAG)−/−, μ+ B cells. Therefore, germline transcription is unlikely to dictate which allele will be rearranged first and rather reflects a general opening on both alleles that must be accompanied by a mechanism allowing one of the two alleles to be rearranged first.

scholarly journals Progressive immunoglobulin gene mutations in chronic lymphocytic leukemia: evidence for antigen-driven intraclonal diversification

Blood ◽  
2006 ◽  
Vol 109 (4) ◽  
pp. 1559-1567 ◽  
Author(s):  
Alicia D. Volkheimer ◽  
J. Brice Weinberg ◽  
Bethany E. Beasley ◽  
John F. Whitesides ◽  
Jon P. Gockerman ◽  
...  
Keyword(s):  
Amino Acid ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Somatic Mutations ◽  
Single Cell Analysis ◽  
Gene Mutations ◽  
Lymphocytic Leukemia ◽  
Light Chains ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Genes

Abstract Somatic mutations of immunoglobulin genes characterize mature memory B cells, and intraclonal B-cell diversification is typically associated with expansion of B-cell clones with greater affinity for antigen (antigen drive). Evidence for a role of antigen in progression of intraclonal chronic lymphocytic leukemia (CLL) cell diversification in patients with mutated immunoglobulin genes has not been previously presented. We performed a single-cell analysis of immunoglobulin heavy and light chains in 6 patients with somatically mutated CLL-cell immunoglobulin genes and identified 2 patients with multiple related (oligoclonal) subgroups of CLL cells. We constructed genealogic trees of these oligoclonal CLL-cell subgroups and assessed the effects of immunoglobulin somatic mutations on the ratios of replacement and silent amino acid changes in the framework and antigen-binding regions (CDRs) of the immunoglobulin heavy and light chains from each oligoclonal CLL-cell population. In one subject, the amino acid changes were consistent with an antigen-driven progression of clonally related CLL-cell populations. In the other subject, intraclonal diversification was associated with immunoglobulin amino acid changes that would have likely lessened antigen affinity. Taken together, these studies support the hypothesis that in some CLL cases intraclonal diversification is dependent on antigen interactions with immunoglobulin receptors.

scholarly journals Germinal Center B Cells Replace Their Antigen Receptors in Dark Zones and Fail Light Zone Entry when Immunoglobulin Gene Mutations are Damaging

Immunity ◽  
2018 ◽  
Vol 49 (3) ◽  
pp. 477-489.e7 ◽  
Author(s):  
Isabelle Stewart ◽  
Daniel Radtke ◽  
Bethan Phillips ◽  
Simon J. McGowan ◽  
Oliver Bannard
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Gene Mutations ◽  
Immunoglobulin Gene ◽  
Antigen Receptors ◽  
Germinal Center B Cells

Localization of recombination activating gene 1/green fluorescent protein (RAG1/GFP) expression in secondary lymphoid organs after immunization with T-dependent antigens in rag1/gfpknockin mice

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2680-2687 ◽  
Author(s):  
Hideya Igarashi ◽  
Naomi Kuwata ◽  
Kumiko Kiyota ◽  
Kiminobu Sumita ◽  
Toshio Suda ◽  
...  
Keyword(s):  
Green Fluorescent Protein ◽  
B Cells ◽  
Fluorescent Protein ◽  
Interleukin 4 ◽  
Immunoglobulin Gene ◽  
Lymphoid Follicles ◽  
Recombination Activating Gene ◽  
Green Fluorescent ◽  
Secondary Lymphoid Organs

Abstract Secondary rearrangements of immunoglobulin gene segments that generate a new antibody repertoire in peripheral B cells have been described as receptor revision and occur by as yet unknown mechanisms. To determine the importance of recombination activating gene (RAG) expression in receptor revision, heterozygous rag1/green fluorescent protein (gfp) knockin mice were used to examine the location of RAG1 expression in the germinal centers (GCs) of lymphoid follicles after immunization with a variety of T-cell–dependent antigens. Immunization of rag1/gfp heterozygous mice orrag1 homozygous knockout mice reconstituted withrag1/gfp heterozygous spleen cells caused the down-regulation of RAG1/GFP signal in GCs. Although some RAG1/GFP+ cells appeared in regions surrounding the peanut agglutinin (PNA)+GL-7+ GC area, RAG1/GFP+ cells did not accumulate in the central region. In addition, the stimulation of spleen B cells with anti-μ antibody plus interleukin-4 (IL-4) or with anti-CD40 monoclonal antibody plus IL-7 did not induce GFP signals at detectable levels in vitro. These results clearly demonstrate that RAG1 re-expression either does not occur or is at extremely low levels in antigen-driven B cells in GCs of secondary lymphoid follicles, suggesting that other mechanisms may mediate the gene rearrangements observed in receptor revision.

scholarly journals Consequences of the recurrent MYD88L265P somatic mutation for B cell tolerance

2014 ◽  
Vol 211 (3) ◽  
pp. 413-426 ◽  
Author(s):  
James Q. Wang ◽  
Yogesh S. Jeelall ◽  
Bruce Beutler ◽  
Keisuke Horikawa ◽  
Christopher C. Goodnow
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Tolerance ◽  
Large B Cell Lymphoma ◽  
Tlr9 Activation

MYD88L265P has recently been discovered as an extraordinarily frequent somatic mutation in benign monoclonal IgM gammopathy, Waldenström’s macroglobulinemia, and diffuse large B cell lymphoma. In this study, we analyze the consequences for antigen-activated primary B cells of acquiring MYD88L265P. The mutation induced rapid B cell division in the absence of exogenous TLR ligands and was inhibited by Unc93b13d mutation and chloroquine or TLR9 deficiency, indicating continued dependence on upstream TLR9 activation. Proliferation and NF-κB activation induced by MYD88L265P were nevertheless rapidly countered by the induction of TNFAIP3, an NF-κB inhibitor frequently inactivated in MYD88L265P–bearing lymphomas, and extinguished by Bim-dependent apoptosis. MYD88L265P caused self-reactive B cells to accumulate in vivo only when apoptosis was opposed by Bcl2 overexpression. These results reveal checkpoints that fortify TLR responses against aberrant B cell proliferation in response to ubiquitous TLR and BCR self-ligands and suggest that tolerance failure requires the accumulation of multiple somatic mutations.

scholarly journals MK5 activates Rag transcription via Foxo1 in developing B cells

2013 ◽  
Vol 210 (8) ◽  
pp. 1621-1634 ◽  
Author(s):  
Kwan T. Chow ◽  
Greg A. Timblin ◽  
Sarah M. McWhirter ◽  
Mark S. Schlissel
Keyword(s):  
B Cells ◽  
Target Genes ◽  
Phosphorylation Site ◽  
Cell Types ◽  
B Cell Development ◽  
Antigen Receptors ◽  
Upstream Regulator ◽  
Recombination Activating Gene ◽  
Necessary And Sufficient ◽  
Direct Regulator

Foxo1 is a critical, direct regulator of Rag (recombination activating gene) transcription during B cell development and is thus essential for the generation of a diverse repertoire of antigen receptors. Although Foxo1 regulation has been widely studied in many cell types, pathways regulating Foxo1 in B cells have not been fully elucidated. By screening a panel of Foxo1 mutants, we identified serine 215 on Foxo1 as a novel phosphorylation site that is essential for the activation of Rag transcription. Mutation of S215 strongly attenuated transactivation of Rag but did not affect most other Foxo1 target genes. We show that MK5, a MAPK-activated protein kinase, is a previously unidentified upstream regulator of Foxo1. MK5 was necessary and sufficient to activate Rag transcription in transformed and primary pro–B cells. Together, our experiments show that MK5 positively regulates Rag transcription via phosphorylation of Foxo1 in developing B cells.

scholarly journals Mapping the Germline and Somatic Mutation Interaction Landscape in Indolent and Aggressive Prostate Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Tarun Karthik Kumar Mamidi ◽  
Jiande Wu ◽  
Chindo Hicks
Keyword(s):  
Signaling Pathways ◽  
Somatic Mutation ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Multiple Gene ◽  
Gene Regulatory ◽  
Aggressive Tumors ◽  
Prostate Cancers ◽  
Mutation Information

Background. A majority of prostate cancers (PCas) are indolent and cause no harm even without treatment. However, a significant proportion of patients with PCa have aggressive tumors that progress rapidly to metastatic disease and are often lethal. PCa develops through somatic mutagenesis, but emerging evidence suggests that germline genetic variation can markedly contribute to tumorigenesis. However, the causal association between genetic susceptibility and tumorigenesis has not been well characterized. The objective of this study was to map the germline and somatic mutation interaction landscape in indolent and aggressive tumors and to discover signatures of mutated genes associated with each type and distinguishing the two types of PCa. Materials and Methods. We integrated germline mutation information from genome-wide association studies (GWAS) with somatic mutation information from The Cancer Genome Atlas (TCGA) using gene expression data from TCGA on indolent and aggressive PCas as the intermediate phenotypes. Germline and somatic mutated genes associated with each type of PCa were functionally characterized using network and pathway analysis. Results. We discovered gene signatures containing germline and somatic mutations associated with each type and distinguishing the two types of PCa. We discovered multiple gene regulatory networks and signaling pathways enriched with germline and somatic mutations including axon guidance, RAR, WINT, MSP-RON, STAT3, PI3K, TR/RxR, and molecular mechanisms of cancer, NF-kB, prostate cancer, GP6, androgen, and VEGF signaling pathways for indolent PCa and MSP-RON, axon guidance, RAR, adipogenesis, and molecular mechanisms of cancer and NF-kB signaling pathways for aggressive PCa. Conclusion. The investigation revealed germline and somatic mutated genes associated with indolent and aggressive PCas and distinguishing the two types of PCa. The study revealed multiple gene regulatory networks and signaling pathways dysregulated by germline and somatic alterations. Integrative analysis combining germline and somatic mutations is a powerful approach to mapping germline and somatic mutation interaction landscape.

scholarly journals Human acute leukemia cell line with the t(4;11) chromosomal rearrangement exhibits B lineage and monocytic characteristics

Blood ◽  
1985 ◽  
Vol 65 (1) ◽  
pp. 21-31 ◽  
Author(s):  
RC Stong ◽  
SJ Korsmeyer ◽  
JL Parkin ◽  
DC Arthur ◽  
JH Kersey
Keyword(s):  
Acute Leukemia ◽  
Cell Line ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Immunoglobulin Gene ◽  
A Cell ◽  
B Lineage

Abstract A cell line, designated RS4;11, was established from the bone marrow of a patient in relapse with an acute leukemia that was characterized by the t(4;11) chromosomal abnormality. The cell line and the patient's fresh leukemic cells both had the t(4;11)(q21;q23) and an isochromosome for the long arm of No. 7. Morphologically, all cells were lymphoid in appearance. Ultrastructurally and cytochemically, approximately 30% of the cells possessed myeloid features. The cells were strongly positive for terminal deoxynucleotidyl transferase. They were HLA-DR positive and expressed surface antigens characteristic for B lineage cells, including those detected by anti-B4, BA-1, BA-2, and PI153/3. Immunoglobulin gene analysis revealed rearrangements of the heavy chain and kappa chain genes. The cells lacked the common acute lymphoblastic leukemia antigen and antigenic markers characteristic of T lineage cells. The cells reacted with the myeloid antibody 1G10 but not with other myeloid monoclonal antibodies. Treatment with 12-O-tetradecanoyl- phorbol-13-acetate induced a monocyte-like phenotype demonstrated by cytochemical, functional, immunologic, and electron microscopic studies. The expression of markers of both early lymphoid and early myeloid cells represents an unusual phenotype and suggests that RS4;11 represents a cell with dual lineage capabilities. To our knowledge, RS4;11 is the first cell line established from t(4;11)-associated acute leukemia.

scholarly journals Analysis with antiidiotype antibody of a patient with chronic lymphocytic leukemia and a large cell lymphoma (Richter's syndrome)

Blood ◽  
1987 ◽  
Vol 70 (1) ◽  
pp. 45-50 ◽  
Author(s):  
LF Bertoli ◽  
H Kubagawa ◽  
GV Borzillo ◽  
M Mayumi ◽  
JT Prchal ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Plasma Cells ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Lymphocytic Leukemia ◽  
Immunoglobulin Gene ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma ◽  
Richter’S Syndrome

Abstract A murine monoclonal antibody made against an idiotypic determinant (Id) of surface IgM/IgD lambda molecules on chronic lymphocytic leukemia (CLL) cells of a 71-year-old woman was used for clonal analysis by two- color immunofluorescence. The anti-Id antibody identified IgM+/IgD+/lambda+ B cells as the predominant cell type of her CLL clone. In addition, substantial proportions of the IgG and IgA B cells and most of the IgM plasma cells in her bone marrow and blood were Id+. Six years after diagnosis, the patient died of respiratory failure due to infiltration of lungs by malignant cells. Autopsy revealed a dramatic change in the tumor cell morphology. The lungs, hilar nodes, and liver were infiltrated by a diffuse large cell lymphoma admixed with the leukemic cells. By immunohistologic staining these anaplastic lymphoma cells were IgM+/IgD-/lambda+ B cells expressing the same Id noted earlier on the CLL cells. The immunoglobulin gene rearrangement pattern on Southern blot analysis was also the same in leukemic blood cells and in the tissues involved by the lymphoma. Thus, the combination of antiidiotype and immunoglobulin gene analyses in this patient with Richter's syndrome revealed that a CLL clone, seemingly “frozen” in differentiation, was actually undergoing isotype switching, differentiation into plasma cells, and evolution into a rapidly growing and fetal lymphoma.

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