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CRTC2 couples genotoxic stress and plasma cell differentiation in the germinal center

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23171 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA131661

REPOSITORIES: GEO

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CRTC2 couples genotoxic stress and plasma cell differentiation in the germinal center

Project description:This SuperSeries is composed of the following subset Series: GSE23169: Transcriptional profiling of Ramos germinal center B cells GSE23170: ChIP-on-chip experiment from Ramos cells to analyze genome-wide CRTC2 binding sites in germinal center B cells Refer to individual Series

2012-01-01 | E-GEOD-23171 | biostudies-arrayexpress

AID-induced genotoxic stress promotes B cell differentiation in the germinal center via ATM and LKB1 signaling.

Project description:During an immune response, B cells undergo rapid proliferation and activation-induced cytidine deaminase (AID)-dependent remodeling of immunoglobulin (IG) genes within germinal centers (GCs) to generate memory B and plasma cells. Unfortunately, the genotoxic stress associated with the GC reaction also promotes most B cell malignancies. Here, we report that exogenous and intrinsic AID-induced DNA strand breaks activate ATM, which signals through an LKB1 intermediate to inactivate CRTC2, a transcriptional coactivator of CREB. Using genome-wide location analysis, we determined that CRTC2 inactivation unexpectedly represses a genetic program that controls GC B cell proliferation, self-renewal, and differentiation while opposing lymphomagenesis. Inhibition of this pathway results in increased GC B cell proliferation, reduced antibody secretion, and impaired terminal differentiation. Multiple distinct pathway disruptions were also identified in human GC B cell lymphoma patient samples. Combined, our data show that CRTC2 inactivation, via physiologic DNA damage response signaling, promotes B cell differentiation in response to genotoxic stress.

| S-EPMC2945612 | biostudies-literature

Lack of affinity signature for germinal center cells that have initiated plasma cell differentiation

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-01-15 | GSE248377 | GEO

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-05-12 | E-GEOD-72832 | biostudies-arrayexpress

Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-05-04 | E-GEOD-46608 | biostudies-arrayexpress

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-05-12 | GSE72832 | GEO

TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.

Project description:TET2 somatic mutations occur in ?10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors.See related commentary by Shingleton and Dave, p. 1515.This article is highlighted in the In This Issue feature, p. 1494.

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B cell differentiation into germinal center and antibody-secreting cells depends on SMARCA5-mediated chromatin remodeling

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-01 | GSE261015 | GEO

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

Project description: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.

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Low CD21 expression defines a population of recent germinal center graduates primed for plasma cell differentiation.

Project description:In this study, we report that antigen-specific CD19+CD27+CD21lo (CD21lo) B cells are transiently induced 14 to 28 days after immunization, at the time germinal centers (GCs) peak. Although clonally related to memory B cells and plasmablasts, CD21lo cells form distinct clades within phylogenetic trees based on accumulated variable gene mutations, supporting exit from active GCs. CD21lo cells express a transcriptional program, suggesting that they are primed for plasma cell differentiation and are refractory to GC differentiation, although they do not spontaneously secrete antibody. In addition, CD21lo cells differentially express multiple cell surface markers and have elevated intracellular levels of Blimp-1 and T-bet protein compared with memory B cells. Together, these data support a model in which CD21lo cells are recent GC graduates that represent a distinct population from CD27+ classical memory cells, are refractory to GC reentry, and are predisposed to differentiate into long-lived plasma cells.

| S-EPMC5896567 | biostudies-literature

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