Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

STAT3 binding to DNA in wildtype vs B cell specific STAT3 knockout mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE120022 | GEO | 2018/11/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

A mouse model of HIES reveals pro and anti-inflammatory functions of STAT3

Project description:Mutations of STAT3 underlie the autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). STAT3 has critical roles in immune cells and thus, hematopoietic stem cell transplantation (HSCT), might be a reasonable therapeutic strategy in this disease. However, STAT3 also has critical functions in non-hematopoietic cells and dissecting the protean roles of STAT3 is limited by the lethality associated with germline deletion of Stat3. Thus, predicting the efficacy of HSCT for HIES is difficult. To begin to dissect the importance of STAT3 in hematopoietic and non-hematopoietic cells as it relates to HIES, we generated a mouse model of this disease. We found that these transgenic mice recapitulate multiple aspects of HIES, including elevated serum IgE and failure to generate Th17 cells. We found that these mice were susceptible to bacterial infection that was partially corrected by HSCT using wild type bone marrow, emphasizing the role played by the epithelium in the pathophysiology of HIES. The effect of IL-6 and IL-10 on BM-DC gene expression was investigated in cell derived from wild type or mut-Stat3 mice

2014-03-06 | E-GEOD-55607 | biostudies-arrayexpress

Expression data from IgE+ and IgG1+ B lymphocytes in mice infected with Nippostrongylus brasiliensis

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

A mouse model of HIES reveals pro and anti-inflammatory functions of STAT3

2014-03-06 | GSE55607 | GEO

ZNF341 controls STAT3 expression and thereby immunocompetence

Project description:Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wildtype-ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindred. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

2018-05-02 | GSE107719 | GEO

Single-cell multi-omics sequencing reveals the functional regulatory landscape of STAT3-V637M Hyper-IgE syndrome

Project description:Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by, among others, the excessive production of IgE and repetitive bacterial/fungal infections. Although STAT3 is a known causative factor of HIES, the biological consequences of STAT3 mutation are not completely understood, especially at the epigenetic level. Here, we used multi-omic approaches to decipher the multidimensional immune disturbance in a male HIES patient harboring STAT3-V637M. In his peripheral blood mononuclear cell (PBMC) we found significant clonal expansion of CD8 T cells (whose expression of CD8 subunits was increased, resulting in enhanced responsiveness to MHC I molecules), but not CD4 T cells and B cells in his. The lack of T cells-B cells interaction could be responsible for the limited number of his B cells, although they exhibited a higher potential in producing immunoglobulin, elevated SPIC binding might bias this process toward IgE isotype production. Immune checkpoint inhibitors, including CTLA4, LAG3, were overexpressed in his PBMC-CD4 T cells, accompanied by reduced CD28 and IL6ST (gp130) expression. For his CD4 T cells, integrative analyses predicted upstream transcription factors (ETV6, KLF13, and RORA) for LAG3, IL6ST, and CD28, respectively. The down-regulated phagocytic, and nitric oxide synthetic genes in his PBMC-monocytes seem to be the culprit of his disseminated bacterial/fungal infection. In his bronchoalveolar lavage fluid (BALF), we identified two macrophages with anti-bacterial properties, which were characterized by CXCL8/S100A8/S100A9, or SOD2, respectively. Together, this study comprehensively described how the immune cell landscape was disturbed in STAT3-V637M HIES and provided a resource for further studies on STAT3 biology.

2023-09-07 | GSE212479 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of mRNA expression of STAT3 deficiency skin

Project description:Dominant-negative mutations of signal transducer and activator of transcription 3 (STAT3) signaling which controls epithelial proliferation in various tissues, leads to atopic dermatitis (AD) in hyper IgE syndrome (HIES). We found that the STAT3 signaling in keratinocytes is required to maintain skin homeostasis through this transcriptome analysis.

2021-10-15 | GSE185585 | GEO

Human ZNF341 deficiency underlies a recessive form of hyper IgE syndrome by disrupting STAT3 transcription-dependent STAT3 activity

Project description:Heterozygosity for human STAT3 dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-IgE syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341. ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including, most notably the STAT3 promoter. The patients’ cells have low basal levels of STAT3 mRNA and protein. The auto-induction of STAT3 production, activation, and function by STAT3-activating cytokines is particularly strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack Th17 cells, have an excess of Th2 cells, and low memory B cells, due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341-dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent auto-induction and sustained activity of STAT3.

2018-06-04 | GSE113945 | GEO

A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

Project description:Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hy- per IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in re- cipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous pa- tients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when over- expressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phos- phorylation, DNA binding, and transcriptional activity. In immor- talized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding muta- tions, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequenc- ing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

2020-04-30 | GSE149602 | GEO

Transcriptome analysis of mouse IgG1 memory B cell subsets

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

A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

2018-05-30 | GSE113194 | GEO