IgH Isotype-Specific B Cell Receptor Dosage Regulates B Cell Fate
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE93209 | GEO | 2017/01/06
SECONDARY ACCESSION(S): PRJNA360298
REPOSITORIES: GEO
Similar Datasets
Project description:The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE cells in these memory responses is particularly unclear. IgE B-cell differentiation is characterized by a transient GC phase, a bias towards the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B-cell receptor function and increased apoptosis. IgE GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B-cell differentiation fates: direct switching generates IgE GC cells, whereas sequential switching gives rise to IgE plasma cells. We propose a comprehensive model for the generation and memory of IgE responses. The purpose of this analysis was to: 1) identify expression differences between IgE and IgG1 B lymphocytes, 2) identify GC Dark Zone (DZ) and Light Zone (LZ) signatures of IgG1 GC cells. For that purpose, we compared in one experiment the gene expression patterns of IgE germinal center (GC) cells, IgG1 GC cells, IgE plasma cells (PC), IgG1 PC and naïve cells. In a second experiment, we compared the expression of IgG1 DZ GC cells with that of IgG1 LZ GC cells. Triplicates obtained from independent sorting experiments were used for all samples except two (IgG1 PC=2 samples; IgE PC=4 samples). Each sample was obtained from a pool of three individual mice. The mice used in the experiment were CeGFP BALB/c mice infected with the parasite N. brasiliensis. CeGFP mice carry an IRES-GFP KI cassette in the 3'UTR of membrane IgE. In these mice, GFP expression marks IgE cells, and a population of IgG1 cells with a rearrangement to Cepsilon in the non-productive (VDJ negative) IgH chromosome.
2013-10-31 | E-GEOD-49033 | biostudies-arrayexpress
Project description:IgE antibody is known as a common mediator of allergic responses, generally produced in type 2 immune responses to allergens. It is known that IgE binding to FcεRI without allergen binding promotes survival or proliferation of mast cells, basophils and other cells. Thus, spontaneously produced IgE, namely natural IgE, can increase an individual’s susceptibility to allergic diseases. Mice with a genetic defect in MyD88, a major signaling molecule downstream of Toll-like receptors, have a high level of serum natural IgE, the mechanism for which remains unknown. Here, we demonstrated that the maintenance of high serum IgE levels depends on memory B cells (MBCs). IgE from plasma cells and the sera from most of Myd88–/– mice, but none of Myd88+/– mice, recognized Streptococcus azizii (S. azizii), a commensal bacterium over-represented in the lung of Myd88–/– mice. IgG1+ MBCs from spleen also recognized S. azizii. The serum IgE levels declined by administration of antibiotics and were boosted by challenge with S. azizii in Myd88–/– mice. Moreover, bulk IgH repertoire analysis revealed that CDR3 sequences were highly shared between IgE+ PCs and IgG1+ or IgG2+ MBCs, indicating the contribution of S. azizii-specific IgG1+ MBCs to the natural IgE production.
2023-01-27 | GSE220657 | GEO
Project description:Human B cell isotype switching origins of IgE
| PRJNA222238 | ENA
Project description:Basophils are blood leukocytes associated to Th2 responses and allergy reactions primarily through the IgE bound to their surface throught the Fc Epsilon hifh affinity receptor. Soluble IgD is an enigmatic antibody isotype whose function remains elusive. We have characterised the presence of this antibody isotype on the surface of basophils where we hypothesise that it plays a role in Th2 responses and allergy reactions.
2018-12-31 | GSE115296 | GEO
Project description:IgE plays an essential role in the pathogenesis of allergies and its production is strongly regulated. A transient IgE germinal center phase and lack of IgE memory cells limit the generation of pathogenic IgE, but this can be overcome by sequential switching of IgG1 cells to IgE. We investigated which population of IgG1 cells can give rise to IgE-producing cells in memory responses. We identified three populations of IgG1 memory B cells (DP:CD73+CD80+, SP:CD73-CD80+, DN:CD73-CD80-) that generate IgE plasma cells of high or low affinity, but none gives rise to IgE germinal center cells or IgE memory cells. The two memory IgG1 populations differ however in their ability to differentiate into IgG1 plasma cells and germinal center cells, and to expand the IgG1 memory B cell pool. To explore the molecular mechanisms that may explain the distinct functions of IgG1 memory B cell subsets we compared their expression by transcriptome analysis using next generation sequencing.
2017-07-03 | GSE83436 | GEO
Project description:A mutation in the Signal Transducer and Activator of Transcription 3 (STAT3) has been linked to incidence of Autosomal Dominant Hyper Immunoglobulin E Syndrome (AD-HIES), a disease characterized by elevated serum IgE antibody. However, how this genetic mutation leads to the phenotype has not been fully understood. We investigated the specific role of STAT3 in the germinal center (GC) B cells and plasma cells for IgE class switching. Through the use of STAT3 conditional knockout mice in a Th2-type immunization model, we demonstrated that CD2-Cre driven STAT3 cKO mice showed elevated IgE and decreased IgG1 in the serum, and a reduction in GC formation. Within the GC, IgG1+ GC B cells were decreased while IgE+ GC B cells were more prevalent. Additionally, these mice exhibited reduced IgG1 and elevated IgE populations of antibody-producing plasma cells. Subsequent experiments using a CD19-Cre B-cell specific cKO mouse established this effect to be B-cell intrinsic. Transcription factors critical for GC and plasma cell differentiation, including Bcl-6 and Aicda, were shown to function as downstream signals of STAT3 regulation. Further ChIP-seq analysis revealed that many genes including Bcl3 and Crtc2 were among the direct STAT3 regulated targets. Mice with STAT3 deficiency in B cells also demonstrated an increase in lung inflammation when used in an asthma-like disease model. This model suggests a negative role for STAT3 in regulating class switching of the GC B cells from the IgG1 to the IgE producing state, which may serve as a therapeutic target for treatment of AD-HIES and other immune disorders.
2018-11-17 | GSE120022 | GEO
Project description:Food allergy is caused by allergen-specific IgE but little is known about the B cell memory of persistent responses. Here we describe in pediatric peanut allergy a population of CD23+IgG1 memory B cells that contains peanut-specific clones and generates IgE plasma cells on activation. Through single cell transcriptomics and B cell receptor (BCR) sequencing, we characterized FCER2/CD23+ IgG1 memory B cells co-expressing IL4R, IL13RA1, IGHE and carrying highly mutated BCRs. Further we found that peanut allergen (Ara h 2)-specific B cells were mostly IgG1 memory cells, carried highly mutated BCRs compared to diphtheria toxin-specific B cells, and expressed FCER2 and germlin IGHE. Our findings suggest that CD23+IgG1+ memory B cells transcribing IGHE are a unique memory population containing precursors for pathogenic IgE in food allergy.
2023-11-16 | GSE208235 | GEO
Project description:During Class Switch Recombination (CSR) B cells replace the Igh Cμ/δ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double strand break (DSBs) in switch regions and subsequent ligation of broken ends. Here we developed an assay to investigate the dynamics of DSB introduction in individual cells. We demonstrate that the upstream switch region Sμ is always targeted first during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR. High Resolution 4C was performed in resting and activated B cells using a bait on the Eμ enhancer
2016-06-16 | E-GEOD-81180 | biostudies-arrayexpress
Project description:During Class Switch Recombination (CSR) B cells replace the Igh Cμ/δ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double strand break (DSBs) in switch regions and subsequent ligation of broken ends. Here we developed an assay to investigate the dynamics of DSB introduction in individual cells. We demonstrate that the upstream switch region Sμ is always targeted first during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR.
2016-06-16 | GSE81180 | GEO
Project description:'Non-coding transcripts originating upstream of the immunoglobulin constant region (I-transcripts) are required to direct activation-induced deaminase to initiate class switching in B cells. Differential regulation of I and I1 transcription in response to interleukin-4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. Here we combine novel mouse reporters and single-cell RNA-seq to reveal the heterogeneity in IL-4 induced I-transcription. Transgenic mice were generated with one allele labelled with an eGFP fluorescent reporter gene in the first exon of the gamma-1 non-coding RNA and one allele with a tdTom fluorescent reporter gene in the first exon of the epsilon non-coding RNA. Ex vivo splenic B cells from these mice were stimulated with IL-4, lipopolysaccharide and B cell activating factor. After 24 hours culture, cell were sorted according to their fluorescence and used for single-cell mRNA-sequencing. Two independent experiments were performed (labelled as ''batch 1'' and ''batch 2'').'
2016-12-08 | E-MTAB-4825 | biostudies-arrayexpress