scholarly journals bcl-2 Transgene Expression Inhibits Apoptosis in the Germinal Center and Reveals Differences in the Selection of Memory B Cells and Bone Marrow Antibody-Forming Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 475-484 ◽  
Author(s):  
Kenneth G.C. Smith ◽  
Amanda Light ◽  
Lorraine A. O'Reilly ◽  
Soon-Meng Ang ◽  
Andreas Strasser ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Germinal Center ◽  
Low Frequency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
High Affinity ◽  
Excessive Number ◽  
Selection Of

Immunization with T cell–dependent antigens generates long-lived memory B cells and antibody-forming cells (AFCs). Both populations originate in germinal centers and, predominantly, produce antibodies with high affinity for antigen. The means by which germinal center B cells are recruited into these populations remains unclear. We have examined affinity maturation of antigen-specific B cells in mice expressing the cell death inhibitor bcl-2 as a transgene. Such mice had reduced apoptosis in germinal centers and an excessive number of memory B cells with a low frequency of V gene somatic mutation, including those mutations encoding amino acid exchanges known to enhance affinity. Despite the frequency of AFCs being increased in bcl-2–transgenic mice, the fraction secreting high-affinity antibody in the bone marrow at day 42 remained unchanged compared with controls. The inability of BCL-2 to alter selection of bone marrow AFCs is consistent with these cells being selected within the germinal center on the basis of their affinity being above some threshold rather than their survival being due to a selective competition for an antigen-based signal. Continuous competition for antigen does, however, explain formation of the memory compartment.

scholarly journals Germinal Centers without T Cells

2000 ◽  
Vol 191 (3) ◽  
pp. 485-494 ◽  
Author(s):  
Carola García de Vinuesa ◽  
Matthew C. Cook ◽  
Jennifer Ball ◽  
Marion Drew ◽  
Yvonne Sunners ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
High Efficiency ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
High Affinity ◽  
Safe Mechanism ◽  
Germinal Center Formation

Germinal centers are critical for affinity maturation of antibody (Ab) responses. This process allows the production of high-efficiency neutralizing Ab that protects against virus infection and bacterial exotoxins. In germinal centers, responding B cells selectively mutate the genes that encode their receptors for antigen. This process can change Ab affinity and specificity. The mutated cells that produce high-affinity Ab are selected to become Ab-forming or memory B cells, whereas cells that have lost affinity or acquired autoreactivity are eliminated. Normally, T cells are critical for germinal center formation and subsequent B cell selection. Both processes involve engagement of CD40 on B cells by T cells. This report describes how high-affinity B cells can be induced to form large germinal centers in response to (4-hydroxy-3-nitrophenyl) acetyl (NP)-Ficoll in the absence of T cells or signaling through CD40 or CD28. This requires extensive cross-linking of the B cell receptors, and a frequency of antigen-specific B cells of at least 1 in 1,000. These germinal centers abort dramatically at the time when mutated high-affinity B cells are normally selected by T cells. Thus, there is a fail-safe mechanism against autoreactivity, even in the event of thymus-independent germinal center formation.

scholarly journals Positive Selection in the Light Zone of Germinal Centers

2021 ◽  
Vol 12 ◽  
Author(s):  
Rinako Nakagawa ◽  
Dinis Pedro Calado
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Plasma Cells ◽  
Selection Process ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Cell Fates ◽  
High Affinity

Germinal centers (GCs) are essential sites for the production of high-affinity antibody secreting plasma cells (PCs) and memory-B cells (MBCs), which form the framework of vaccination. Affinity maturation and permissive selection in GCs are key for the production of PCs and MBCs, respectively. For these purposes, GCs positively select “fit” cells in the light zone of the GC and instructs them for one of three known B cell fates: PCs, MBCs and persistent GC-B cells as dark zone entrants. In this review, we provide an overview of the positive selection process and discuss its mechanisms and how B cell fates are instructed.

scholarly journals The Development of Optimally Responsive Plasmodium-specific CD73+CD80+ IgM+ Memory B cells Requires Intrinsic BCL6 expression but not CD4+ Tfh cells

2019 ◽  
Author(s):  
Gretchen Harms Pritchard ◽  
Akshay T. Krishnamurty ◽  
Jason Netland ◽  
E. Nicole Arroyo ◽  
Kennidy K. Takehara ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Plasma Cells ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Effector Cells ◽  
High Affinity ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Bcl6 Expression

SummaryHumoral immunity depends upon the development of long-lived, antibody-secreting plasma cells and rapidly responsive memory B cells (MBCs). The differentiation of high affinity, class-switched MBCs after immunization is critically dependent upon BCL6 expression in germinal center (GC) B cells and CD4+ T follicular helper (Tfh) cells. It is less well understood how more recently described MBC subsets are generated, including the CD73+CD80+ IgM+ MBCs that initially form antibody-secreting effector cells in response to a secondary Plasmodium infection. Herein, we interrogated how BCL6 expression in both B and CD4+ T cells influenced the formation of heterogeneous Plasmodium-specific MBC populations. All Plasmodium-specific CD73+CD80+ MBCs required BCL6 expression for their formation, suggesting germinal center dependence. Further dissection of the CD4+ T and B cell interactions however revealed that somatically hypermutated CD73+CD80+ IgM+ MBCs can form not only in the absence of germinal centers, but also in the absence of CXCR5+ CD4+ Tfh cells.

scholarly journals Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation

2006 ◽  
Vol 203 (4) ◽  
pp. 1081-1091 ◽  
Author(s):  
Didrik Paus ◽  
Tri Giang Phan ◽  
Tyani D. Chan ◽  
Sandra Gardam ◽  
Antony Basten ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
High Affinity ◽  
Germinal Center B Cell

B cells responding to T-dependent antigen either differentiate rapidly into extrafollicular plasma cells or enter germinal centers and undergo somatic hypermutation and affinity maturation. However, the physiological cues that direct B cell differentiation down one pathway versus the other are unknown. Here we show that the strength of the initial interaction between B cell receptor (BCR) and antigen is a primary determinant of this decision. B cells expressing a defined BCR specificity for hen egg lysozyme (HEL) were challenged with sheep red blood cell conjugates of a series of recombinant mutant HEL proteins engineered to bind this BCR over a 10,000-fold affinity range. Decreasing either initial BCR affinity or antigen density was found to selectively remove the extrafollicular plasma cell response but leave the germinal center response intact. Moreover, analysis of competing B cells revealed that high affinity specificities are more prevalent in the extrafollicular plasma cell versus the germinal center B cell response. Thus, the effectiveness of early T-dependent antibody responses is optimized by preferentially steering B cells reactive against either high affinity or abundant epitopes toward extrafollicular plasma cell differentiation. Conversely, responding clones with weaker antigen reactivity are primarily directed to germinal centers where they undergo affinity maturation.

scholarly journals The Normal Counterpart of IgD Myeloma Cells in Germinal Center Displays Extensively Mutated IgVH Gene, Cμ–Cδ Switch, and λ Light Chain Expression

1998 ◽  
Vol 187 (8) ◽  
pp. 1169-1178 ◽  
Author(s):  
Christophe Arpin ◽  
Odette de Bouteiller ◽  
Diane Razanajaona ◽  
Isabelle Fugier-Vivier ◽  
Francine Brière ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Light Chain ◽  
Germinal Center ◽  
Plasma Cells ◽  
Precursor Cells ◽  
Memory B Cells ◽  
Hematopoietic Stem ◽  
Myeloma Cells ◽  
Λ Light Chain

Human myeloma are incurable hematologic cancers of immunoglobulin-secreting plasma cells in bone marrow. Although malignant plasma cells can be almost eradicated from the patient's bone marrow by chemotherapy, drug-resistant myeloma precursor cells persist in an apparently cryptic compartment. Controversy exists as to whether myeloma precursor cells are hematopoietic stem cells, pre–B cells, germinal center (GC) B cells, circulating memory cells, or plasma blasts. This situation reflects what has been a general problem in cancer research for years: how to compare a tumor with its normal counterpart. Although several studies have demonstrated somatically mutated immunoglobulin variable region genes in multiple myeloma, it is unclear if myeloma cells are derived from GCs or post-GC memory B cells. Immunoglobulin (Ig)D-secreting myeloma have two unique immunoglobulin features, including a biased λ light chain expression and a Cμ–Cδ isotype switch. Using surface markers, we have previously isolated a population of surface IgM−IgD+CD38+ GC B cells that carry the most impressive somatic mutation in their IgV genes. Here we show that this population of GC B cells displays the two molecular features of IgD-secreting myeloma cells: a biased λ light chain expression and a Cμ–Cδ isotype switch. The demonstration of these peculiar GC B cells to differentiate into IgD-secreting plasma cells but not memory B cells both in vivo and in vitro suggests that IgD-secreting plasma and myeloma cells are derived from GCs.

scholarly journals Germinal centers in human lymph nodes contain reactivated memory B cells

2007 ◽  
Vol 204 (11) ◽  
pp. 2655-2665 ◽  
Author(s):  
Richard J. Bende ◽  
Febe van Maldegem ◽  
Martijn Triesscheijn ◽  
Thera A.M. Wormhoudt ◽  
Richard Guijt ◽  
...  
Keyword(s):  
B Cells ◽  
Lymph Nodes ◽  
Germinal Center ◽  
Lymphoid Tissue ◽  
Somatic Hypermutation ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Cell Clones ◽  
Clonal Origin ◽  
Successive Recall

To reveal migration trails of antigen-responsive B cells in lymphoid tissue, we analyzed immunoglobulin (Ig)M-VH and IgG-VH transcripts of germinal center (GC) samples microdissected from three reactive human lymph nodes. Single B cell clones were found in multiple GCs, one clone even in as many as 19 GCs. In several GCs, IgM and IgG variants of the same clonal origin were identified. The offspring of individual hypermutated IgG memory clones were traced in multiple GCs, indicating repeated engagement of memory B cells in GC reactions. These findings imply that recurring somatic hypermutation progressively drives the Ig repertoire of memory B cells to higher affinities and infer that transforming genetic hits in non-Ig genes during lymphomagenesis do not have to arise during a single GC passage, but can be collected during successive recall responses.

High affinity IgM+ memory B cells are generated through a germinal center-dependent pathway

2015 ◽  
Vol 68 (2) ◽  
pp. 617-627 ◽  
Author(s):  
Yasushi Hara ◽  
Yasuyuki Tashiro ◽  
Akikazu Murakami ◽  
Miyuki Nishimura ◽  
Takeyuki Shimizu ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Memory B Cells ◽  
High Affinity ◽  
Dependent Pathway

scholarly journals Selection of antigen-specific, idiotype-positive B cells in transgenic mice expressing a rearranged M167-mu heavy chain gene.

1991 ◽  
Vol 174 (5) ◽  
pp. 1189-1201 ◽  
Author(s):  
J J Kenny ◽  
C O'Connell ◽  
D G Sieckmann ◽  
R T Fischer ◽  
D L Longo
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
Flow Cytometric Analysis ◽  
Low Frequency ◽  
Surface Expression ◽  
Chain Gene ◽  
Large Numbers ◽  
Selection Of

Flow cytometric analysis of antigen-specific, idiotype-positive (id+), B cell development in transgenic mice expressing a rearranged M167-mu gene shows that large numbers of phosphocholine (PC)-specific, M167-id+ B cells develop in the spleen and bone marrow of these mice. Random rearrangement of endogenous V kappa genes, in the absence of a subsequent receptor-driven selection, should give rise to equal numbers of T15- and M167-id+ B cells. The observed 100-500-fold amplification of M167-id+ B cells expressing an endogenous encoded V kappa 24]kappa 5 light chain in association with the M167 VH1-id transgene product appears to be an antigen driven, receptor-mediated process, since no amplification of non-PC-binding M167 VH1/V kappa 22, T15-id+ B cells occurs in these mu-only transgenic mice. The selection and amplification of antigen-specific, M167-id+ B cells requires surface expression of the mu transgene product; thus, no enhancement of M167-id+ B cells occurs in the M167 mu delta mem-transgenic mice, which cannot insert the mu transgene product into the B cell membrane. Surprisingly, no selection of PC-specific B cells occurs in M167-kappa-transgenic mice although large numbers of B cells expressing a crossreactive M167-id are present in the spleen and bone marrow of these mice. The failure to develop detectable numbers of M167-id+, PC-specific B cells in M167-kappa-transgenic mice may be due to a very low frequency of M167-VH-region formation during endogenous rearrangement of VH1 to D-JH segments. The somatic generation of the M167 version of a rearranged VH1 gene may occur in less than one of every 10(5) bone marrow B cells, and a 500-fold amplification of this M167-Id+ B cell would not be detectable by flow cytometry even though the anti-PC antibody produced by these B cells is detectable in the serum of M167-kappa-transgenic mice after immunization with PC.

miRNA Profiling of B Cell Subsets: Specific miRNA Profile for Germinal Center B Cells with a Marked Variation Between Centroblast and Centrocytes.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1459-1459
Author(s):  
Lu Ping Tan ◽  
Miao Wang ◽  
Jan-Lukas Robertus ◽  
Rikst Nynke Schakel ◽  
Johan H Gibcus ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Mirna Profile ◽  
Mantle Zone ◽  
Tissue Sections ◽  
Germinal Center B Cell ◽  
Germinal Center B Cells

Abstract MiRNAs are a new class of small RNAs, of 19–23 nucleotides that were discovered less than two decades ago. These tiny RNAs can negatively regulate genes at the post-transcriptional level by either triggering translational repression or direct cleavage of mRNAs. It has become evident that miRNAs are involved in hematopoiesis and that the aberrant expression of miRNAs may give rise to hematopoietic malignancies. The aim of our study was to characterize the miRNA profile of naïve, germinal center and memory B cells sorted from tonsils and review expression of selected miRNAs in tonsils and in B cell malignancies by miRNA in situ hybridization (ISH). Quantitative (q)RT-PCR profiling revealed that several miRNAs were elevated in germinal center B cells, including miR-17–5p, miR-106a and miR-181b. miR-150 was one of the most abundant miRNAs in all subsets, but the expression level was more than 10 fold lower in germinal center B cell as compared to the other two subsets. MiRNA ISH on tonsillar tissue sections confirmed findings from the profiling work, and at the same time depicted differences in staining intensities within germinal centers. According to miRNA ISH, expression levels of miR-17-5p, miR-106a, and miR-181b were indeed higher in germinal center B cells as compared to naïve and memory B cells in the mantle zone. Surprisingly, we also observed gradual decrease of miR-17-5p, miR-106a, and miR-181b staining from dark to light zone in the germinal centers. Moreover, miRNA ISH with a probe for miR-150 demonstrated an interesting staining pattern in lymph node tissue sections. Naïve and memory B cells located in the mantle zone showed a higher miR-150 expression as compared to most of the cells in the germinal centers. However, within the germinal centers a minority of cells showed a much stronger cytoplasmic staining in part of the blasts located specifically in the dark zone. This indicated that part of the centroblasts have a high expression level of miR-150. The level of miR-150 was surprisingly low in 22 B cell lymphoma cell lines, irrespective of germinal center or non germinal center B cell origin. This seemingly negative association of miR-150 with proliferation suggests a role in B cell growth/death. We observed an inverse expression pattern of miR-150 and Survivin in the germinal centers by miRNA ISH and immunohistochemistry. Moreover, induction of miR-150 using synthetic mature miR-150 duplex resulted in reduced Survivin expression levels. Our results suggested that aside the experimentally proven target c-Myb, Survivin may also be regulated by miR-150. In conclusion, we have revealed a unique miRNA profile of naïve, germinal center and memory B cells sorted from normal tonsils and the results were confirmed by miRNA ISH. Within the germinal centers a marked difference was observed between the light zone and the dark zone.

scholarly journals Intrinsic properties of human germinal center B cells set antigen affinity thresholds

2018 ◽  
Vol 3 (29) ◽  
pp. eaau6598 ◽  
Author(s):  
Kihyuck Kwak ◽  
Nicolas Quizon ◽  
Haewon Sohn ◽  
Avva Saniee ◽  
Javier Manzella-Lapeira ◽  
...  
Keyword(s):  
B Cells ◽  
Germinal Center ◽  
Synapse Formation ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Intrinsic Properties ◽  
High Affinity ◽  
Follicular Helper ◽  
Bcr Signaling ◽  
Engagement And Disengagement

Protective antibody responses to vaccination or infection depend on affinity maturation, a process by which high-affinity germinal center (GC) B cells are selected on the basis of their ability to bind, gather, and present antigen to T follicular helper (Tfh) cells. Here, we show that human GC B cells have intrinsically higher-affinity thresholds for both B cell antigen receptor (BCR) signaling and antigen gathering as compared with naïve B cells and that these functions are mediated by distinct cellular structures and pathways that ultimately lead to antigen affinity– and Tfh cell–dependent differentiation to plasma cells. GC B cells bound antigen through highly dynamic, actin- and ezrin-rich pod-like structures that concentrated BCRs. The behavior of these structures was dictated by the intrinsic antigen affinity thresholds of GC B cells. Low-affinity antigens triggered continuous engagement and disengagement of membrane-associated antigens, whereas high-affinity antigens induced stable synapse formation. The pod-like structures also mediated affinity-dependent antigen internalization by unconventional pathways distinct from those of naïve B cells. Thus, intrinsic properties of human GC B cells set thresholds for affinity selection.

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