scholarly journals A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition

2020 ◽  
Vol 3 (10) ◽  
pp. e202000654
Author(s):  
Mario Cocco ◽  
Matthew A Care ◽  
Amel Saadi ◽  
Muna Al-Maskari ◽  
Gina Doody ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Integrated Analysis ◽  
Plasma Cell Myeloma ◽  
Signal Loss ◽  
Secreting Cell ◽  
Antibody Secreting Cell ◽  
Er Stress Response ◽  
Gene Modules ◽  
Gene Regulatory

The activated B-cell (ABC) to plasmablast transition encompasses the cusp of antibody-secreting cell (ASC) differentiation. We explore this transition with integrated analysis in human cells, focusing on changes that follow removal from CD40-mediated signals. Within hours of input signal loss, cell growth programs shift toward enhanced proliferation, accompanied by ER-stress response, and up-regulation of ASC features. Clustering of genomic occupancy for IRF4, BLIMP1, XBP1, and CTCF with histone marks identifies a dichotomy: XBP1 and IRF4 link to induced but not repressed gene modules in plasmablasts, whereas BLIMP1 links to modules of ABC genes that are repressed, but not to activated genes. Between ABC and plasmablast states, IRF4 shifts away from AP1/IRF composite elements while maintaining occupancy at IRF and ETS/IRF elements. This parallels the loss of BATF expression, which is identified as a potential BLIMP1 target. In plasmablasts, IRF4 acquires an association with CTCF, a feature maintained in plasma cell myeloma lines. Thus, shifting occupancy links IRF4 to both ABC and ASC gene expression, whereas BLIMP1 occupancy links to repression of the activation state.

scholarly journals A dichotomy in association of core transcription factors and gene regulation during the activated B-cell to plasmablast transition

2019 ◽  
Author(s):  
Mario Cocco ◽  
Matthew A Care ◽  
Muna Al-Maskari ◽  
Gina Doody ◽  
Reuben Tooze
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
B Cell ◽  
Cell Activation ◽  
B Cell Activation ◽  
Signal Loss ◽  
Antibody Secreting Cell ◽  
Er Stress Response ◽  
Gene Correlation ◽  
Time Courses

AbstractThe activated B-cell (ABC) to plasmablast transition is the cusp of antibody secreting cell (ASC) differentiation but is incompletely defined. We apply expression time-courses, parsimonious gene correlation network analysis, and ChIP-seq to explore this in human cells. The transition initiates with input signal loss leading within hours from cell growth dominant programs to enhanced proliferation, accompanied from 24h by ER-stress response, secretory optimization and upregulation of ASC features. Clustering of genomic occupancy for ASC transcription factors (TFs) IRF4, BLIMP1 and XBP1 with CTCF and histone marks defines distinct patterns for each factor in plasmablasts. Integrating TF-associated clusters and modular gene expression identifies a dichotomy: XBP1 and IRF4 significantly link to gene modules induced in plasmablasts, but not to modules of repressed genes, while BLIMP1 links to modules of ABC genes repressed in plasmablasts but is not significantly associated with modules induced in plasmablasts. Pharmacological inhibition of the G9A (EHMT2) histone-methytransferase, a BLIMP1 co-factor that catalyzes repressive H3K9me2 marks, leaves functional ASC differentiation intact but de-represses ABC-state genes. Thus, in human plasmablasts IRF4 and XBP1 emerge as the dominant association with ASC gene expression, while BLIMP1 links to repressed modules with particular focus in repression of the B-cell activation state.

Integrated Analysis Of Genomic and Gene Expression Profiles In Follicular Lymphoma Reveals Subsets and Driver Genes Of Potential Microenvironmental Importance

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2487-2487
Author(s):  
Ondrej Havranek ◽  
Jason R. Westin ◽  
Min Zhang ◽  
Seema Rawal ◽  
Larry W. Kwak ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cells ◽  
Copy Number ◽  
Integrated Analysis ◽  
Driver Genes ◽  
Gene Modules ◽  
Cell Fractions

Abstract Background The immune microenvironment in follicular lymphoma (FL) impacts its clinical course, but the interaction between FL cells and host immune cells is poorly understood, and may be influenced by large genetic abnormalities in FL cells. Regions of copy number variation (CNV) and copy-neutral loss of heterozygosity (cnLOH) are detectable by single nucleotide polymorphism (SNP) arrays and frequently found in FL, but the critical “driver genes” within them are largely unidentified. Methods Cell suspensions from tumor biopsies of 66 untreated FL patients were sorted into “B cell” and non-B fractions by immunomagnetic depletion targeting CD3 or CD19 and CD20 respectively. High-resolution Illumina Omni5 SNP arrays were used to profile genomic DNA from B cell fractions and germline DNA (from non-B fractions or peripheral blood cells). Nexus Copy Number software (BioDiscovery) compared paired profiles to determine tumor-specific CNV and cnLOH abnormalities of each patient. Genes within overlapping recurrently-altered regions were identified by the JISTIC algorithm (PMID: 20398270). For 43 of these patients, whole-genome gene expression profiling (GEP) of both fractions was done on Illumina HT12v4 arrays. CONEXIC module network analysis (PMID: 21129771) identified candidate driver genes, based on correlation of their expression in B-cell fractions with that of modules of genes in B-cell or non-B fractions. Results Comparing tumor vs. germline profiles in SNP array analysis clarified the detection of tumor-specific CNV, and enabled the detection of cnLOH. The aggregate genomic profile of regions affected by CNV in our 66 FL samples was highly similar to results of previous FL studies. Most frequent (each in 25-35% of samples) were deletions of 1p36 or a large part of 6q, amplifications of 1q, 7p/q, 12q, 17q, or 18p/q, and cnLOH at 16p. The distribution of these abnormalities suggested that FL can be divided into subgroups based on several large mutually-exclusive genomic aberrations: -10q, -16p, +12q, and, less clearly, -1p/1q+. Novel analysis combining copy number values with corresponding SNP frequencies also identified abnormalities of lower frequency within samples, suggestive of tumor subclones with potential growth advantages, notably including deletions at 13q14 and 19p12 and amplification of 16p13. JISTIC identified 715 expressed genes within amplified regions and 413 expressed genes within deleted regions (329 genes) or regions of cnLOH (84 genes). CONEXIC identified 62 and 68 of these genes as candidate drivers regulating expression of gene modules in tumor B cells and infiltrating immune cells, respectively. Several regulators of B-cell modules were already described in FL or other hematological malignancies: MDM2 (12q15, amplified in 26%), an E3 ubiquitin ligase whose targets include TP53; NME1 (17q21.33, amplified in 21%), part of the nucleoside diphosphate kinase complex, overexpressed and correlated with poor prognosis in AML; or B-cell receptor-associated CD79B (17q23.3, amplified in 21%), mutated and functionally significant in diffuse large B-cell lymphoma. Validating MDM2 as a driver gene, Gene Set Enrichment Analysis showed strong positive association between expression of MDM2 and that of proliferation signatures in B cells, including signatures of genes downregulated by TP53. Genes affecting the interaction between tumor B cells and the FL microenvironment plausibly regulate module expression in both B cells and non-B cells. Such dual candidate driver genes included PHIP (6q14.1, deleted in 27%), a binding partner of insulin receptor substrate-1, overexpressed in melanoma and linked to its metastasis and progression; SMARCC2 (12q13.2, amplified in 25%), part of the ATP-dependent chromatin remodeling complex SNF/SWI, mutated in some carcinomas; SFR1 (10q25.1, deleted in 18%), involved in DNA homologous recombination; and BUD31(7q22.1, amplified in 21%), a homolog of a yeast protein involved in pre-mRNA splicing. Conclusions CNV and cnLOH abnormalities are frequent in FL, and may identify subgroups within FL. Integrated analysis finds known candidate driver genes within recurrently-altered regions, appearing to regulate expression of gene modules in B cells. Novel candidate driver genes that appear to regulate modules in both B and non-B cells may shape the FL microenvironment in important ways, and are being investigated experimentally. Disclosures: No relevant conflicts of interest to declare.

scholarly journals EZH2 Represses the B Cell Transcriptional Program and Regulates Antibody-Secreting Cell Metabolism and Antibody Production

2017 ◽  
Vol 200 (3) ◽  
pp. 1039-1052 ◽  
Author(s):  
Muyao Guo ◽  
Madeline J. Price ◽  
Dillon G. Patterson ◽  
Benjamin G. Barwick ◽  
Robert R. Haines ◽  
...  
Keyword(s):  
B Cell ◽  
Antibody Production ◽  
Cell Metabolism ◽  
Transcriptional Program ◽  
Secreting Cell ◽  
Antibody Secreting Cell

scholarly journals Virus-Specific Antibody Secreting Cell, Memory B-cell, and Sero-Antibody Responses in the Human Influenza Challenge Model

2014 ◽  
Vol 209 (9) ◽  
pp. 1354-1361 ◽  
Author(s):  
Kuan-Ying Arthur Huang ◽  
Chris Ka-Fai Li ◽  
Elizabeth Clutterbuck ◽  
Cecilia Chui ◽  
Tom Wilkinson ◽  
...  
Keyword(s):  
B Cell ◽  
Specific Antibody ◽  
Antibody Responses ◽  
Human Influenza ◽  
Secreting Cell ◽  
Cell Memory ◽  
Memory B Cell ◽  
Antibody Secreting Cell ◽  
Virus Specific Antibody

Uniform Expression of Notch1, Suppressor of B-Cell–Specific Gene Expression, in Plasmablastic Lymphoma

2011 ◽  
Vol 135 (6) ◽  
pp. 770-775
Author(s):  
Adam C. Seegmiller ◽  
Huan-You Wang ◽  
Christa Hladik ◽  
Weina Chen
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Plasma Cell ◽  
Primary Effusion Lymphoma ◽  
Mtor Pathway ◽  
Plasmablastic Lymphoma ◽  
Cell Phenotype ◽  
Specific Gene ◽  
Plasma Cell Myeloma ◽  
Specific Gene Expression

Abstract Context.—Although the loss of B-lineage–specific gene expression is a distinctive feature of plasmablastic lymphoma, the underlying mechanism remains poorly understood. A candidate for this mechanism is Notch1 signaling, which interferes with the activity of B-cell–specific transcription factors E2A and early B-cell factor and positively regulates the mammalian target of rapamycin (mTOR) pathway. Objective.—To explore the mechanism of loss of B-cell phenotype by correlating expression of B-cell markers with that of Notch1 and downstream targets of the mTOR pathway in plasmablastic lymphoma. Design.—A combination of flow cytometric and immunohistochemical immunophenotyping techniques was used on 9 cases of plasmablastic lymphoma to correlate loss of B-cell markers with expression of Notch1 and downstream activation of the mTOR pathway. These results are compared with 5 cases of primary effusion lymphoma and 21 cases of plasma cell myeloma. Results.—Plasmablastic lymphoma cases exhibit nearly complete loss of B-cell–associated markers and uniform expression of Notch1, with a predominantly nuclear staining pattern. There is a concurrent activation of the mTOR pathway, indicated by expression of mTOR targets eukaryotic initiation factor 4E–binding protein 1 and phosphorylated ribosomal protein S6 in most cases. Similar results are seen in cases of primary effusion lymphoma and plasma cell myeloma. Conclusions.—These findings suggest that activation of Notch1 may be involved in suppression of B-cell–specific gene expression and global loss of the B-cell phenotype in plasmablastic lymphoma, similar to primary effusion lymphoma and plasma cell myeloma. Thus, there might be a role for the Notch1 and mTOR pathways in the pathogenesis and therapy of plasmablastic lymphoma.

scholarly journals Comparison of Memory B Cell, Antibody-Secreting Cell, and Plasma Antibody Responses in Young Children, Older Children, and Adults with Infection Caused by Vibrio cholerae O1 El Tor Ogawa in Bangladesh

2011 ◽  
Vol 18 (8) ◽  
pp. 1317-1325 ◽  
Author(s):  
Daniel T. Leung ◽  
Mohammad Arif Rahman ◽  
M. Mohasin ◽  
M. Asrafuzzaman Riyadh ◽  
Sweta M. Patel ◽  
...  
Keyword(s):  
Young Children ◽  
Immune Responses ◽  
B Cell ◽  
Protective Efficacy ◽  
Age Groups ◽  
Older Children ◽  
Secreting Cell ◽  
Content Type ◽  
Antibody Secreting Cell ◽  
Plasma Antibody

ABSTRACTChildren bear a large component of the global burden of cholera. Despite this, little is known about immune responses to cholera in children, especially those under 5 years of age. Cholera vaccine studies have demonstrated lower long-term protective efficacy in young children than in older children and adults. Memory B cell (MBC) responses may correlate with duration of protection following infection and vaccination. Here we report a comparison of immune responses in young children (3 to 5 years of age;n= 17), older children (6 to 17 years of age;n= 17), and adults (18 to 60 years of age;n= 68) hospitalized with cholera in Dhaka, Bangladesh. We found that young children had lower baseline vibriocidal antibody titers and higher fold increases in titer between day 2 and day 7 than adults. Young children had higher baseline IgG plasma antibody levels toVibrio choleraeantigens, although the magnitudes of responses at days 7 and 30 were similar across age groups. As a surrogate marker for mucosal immune responses, we assessed day 7 antibody-secreting cell (ASC) responses. These were comparable across age groups, although there was a trend for older age groups to have higher levels of lipopolysaccharide-specific IgA ASC responses. All age groups developed comparable MBC responses toV. choleraelipopolysaccharide and cholera toxin B subunit at day 30. These findings suggest that young children are able to mount robust vibriocidal, plasma antibody, ASC, and MBC responses againstV. choleraeO1, suggesting that under an optimal vaccination strategy, young children could achieve protective efficacy comparable to that induced in adults.

scholarly journals Spatiotemporal Analysis of B Cell- and Antibody Secreting Cell-Subsets in Human Melanoma Reveals Metastasis-, Tumor Stage-, and Age-Associated Dynamics

2021 ◽  
Vol 9 ◽  
Author(s):  
Minyi Chen ◽  
Franziska Werner ◽  
Christine Wagner ◽  
Martin Simon ◽  
Erika Richtig ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Spatiotemporal Analysis ◽  
Tumor Stage ◽  
Human Melanoma ◽  
Secreting Cell ◽  
Primary Tumors ◽  
Antibody Secreting Cell ◽  
Cell Subpopulations ◽  
Metastatic Sites

Background: The role of tumor-associated B cells in human cancer is only starting to emerge. B cells typically undergo a series of developmental changes in phenotype and function, however, data on the composition of the B cell population in human melanoma are largely absent including changes during tumor progression and their potential clinical significance.Methods: In this study, we compared the number and distribution of six major B cell and antibody secreting cell subpopulations outside tertiary lymphoid structures in whole tumor sections of 154 human cutaneous melanoma samples (53 primary tumors without subsequent metastasis, 44 primary tumors with metastasis, 57 metastatic samples) obtained by seven color multiplex immunohistochemistry and automated tissue imaging and analysis.Results: In primary melanomas, we observed the highest numbers for plasmablast-like, memory-like, and activated B cell subtypes. These cells showed a patchy, predominant paratumoral distribution at the invasive tumor-stroma margin. Plasma cell-like cells were hardly detected, germinal center- and transitional/regulatory-like B cells not at all. Of the major clinicopathologic prognostic factors for primary melanomas, metastasis was associated with decreased memory-like B cell numbers and a higher age associated with higher plasmablast-like cell numbers. When we compared the composition of B cell subpopulations in primary melanomas and metastatic samples, we found a significantly higher proportion of plasma cell-like cells at distant metastatic sites and a higher proportion of memory-like B cells at locoregional than distant metastatic sites. Both cell types were detected mainly in the para- and intratumoral stroma.Conclusion: These data provide a first comprehensive and comparative spatiotemporal analysis of major B cell and antibody secreting cell subpopulations in human melanoma and describe metastasis-, tumor stage-, and age-associated dynamics, an important premise for B cell-related biomarker and therapy studies.

scholarly journals Soluble Markers of Antibody Secreting Cell Function as Predictors of Infection Risk in Rheumatoid Arthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Maria J. Gutierrez ◽  
Stephen V. Desiderio ◽  
Nae-Yuh Wang ◽  
Erika Darrah ◽  
Laura Cappelli ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
B Cell ◽  
Serum Protein ◽  
Cell Function ◽  
Systemic Autoimmune Disease ◽  
Secreting Cell ◽  
Soluble Factors ◽  
Antibody Secreting Cell ◽  
Protein Levels ◽  
Increased Risk

Background. Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with immune dysregulation and increased risk of infections. The presence of autoantibodies and immunoglobulin abnormalities indicates B-cell and antibody-secreting cell (ASC) dysfunction. We hypothesize that soluble factors associated with B-cell and ASC activity are decreased in RA patients and that this is linked to higher susceptibility to infections.Methods. Using the Johns Hopkins Arthritis Cohort and Biorepository, we contrasted serum protein levels of soluble factors involved in B-cell activation (CD40, CD40L) and B-cell/ASC homing (CXCL10, CXCL11, and CXCL13) or survival (BAFF, APRIL, TACI, and BCMA) in 10 healthy subjects and 23 adult RA patients (aged 24-65 years). We subdivided RA patients into those with (n=17) and those without infections (n=6) within a 2-year period. In order to reduce the effect of RA treatment, we only included patients receiving methotrexate monotherapy or no RA treatments at baseline. Soluble serum protein levels of B-cell/ASC factors were quantified by multiplex immunoassays.Results. We identified that (1) serum levels of soluble BCMA, APRIL, CD40, and CD40L were significantly decreased in RA patients relative to healthy individuals; (2) serum soluble BCMA, predominantly released by ASC, correlated with serum concentrations of class-switched immunoglobulins, IgG and IgA; and (3) RA patients with a history of infections had significantly lower soluble BCMA levels compared with healthy donors and with RA patients without infections.Conclusions. Our study using soluble factors linked to B-cell/ASC activation and survival suggests that there is a paucity of ASC in a subset of RA patients and that this may be linked to altered antibody production and increased risk of infections. Further delineating the link between ASC and infection susceptibility in RA may optimize disease management and provide novel insights into disease pathogenesis that are susceptible to intervention.

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