B-cell development in progressively transformed germinal centers: similarities and differences compared with classical germinal centers and lymphocyte-predominant Hodgkin disease

Blood ◽  
2001 ◽  
Vol 97 (3) ◽  
pp. 714-719 ◽  
Author(s):  
Andreas Bräuninger ◽  
Wentao Yang ◽  
Hans-Heinrich Wacker ◽  
Klaus Rajewsky ◽  
Ralf Küppers ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Clonal Expansion ◽  
Germinal Centers ◽  
Hodgkin Disease ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Immunoglobulin Gene Rearrangements

Abstract Progressively transformed germinal centers (PTGCs) are histologic structures mainly composed of small resting B cells and intermingled proliferating centroblast-like cells. The B-cell differentiation processes within PTGCs and their relation to classical germinal centers (GC) and to lymphocyte-predominant Hodgkin disease (LPHD), with which PTGCs are often associated, are largely unknown. To address these issues, single small resting (Ki67−) and proliferating (Ki67+) centroblast-like cells were isolated from 7 PTGCs of 5 lymph nodes, and rearranged immunoglobulin genes were amplified and sequenced. Most small resting B cells were clonally unrelated, and most carried unmutated immunoglobulin gene rearrangements resembling mantle zone B cells. Small resting B cells with mutated immunoglobulin gene rearrangements may represent centrocytes, memory B cells, or both. Among the centroblast-like Ki67+ cells, expanded B-cell clones were observed in 6 of 7 PTGCs analyzed. Clonally related V region genes showed extensive intraclonal diversity, and the mutation pattern indicated stringent selection of the cells for the expression of functional antigen receptors. Thus, somatic hypermutation, clonal expansion, and selection occur also in the disorganized PTGC microenvironment, as in classical GCs. In lymph nodes affected by PTGCs, no clonal expansion across the borders of individual PTGCs was observed, distinguishing PTGCs from LPHD.

scholarly journals A single pre-B cell can give rise to antigen-specific B cells that utilize distinct immunoglobulin gene rearrangements.

1990 ◽  
Vol 172 (3) ◽  
pp. 815-825 ◽  
Author(s):  
A J Caton
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Clone ◽  
Gene Segment ◽  
Chain Gene ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Immune Repertoire ◽  
Influenza Virus Hemagglutinin ◽  
Immunoglobulin Gene Rearrangements

A group of hybridomas that express antibodies with related specificities for the influenza virus hemagglutinin (HA), that represent B cells that were the clonal progeny of a single pre-B cell, and that utilized distinct L chain gene rearrangements have been characterized. The clonal relationship was established by the sharing of H chain gene rearrangements at both the productive and the nonproductive alleles. Among these hybridomas, one group had rearranged only one of its kappa alleles, having joined a V kappa 24 gene to the J kappa 2 gene segment. The other group utilized the same V kappa 24 gene segment in productive rearrangement to the J kappa 5 gene segment, and shared an aberrant rearrangements among members of the same B cell clone can normally occur, and can contribute to the generation and diversification of the immune repertoire that is available for the recognition of foreign antigens. Mechanisms by which the distinct rearrangements expressed by the hybridomas might have been generated are discussed.

scholarly journals Survival and Clonal Expansion of Mutating “Forbidden” (Immunoglobulin Receptor–Deficient) Epstein-Barr Virus–Infected B Cells in Angioimmunoblastic T Cell Lymphoma

2001 ◽  
Vol 194 (7) ◽  
pp. 927-940 ◽  
Author(s):  
Andreas Bräuninger ◽  
Tilmann Spieker ◽  
Klaus Willenbrock ◽  
Philippe Gaulard ◽  
Hans-Heinrich Wacker ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Lymph Nodes ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Clonal Expansion ◽  
Barr Virus ◽  
Cell Clones ◽  
Epstein Barr

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is a peculiar T cell lymphoma, as expanding B cell clones are often present besides the malignant T cell clones. In addition, large numbers of Epstein-Barr virus (EBV)-infected B cells are frequently observed. To analyze the differentiation status and clonal composition of EBV-harboring B cells in AILD, single EBV-infected cells were micromanipulated from lymph nodes of six patients with frequent EBV+ cells and their rearranged immunoglobulin (Ig) genes analyzed. Most EBV-infected B cells carried mutated Ig genes, indicating that in AILD, EBV preferentially resides in memory and/or germinal center B cells. EBV+ B cell clones observed in all six cases ranged from small polyclonal to large monoclonal expansions and often showed ongoing somatic hypermutation while EBV− B cells showed little tendency for clonal expansion. Surprisingly, many members of expanding B cell clones had acquired destructive mutations in originally functional V gene rearrangements and showed an unfavorable high load of replacement mutations in the framework regions, indicating that they accumulated mutations over repeated rounds of mutation and division while not being selected through their antigen receptor. This sustained selection-free accumulation of somatic mutations is unique to AILD. Moreover, the survival and clonal expansion of “forbidden” (i.e., Ig-deficient) B cells has not been observed before in vivo and thus represents a novel type of viral latency in the B cell compartment. It is likely the interplay between the microenvironment in AILD lymph nodes and the viral transformation that leads to the survival and clonal expansion of Ig-less B cells.

scholarly journals Viral Superantigen Drives Extrafollicular and Follicular B Cell Differentiation Leading to Virus-specific Antibody Production

1997 ◽  
Vol 185 (3) ◽  
pp. 551-562 ◽  
Author(s):  
Sanjiv A. Luther ◽  
Adam Gulbranson-Judge ◽  
Hans Acha-Orbea ◽  
Ian C.M. MacLennan
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Antibody Production ◽  
Specific Antibody ◽  
Germinal Centers ◽  
B Cell Differentiation ◽  
Virus Specific Antibody ◽  
Specific Antibody Production

Mouse mammary tumor virus (MMTV[SW]) encodes a superantigen expressed by infected B cells. It evokes an antibody response specific for viral envelope protein, indicating selective activation of antigen-specific B cells. The response to MMTV(SW) in draining lymph nodes was compared with the response to haptenated chicken gamma globulin (NP-CGG) using flow cytometry and immunohistology. T cell priming occurs in both responses, with T cells proliferating in association with interdigitating dendritic cells in the T zone. T cell proliferation continues in the presence of B cells in the outer T zone, and B blasts then undergo exponential growth and differentiation into plasma cells in the medullary cords. Germinal centers develop in both responses, but those induced by MMTV(SW) appear later and are smaller. Most T cells activated in the T zone and germinal centers in the MMTV(SW) response are superantigen specific and these persist for weeks in lymph nodes draining the site MMTV(SW) injection; this contrasts with the selective loss of superantigen-specific T cells from other secondary lymphoid tissues. The results indicate that this viral superantigen, when expressed by professional antigen-presenting cells, drives extrafollicular and follicular B cell differentiation leading to virus-specific antibody production.

scholarly journals The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

2017 ◽  
Vol 37 (24) ◽  
Author(s):  
Toru Tamahara ◽  
Kyoko Ochiai ◽  
Akihiko Muto ◽  
Yukinari Kato ◽  
Nicolas Sax ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Class Switch Recombination ◽  
Cyclin D3 ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Class Switch

ABSTRACT The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the Ccnd3 gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.

Control of immunoglobulin gene rearrangements in developing B cells

1997 ◽  
Vol 9 (2) ◽  
pp. 233-238 ◽  
Author(s):  
Fotini Papavasiliou ◽  
Mila Jankovic ◽  
Shiaoching Gong ◽  
Michel C Nussenzweig
Keyword(s):  
B Cells ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Gene Rearrangements

scholarly journals The value of detecting immunoglobulin gene rearrangements in the diagnosis of B-cell lymphoma

Oncotarget ◽  
2017 ◽  
Vol 8 (44) ◽  
pp. 77009-77019 ◽  
Author(s):  
Can Lu ◽  
QiuYan He ◽  
Wei Zhu ◽  
ChunYan Fu ◽  
JianHua Zhou ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Rearrangements ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Gene Rearrangements

Marginal-Zone B Cells in the Human Lymph Node and Spleen Show Somatic Hypermutations and Display Clonal Expansion

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 226-234 ◽  
Author(s):  
Anne Tierens ◽  
Jan Delabie ◽  
Lieve Michiels ◽  
Peter Vandenberghe ◽  
Chris De Wolf-Peeters
Keyword(s):  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Somatic Hypermutation ◽  
Clonal Expansion ◽  
Germinal Centers ◽  
Proliferating Cells ◽  
Ki 67 ◽  
Marginal Zone B Cells ◽  
Vh Genes

Abstract Splenic marginal-zone B cells, marginal-zone B cells of Peyer’s patches in the gut, and nodal marginal-zone B cells (also identified as monocytoid B cells) share a similar morphology and immunophenotype. These cells likely represent a distinct subset of B cells in humans and rodents, but their precise ontogenetic relationship as well as their origin from B cells of the germinal center is still debated. To study this, we performed a mutation analysis of the rearranged immunoglobulin variable genes (VH) of microdissected single nodal and splenic marginal-zone cells. In addition, we investigated the presence of proliferating cells and B-cell clones in the human splenic and nodal marginal zone as well as adjacent germinal centers. This was performed by immunohistochemical staining for the Ki-67 antigen and denaturing gradient gel analysis of amplified immunoglobulin heavy chain genes’ complementarity determining region 3 of microdissected cell clusters. A variable subset of nodal and splenic marginal-zone B cells showed somatic mutations in their rearranged VH genes, indicating that both virgin and memory B cells are present in the nodal and splenic marginal zone. Nodal and splenic marginal-zone B cells preferentially rearranged VH3 family genes such as DP47, DP49, DP54, and DP58. A preferential rearrangement of the same VH genes has been shown by others in the peripheral CD5− IgM+ B cells. These data suggest that the splenic and nodal marginal-zone B cells are closely related B-cell subsets. We also showed that marginal-zone B cells may cycle and that clones of B cells are frequently detected in the nodal as well as the splenic marginal zone. These clones are not related to those present in adjacent germinal centers. These data favor the hypothesis that clonal expansion occurs in the marginal zone. Whether the somatic hypermutation mechanism is activated during the clonal expansion in the marginal zone and which type of immune response triggers the clonal expansion need to be elucidated.

scholarly journals Selection at Multiple Checkpoints Focuses VH12 B Cell Differentiation toward a Single B-1 Cell Specificity

1999 ◽  
Vol 190 (7) ◽  
pp. 903-914 ◽  
Author(s):  
Calin Tatu ◽  
Jian Ye ◽  
Larry W. Arnold ◽  
Stephen H. Clarke
Keyword(s):  
Gene Expression ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
High Frequency ◽  
Clonal Expansion ◽  
Selective Advantage ◽  
B Cell Differentiation ◽  
Cell Specificity ◽  
Selective Elimination

Phosphatidyl choline (PtC)-specific B cells segregate to the B-1 subset, where they comprise up to 10% of the B-1 repertoire. About half express VH12 and Vκ4/5H and are restricted in VHCDR3. We have previously reported that anti-PtC VHCDR3 is enriched among VH12-expressing cells by selective elimination of pre-B cells. We report here a bias for Vκ4/5H expression among VH12-expressing B cells, even among those that do not bind PtC and are not B-1. This is due in part to an inability of VH12 to associate with many light (L) chains but must also be due to a selective advantage in survival or clonal expansion in the periphery for Vκ4/5H-expressing cells. Thus, the bias for Vκ4/5H expression is independent of PtC binding, and, as segregation to B-1 occurs after Ig gene expression, it precedes segregation to the B-1 subset. In 6-1 mice, splenic B-1 cells reside in follicles but segregate to follicles distinct from those that contain B-2 cells. These data indicate that selection at multiple developmental checkpoints ensures the co-expression of an anti-PtC VHCDR3 and L chain in a high frequency of VH12 B cells. This focus toward specificity for PtC facilitates the development of a large anti-PtC B-1 repertoire.

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