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Gene Expression Profiles of CD21low B cells in Common Variable Immunodeficiency

ABSTRACT: The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. Since these circulating atypical B cells in the blood of CVID patients could not be assigned to any certain B cell differentiation stage in the periphery, they were designated as CD21low B cells. Although, CD21low B cells are polyclonal and unmutated IgM+IgD+ B cells like naive B cells in the peripheral blood, they reveal several distinct phenotypic and functional features. In order to uncover the the global programme of gene expression underlying these differences and changes in CD21low B cells we have performed microarray hybridization experiments and identified differentially expressed genes which define a distinct gene expression profile in CD21low B cells compared to naive B cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE17269 | GEO | 2009/07/30

SECONDARY ACCESSION(S): PRJNA119125

REPOSITORIES: GEO

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Gene Expression Profiles of CD21low B cells in Common Variable Immunodeficiency

Project description:The homeostasis of circulating B cell subsets in the peripheral blood of healthy adults is well regulated, but in disease it can be severely disturbed. Thus, a subgroup of patients with common variable immunodeficiency (CVID) presents with an extraordinary expansion of an unusual B cell population characterized by the low expression of CD21. Since these circulating atypical B cells in the blood of CVID patients could not be assigned to any certain B cell differentiation stage in the periphery, they were designated as CD21low B cells. Although, CD21low B cells are polyclonal and unmutated IgM+IgD+ B cells like naive B cells in the peripheral blood, they reveal several distinct phenotypic and functional features. In order to uncover the the global programme of gene expression underlying these differences and changes in CD21low B cells we have performed microarray hybridization experiments and identified differentially expressed genes which define a distinct gene expression profile in CD21low B cells compared to naive B cells. Leucocytes were separated by Ficoll gradient from peripheral blood of healthy donors (HD) and CVID patients. CD19+CD27-CD38+CD21+ naive B cells of HD as well as naive and CD19hiCD27-CD38lowCD21low (CD21low) B cells of CVID patients were sorted using a MoFlow cell sorter. RNA was extracted from sorted ex vivo B cell subpopulations and hybridized on Affymetrix microarrays. Gene expression profiles were compared between CD21low B cells and naive B cells of CVID patients as well as HD naive B cells.

2009-07-30 | E-GEOD-17269 | biostudies-arrayexpress

Identification of IVIg regulated genes in human peripheral blood monocytes from Common Variable Immunodeficiency patients (CVID) [CD14+]

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Complement receptor 2/CD21– human naive B cells contain mostly autoreactive unresponsive clones

Project description:Complement receptor 2–negative (CR2/CD21–) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21–/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21–/lo B cells in their blood. A majority of CD21–/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21–/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21–/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.

2009-12-01 | GSE13917 | GEO

IgM from common variable immunodeficiency patients narrowly recognizes erythrocyte and platelet glycans

Project description:Autoantibody-mediated cytopenias (AICs) regularly occur in profoundly IgG-deficient common variable immunodeficiency (CVID) patients. The isotypes, antigenic targets, and origin(s) of disease-causing autoantibodies in this patient population are unclear. Herein, we report that erythrocytes and platelets from CVID patients with AICs (CVID+AIC) are coated with autoreactive IgM. Glycan array-based analyses of CVID+AIC plasma IgM revealed narrow reactivities to erythrocytic I/i antigens and platelet expressed I/i antigen-related glycans but starkly lower binding to hundreds of other pathogen and tumor-associated carbohydrates. Polyclonal B-cell receptors with corresponding I/i antigen reactivities were highly enriched among CVID+AIC circulating marginal zone (MZ) B cells. Within secondary lymphoid tissues, MZ B cells secreted copious IgM when activated by IL-10 secreting FOXP3-CD25hiTfh cells. In lymph nodes from immunocompetent controls, MZ B cells localized outside of GCs near rare FOXP3-CD25+ cells and plentiful FOXP3+ regulatory T cells. In CVID+AIC lymph nodes, counterpart cells localized to similar anatomic positions but CD25hiTfh cells greatly outnumbered regulatory T cells. In total, our findings indicate glycan-reactive IgM autoantibodies produced outside of GC borders may contribute to the autoimmune pathogenesis of CVID.

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Deciphering imprints of impaired memory B-cell maturation in germinal centers of patients with Common variable immunodeficiency

Project description:Common variable immunodeficiency (CVID), characterized by recurrent infections, low serum class-switched immunoglobulin isotypes and poor antigen specific antibody responses, comprises a heterogeneous patient population in terms of clinical presentation and underlying etiology. The diagnosis is regularly associated with a severe decrease of germinal center (GC) derived B-cell populations in peripheral blood. However, data from B-cell differentiation within GC is limited. We present a multiplex approach combining histology, flow cytometry and B-cell receptor repertoire analysis of sorted GC B-cell populations allowing the modelling of distinct disturbances in GCs of three CVID patients. Our results reflect pathophysiological heterogeneity underlying the reduced circulating pool of post-GC memory B cells and plasmablasts in the three patients. In patient 1, quantitative and qualitative B-cell development in GCs is relatively normal. In patient 2, irregular shaped GCs are associated with reduced somatic hypermutation (SHM), antigen selection and class-switching, while in patient 3, high SHM, impaired antigen selection and class-switching with large single clones imply increased re-cycling of cells within the irregular shaped GCs. In lymph nodes of patients 2 and 3, only limited numbers of memory B cells and plasma cells are formed. While reduced numbers of circulating post GC B cells is a general phenomenon in CVID, the integrated approach exemplified distinct defects during GC maturation ranging from near normal morphology and function to severe disturbances with different facets of impaired maturation of memory B cells and/or plasma cells. Integrated dissection of disturbed GC B-cell maturation by histology, flowcytometry and BCR repertoire analysis reveals essential steps during memory formation.

2022-09-19 | GSE213361 | GEO

Comparisons of Nasal Polyp ASC, Nasal polyp IgD+ (naïve-like) B cells, and Blood naïve B cells

Project description:Here we investigate the transcriptional landscapes of nasal polyp IgD+ (naïve-like) B cells, nasal polyp ASC, and blood naïve B cells using RNA-seq. These data found that nasal polypP IgD+ naïve-like B cells are activated and similar to nasal polyp ASC and distinct from circulating B cells in the blood.

2021-05-20 | GSE174681 | GEO

Gastrointestinal symptoms and pathology in patients with Common variable immunodeficiency

Project description:Based on the findings of increased IEL in duodenal biopsies in CVID, an overlap with celiac disease has been suggested. In the present study, increased IEL, in particular in the pars descendens of the duodenum, was one of the most frequent histopathological finding. We therefore examined the gene expression profile in pars descendens of duodenum in CVID patients with increased IEL (n=13, IEL mean 34 [range 22-56] IEL/100 EC), CVID with normal levels of IEL (n=7), celiac disease (n=10, Marsh grade 3a or above) and healthy controls (n=17) by gene expression microarray GI histopathological findings in 53 CVID patients that underwent upper and lower endoscopic examination were addressed. For the microarray analysis 20 CVID (7 CVID_normal and 13 CVID with incresed IEL), 10 patients with celiac diseases and 17 healthy controls were included.

2015-09-02 | E-GEOD-72625 | biostudies-arrayexpress

Identification of IVIg regulated genes in human peripheral blood B cells by gene expression analysis before and after IVIg infusion in CVID patients [CD20]

Project description:Identification of IVIg regulated genes in human peripheral blood B cells by gene expression analysis before and after IVIg infusion in CVID patients

2022-05-03 | GSE158576 | GEO

Transcription profiling of human heumatoid arthritis or common variable immunodeficiency patients reveals defective receptor editing results in the appearance of anergic B cells in humans

Project description:B cell tolerance is established using deletion, anergy and receptor editing mediated by secondary recombination but it is unclear why autoreactive B cells choose a tolerance mechanism over another. We identified subgroups of patients with either rheumatoid arthritis or common variable immunodeficiency who presented defects in secondary recombination, which correlated with unusual CD21-/lo naïve B cells in their blood. CD21-/lo B cells were unable to induce calcium flux, get activated or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these B cells are anergic. Moreover, CD21-/lo B cells are often autoreactive and may express anti-nuclear antibodies. Thus, anergy can be a default tolerance mechanism mainly induced when receptor editing fails to silence developing autoreactive B cells. Experiment Overall Design: RNA was extracted from batch sorted CD19+CD21+CD10-CD27- and CD19+CD21-CD10-CD27- naïve B cells isolated from donors using the Absolutely RNA microprep kit (Stratagene). 100-200 ng of RNA was obtained per sample, and the quality of the purified RNA was assessed by the Bioanalyzer from Agilent. Using the Ovation biotin system kit from Nugen, 30-50ng of RNA was amplified and labeled to produce cDNA. Labeled cDNA was hybridized on chips containing the whole human genome (Human Genome U133 2.0 from Affymetrix). Data from CD21+ and CD21- B cell populations were compared in order to determine the gene signature of the newly described CD21- B cells.

2009-12-04 | E-GEOD-13917 | biostudies-arrayexpress

Role of IgD in B cell anergy

Project description:To define the global landscape of mRNA changes in anergic B cells, and how this affected by surface IgD, mature CD93-CD23+ HEL-binding B cells were sorted from spleens of independent transgenic mice of the following genotypes: MD4, naïve B cells coexpressing IgM and IgD; MD4:ML5, anergic B cells coexpressing IgM and IgD; MM4, naive B cells expressing only IgM; MM4:ML5, anergic B cells expressing only IgM; DD6, naive B cells expressing only IgD; DD6:ML5, anergic B cells expressing only IgD.

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