Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB14546 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR1467830_1.fastq.gz | Fastqsanger.gz | |||
| ERR1467830_2.fastq.gz | Fastqsanger.gz | |||
| ERR1467840_1.fastq.gz | Fastqsanger.gz | |||
| ERR1467840_2.fastq.gz | Fastqsanger.gz | |||
| ERR1467850_1.fastq.gz | Fastqsanger.gz |
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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
Project description:Allergy is one of the most prevalent chronic diseases, affecting hundreds of millions of people worldwide. In allergy, environmental allergens induce B cells to undergo class switch recombination and produce Immunoglobulin E (IgE) antibodies. IgE is a key molecule that mediates allergic responses by coating mast cell or basophil surfaces and inducing degranulation upon binding a specific allergen. IgE can also be spontaneously produced in the absence of exogenous allergens, yet the origin, regulation, and functions of such “natural” IgE still remains largely unknown. Here, we discovered that glucocorticoids, which are steroid stress hormones, enhance IgE isotype class switching in B cells both in vivo and ex vivo without antigenic challenge. Such IgE class switching is promoted by B cell-intrinsic glucocorticoid receptor signaling that reinforces CD40 signaling and synergizes with the IL-4/STAT6 pathway. In addition, we found that rare B cells in the mesenteric lymph nodes are responsible for the production of glucocorticoid-inducible IgE. Furthermore, we showed that locally produced glucocorticoids in the gut may induce natural IgE during perturbations of gut homeostasis such as dysbiosis. Notably, mice preemptively treated with glucocorticoids were protected from subsequent IgE-mediated pathogenic anaphylaxis in vivo. Together, our results suggest that glucocorticoids, classically considered to be broadly immunosuppressive, have a selective immunostimulatory role in B cells.
2022-09-09 | GSE203542 | GEO
Project description:Noncoding 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 Iε and Iγ1 transcription in response to interleukin 4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. In this study, we combine novel mouse reporters and single-cell RNA sequencing to reveal the heterogeneity in IL-4-induced I transcription. We identify an early population of cells expressing Iε but not Iγ1 and demonstrate that early Iε transcription leads to switching to IgE and occurs at lower activation levels than Iγ1. Our results reveal how probabilistic transcription with a lower activation threshold for Iε directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma.
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Project description:Understanding the transcriptional signature of IgE producing cells is fundamental to plasma cell biology. IgE PCs from bone marrow (BM) upregulated genes associated with pro-survival, and BM homing, whereas IgE PCs from draining lymph nodes (dLN) expressed genes associated with recent class-switching and differenatiation. Finally, IgE PCs exhibited higher expression of ER stress and protein coding compared to IgG1.
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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: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.
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Project description:Ribosomes have long been thought of as homogeneous macromolecular machines, but recent evidence suggests they are heterogeneous and could be specialised to regulate translation. Here, we have isolated ribosomal complexes and characterised their protein content across 4 tissues of Drosophila melanogaster via TMT-MS. We find that testes and ovaries contain the most heterogeneous ribosome populations, which occurs through a combination of ribosomal protein paralog-enrichment and ribosomal protein paralog-switching. We have also solved structures of ribosomes isolated from tissues by cryo-EM, revealing differences in precise ribosomal arrangement for testis and ovary 80S ribosomes. Differences in the amino acid composition of paralog pairs and their localisation on the ribosome exterior indicate paralog-switching could alter the ribosome surface, enabling different proteins to regulate translation. One testis-specific paralog-switching pair is also found in humans, suggesting this is a conserved site of ribosome heterogeneity. Overall, this work allows us to propose that mRNA translation might be regulated in the gonads through ribosome heterogeneity, providing a potential means of ribosome specialisation.
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