Single-cell ATAC-seq analysis of human plasma cell differentiation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE242324 | GEO | 2024/04/25
REPOSITORIES: GEO
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Project description:We performed single-cell RNAseq on the four populations (MBC, prePB, PB and PC) generated during normal plasma cell differentiation
2024-04-25 | GSE242330 | GEO
Project description:Waldenströms macroglobulinemia (WM) is a rare lymphoproliferative disorder with apparent morphologic and immunophenotypic heterogeneity and its origins are still poorly understood. In this study, using Gene-Expression Profiling (GEP), we compared the global mRNA expression patterns of CD19+ WM B cells (WM-BC) and CD138+ WM plasma cells (WM-PC) with those of normal CD19+ peripheral blood B cells (PB-BC), tonsil-BC (T-BC), CD138+ T-PC and bone marrow PC (N-PC). Experiment Overall Design: The sample cohort studied consisted of CD19-selected peripheral blood B cells (PB-BC; n = 7), tonsil B cells (T-BC; n = 7), bone marrow B cells from WM (WM-BC; n = 12), tonsil plasma cells (T-PC; n = 9), bone marrow plasma cells from healthy donors (N-PC; n = 10), WM plasma cells (WM-PC, n = 9), and MM plasma cells (MM-PC; n = 11).
2008-12-05 | E-GEOD-9656 | biostudies-arrayexpress
Project description:We carried out a single-cell (sc) multiomic analysis on a series of MYD88 mutated Waldenström macroglobulinemia (WM) cases and identified two distinct subtypes of disease, memory B-cell-like (MBC-like) and plasma cell-like (PC-like), based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully towards a plasma cell (PC) and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the memory B-cell (MBC) stage, upregulates key MBC genes, and is characterized by upregulated BCR and AKT/mTOR signaling. In contrast, the PC-like subtype can partially differentiate towards a PC, upregulates key PC genes, has enhanced NF-kB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined scRNA-sequencing and scATAC-sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the two disease subtypes were validated further using hierarchical clustering of bulk RNA-seq data from a secondary set of cases. The biological significance of the subtypes was further established using whole genome sequencing, where it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as two disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features with potential implications for WM treatment strategies.
2025-05-02 | GSE296167 | GEO
Project description:To explore events that govern the differentiation of human naïve B cells (NBCs) into memory B cells and plasma cells (PCs), we designed an in vitro 2-step culture model leading non-switched NBC precursors to differentiate into two cell compartments: CD20loCD38hi and CD20+CD38+. Both populations are characterized by distinct cell fates, the former one corresponding to plasmablasts that undergo PC terminal differentiation, with intermingled relationship between cell division and bona fide differentiation two events that are usually viewed as mutually exclusive. Postulating that extracellular cues mediated by distinct receptor-ligand interactions are likely involved in this phenomenon we explored one by one factors used in our model and found that T-cell-produced IL-2 was critical for the PC’s commitment. Interestingly, this IL-2 effect operates independently of proliferation and survival functions and required an ERK signaling. Based on our study we proposed to complete previous scheme of PRDM1/Blimp-1 controlling PC differentiation by adding the T-cell-delivered IL-2 effect, which sustains indirectly the mitogenic-induced Blimp-1 expression by downregulating IRF8 and BACH2 via an ERK signal This study highlight early events that could take place when cognate B and T cells meet and interact before seeding follicle, where crucial inputs may condition final GC B destiny. GEP was performed on the RNA of purified B cells from 3 healthy blood donors, stimulated at Day 0 and with addition or not of IL-2. Four time points were assessed Day 0, Day 0+16h, Day 0+22h and Day 4.
2012-04-08 | E-GEOD-36975 | biostudies-arrayexpress
Project description:Objective: Production of pathogenic autoantibodies by self-reactive plasma cells (PC) is a hallmark of autoimmune diseases. Investigating the prevalence of PC in autoimmune disease and their relationship with known pathogenic pathways may increase our understanding of the role of PC in disease progression and treatment response. Methods: We developed a sensitive gene expression based method to overcome the challenges of measuring PC using flow cytometry. Whole genome microarray analysis of sorted cellular fractions identified a panel of genes, IGHA, IGJ, IGKC, IGKV, and TNFRSF17, expressed predominantly in PC. The sensitivity of the PC signature score created from the combined expression levels of these genes was assessed through ex vivo experiments with sorted cells. This PC gene expression signature was used for monitoring changes in PC levels following anti-CD19 therapy; evaluating the relationship between PC and other autoimmune disease-related genes; and estimating PC levels in affected blood and tissue from multiple autoimmune diseases. Results: The PC signature was highly sensitive and capable of detecting as few as 300 PCs. The PC signature was reduced over 90% in scleroderma patients following anti-CD19 treatment and this reduction was highly correlated (r = 0.77) with inhibition of collagen gene expression. Evaluation of multiple autoimmune diseases revealed 30-35% of lupus, rheumatoid arthritis, and scleroderma patients with increased PC levels. Conclusion: This newly developed PC signature provides a robust and accurate method to measure PC levels in the clinic. Our results highlight subsets of patients across multiple autoimmune diseases that may benefit from PC depleting therapy. MI-CP200 is a Phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of escalating single IV doses of MEDI-551 in adult subjects with scleroderma. In this study, 5 cohorts of subjects (n=25) received 1 of 5 single IV doses of MEDI-551 (0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo. Twenty-four healthy donor control samples are also included.
2013-03-28 | E-GEOD-45536 | biostudies-arrayexpress
Project description:B cells differentiate into antibody-producing plasma cells, which are critical for humoral immunity, autoimmunity, and vaccine responses. Despite the importance of environmental stressors on regulating humoral immune responses, the influence of pH on PC differentiation has not been described. Here, we identified SLC4A7, a sodium/bicarbonate cotransporter, as a selective regulator of PC differentiation. SLC4A7 deletion impaired the formation of PCs and humoral immunity to influenza A virus infection in mice. Mechanistically, we find that SLC4A7 prevents acidification of intracellular pH and thus maintains lysosomal function and mTORC1 activity. Loss of SLC4A7 suppresses PC differentiation under conditions of extracellular acidosis in vitro and in a mouse model of metabolic acidosis. Here we reveal a novel relationship between the regulation of intracellular pH by SLC4A7 and mTORC1-dependent PC differentiation and humoral immunity.
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2022-09-06 | GSE189775 | GEO
Project description:MYC acts as a rheostat during plasma cell (PC) differentiation, linking B-cell activation to cell growth and division. Tight control over MYC is an essential feature of the network controlling differentiation. Deregulation of MYC is common in aggressive B-cell neoplasms, driving cellular transformation, and is often accompanied by apoptotic protection conferred by BCL2. Here we assess how acutely enforced MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. In the context of a permissive state for PC differentiation such acute deregulation does not suffice to transform human B-cells. Instead MYC drives a sequence of metabolic and growth-related expression programs while suppressing the transition to immunoglobulin secretion and thus establishes an aberrant differentiation state. The ability of MYC to establish this aberrant state depends on MB0 and MBII of its transactivation domain. Dependence on MBII is profound and can be resolved to conserved residue W135.
2025-07-22 | GSE262807 | GEO
Project description:MYC acts as a rheostat during plasma cell (PC) differentiation, linking B-cell activation to cell growth and division. Tight control over MYC is an essential feature of the network controlling differentiation. Deregulation of MYC is common in aggressive B-cell neoplasms, driving cellular transformation, and is often accompanied by apoptotic protection conferred by BCL2. Here we assess how acutely enforced MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. In the context of a permissive state for PC differentiation such acute deregulation does not suffice to transform human B-cells. Instead MYC drives a sequence of metabolic and growth-related expression programs while suppressing the transition to immunoglobulin secretion and thus establishes an aberrant differentiation state. The ability of MYC to establish this aberrant state depends on MB0 and MBII of its transactivation domain. Dependence on MBII is profound and can be resolved to conserved residue W135.
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Project description:MYC acts as a rheostat during plasma cell (PC) differentiation, linking B-cell activation to cell growth and division. Tight control over MYC is an essential feature of the network controlling differentiation. Deregulation of MYC is common in aggressive B-cell neoplasms, driving cellular transformation, and is often accompanied by apoptotic protection conferred by BCL2. Here we assess how acutely enforced MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. In the context of a permissive state for PC differentiation such acute deregulation does not suffice to transform human B-cells. Instead MYC drives a sequence of metabolic and growth-related expression programs while suppressing the transition to immunoglobulin secretion and thus establishes an aberrant differentiation state. The ability of MYC to establish this aberrant state depends on MB0 and MBII of its transactivation domain. Dependence on MBII is profound and can be resolved to conserved residue W135.
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