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T Cell Intrinsic Responses to TGFβ Regulates Allergen Sensitization By Modulating Type 2 T Follicular Helper Cell Development

ABSTRACT: Immunoglobulin E (IgE) is a potent mediator of allergic diseases, but the mechanisms that regulate IgE responses to innocuous environmental and food antigens remain unclear. Patients with Loeys-Dietz syndrome (LDS) who have mutations in genes encoding the TGFβ receptor are predisposed to IgE-mediated disorders. Here, using patient samples and a mouse model, we demonstrate that LDS mutations lead to reduced canonical TGFβ signaling, elevated total and allergen-specific IgE, increased type 2 follicular helper T cells (Tfh2), and exaggerated germinal center activity that was not prevented by the presence of wild type T regulatory cells. T cell intrinsic defects in LDS mice resulted in spontaneous sensitization to orally administered OVA, and inhibition of mammalian target of rapamycin (mTOR) prevented the exaggerated Tfh and IgE responses to OVA. Thus, TGFβ limits human and mouse Tfh2 cell development via the phosphatidylinositol-3-OH kinase gamma (PI3Kg)/AKT/mTOR pathway, and disruption of this pathway promotes allergic inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE203379 | GEO | 2023/08/01

REPOSITORIES: GEO

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T Cell Intrinsic Responses to TGFβ Regulates Allergen Sensitization By Modulating Type 2 T Follicular Helper Cell Development

Project description:Immunoglobulin E (IgE) is a potent mediator of allergic diseases, but the mechanisms that regulate IgE responses to innocuous environmental and food antigens remain unclear. Patients with Loeys-Dietz syndrome (LDS) who have mutations in genes encoding the TGFβ receptor are predisposed to IgE-mediated disorders. Here, using patient samples and a mouse model, we demonstrate that LDS mutations lead to reduced canonical TGFβ signaling, elevated total and allergen-specific IgE, increased type 2 follicular helper T cells (Tfh2), and exaggerated germinal center activity that was not prevented by the presence of wild type T regulatory cells. T cell intrinsic defects in LDS mice resulted in spontaneous sensitization to orally administered OVA, and inhibition of mammalian target of rapamycin (mTOR) prevented the exaggerated Tfh and IgE responses to OVA. Thus, TGFβ limits human and mouse Tfh2 cell development via the phosphatidylinositol-3-OH kinase gamma (PI3Kg)/AKT/mTOR pathway, and disruption of this pathway promotes allergic inflammation.

2023-08-01 | GSE202688 | GEO

Gene expression of LDS-OECs

Project description:The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor Î² (TGF-Î²) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. We investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS to gain further insight into the pathophysiology of the disorder. We performed gene expression profiling using microarray analysis followed by quantitative PCR for verification of gene expression. OECs isolated from age- and sex-matched healthy donors served as reference control. 3 OEC clones from different LDS patients were compared to their respective age- and sex-matched OEC clone isolated from healthy donors.

2013-06-27 | E-GEOD-38961 | biostudies-arrayexpress

Origins and diversity of pan-isotype human bone marrow plasma cells

Project description:Bone marrow plasma cells (BMPCs) produce durable, infection-resistant IgM, IgG, and IgA antibodies, but in some cases, pro-allergic IgE. Despite this, BMPC sources are unclear. We charted single BMPC transcriptional and clonal heterogeneity in peanut-allergic and non-allergic humans across CD19 protein expression—due to CD19’s inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional modules. Additionally, distributions of somatic hypermutation and intraclonal antibody sequence variance suggest CD19low and CD19high BMPCs arise from recalled memory and germinal center B cells, respectively. Most IgE BMPCs were from peanut-allergic individuals; some bound peanut and potently prevented peanut-driven anaphylaxis in a mouse model. These findings shed light on BMPC origins and identify the bone marrow as a likely source for long-lived pathogenic IgE in peanut allergy.

2024-05-01 | GSE262896 | GEO

Tomosyn is upregulated by IgE and functions as a PKC-regulated fusion clamp in mast cell degranulation

Project description:The regulation of soluble N ethylmaleimide sensitive factor attachment receptor (SNARE) mediated membrane fusion by upstream signaling events is poorly understood. Here we show that the SNARE binding protein tomosyn-1 negatively regulates type I IgE Fc receptor (FcRI) induced degranulation of mast cells. After FcRI stimulation, tomosyn-1 (also STXBP5) was phosphorylated on serine and threonine residues and dissociated from the SNARE protein syntaxin 4 (STX4), followed by association with syntaxin 3 (STX3). Protein kinase A (PKA) and protein kinase C (PKC) prevented these activities. We identified PKC as the major kinase required for tomosyn-1 threonine phosphorylation and for the regulation of the interaction with STXs. Incubation with high IgE concentrations induced tomosyn-1 expression in cultured mast cells. In basophils from allergic patients with normal total IgE serum titers tomosyn-1 expression was lower than in patients with high IgE titers who expressed tomosyn-1 to the same extent as non-allergic subjects. Our findings identified tomosyn-1 as a negative regulator of mast cell degranulation that required PKC to switch its interaction with STX partners during fusion. The IgE-mediated upregulation of tomosyn-1 in allergic patients may represent a counter-regulatory mechanism to limit disease development.

2018-07-04 | PXD010047 | Pride

Gene expression of LDS-OECs

Project description:The Loeys-Dietz syndrome (LDS) is an inherited connective tissue disorder caused by mutations in the transforming growth factor β (TGF-β) receptors TGFBR1 or TGFBR2. Most patients with LDS develop severe aortic aneurysms resulting in early need of surgical intervention. We investigated circulating outgrowth endothelial cells (OEC) from the peripheral blood of LDS to gain further insight into the pathophysiology of the disorder. We performed gene expression profiling using microarray analysis followed by quantitative PCR for verification of gene expression. OECs isolated from age- and sex-matched healthy donors served as reference control.

2013-06-27 | GSE38961 | GEO

Transcription profiling of mouse model of diesel enhanced allergic sensitization

Project description:Diesel exhaust (DE) has been shown to enhance allergic sensitization in animals following high dose instillation or chronic inhalation exposure scenarios. The purpose of this study was to determine if short term exposures to diluted DE enhance allergic immune responses to antigen, and identify possible mechanisms using microarray technology. BALB/c mice were exposed to filtered air or diluted DE to yield particle concentrations of 500 or 2000 Âµg/m3 4 hr/day on days 0-4. Mice were sensitized intranasally with ovalbumin (OVA) antigen or saline on days 0-2, and 18 and all were challenged with OVA on day 28. Mice were necropsied either 4 hrs after the last DE exposure on day 4, or 18, 48, and 96 hrs after challenge. Immunological endpoints included OVA-specific serum IgE, biochemical and cellular profiles of bronchoalveolar lavage (BAL), and cytokine production in the BAL. OVA-sensitized mice exposed to both concentrations of DE had increased eosinophils, neutrophils, lymphocytes, and IL-6 post-challenge compared to OVA control, while DE/saline exposure yielded increases in neutrophils at the high dose only. Microarray analysis demonstrated distinct gene expression profiles for the high dose DE/OVA and DE/saline groups. DE/OVA induced pathways involved in oxidative stress and metabolism while DE in the absence of allergen sensitization modulated cell cycle control, growth and differentiation, G-proteins, and cell adhesion pathways. This study shows for the first time early changes in gene expression induced by the combination of diesel exhaust inhalation and antigen sensitization, which resulted in stronger development of an allergic asthma phenotype. Experiment Overall Design: Lung RNA was isolated from mice exposed to filtered air, 500 ug/m3 DE, or 2000 ug/m3 DE with or without OVA for a total of 6 exposure groups. Each group had 4 replicates for a total of 24 microarrays.

2008-06-16 | E-GEOD-9383 | biostudies-arrayexpress

The impact of IgE in gut and serum metabolomes in a murine experimental model of allergic enteritis

Project description:The pathological mechanism of the gastrointestinal forms of food allergies is less understood in comparison to other clinical phenotypes, such as asthma, and anaphylaxis, partly due to difficulty in the access to intestinal tissues and because of a highly complex interplay between microbiota and intestinal mucosa. Importantly, a high level of IgE is a poor prognostic factor in gastrointestinal allergies. This study aimed to investigate how IgE influences the development of intestinal inflammation and the metabolome in allergic enteritis (AE), using IgE knock-in (IgEki) mice expressing high levels of IgE. Ovalbumin-sensitized and egg-white diet fed (OVA/EW) BALB/c WT mice developed moderate AE, whereas OVA/EW IgEki mice induced more aggravated intestinal inflammation with enhanced eosinophil accumulation.

2022-07-19 | ST002236 | MetabolomicsWorkbench

Next Generation Sequencing Facilitates Quantitative Analysis of TFH2 cell Transcriptomes

Project description:Emergence of IgE antibodies that bind allergens with high affinity is highly correlated with the severity of anaphylaxis. However, the underlying molecular mechanisms by which high-affinity IgE is generated remain poorly understood. We discovered that IL-13-producing T follicular helper (TFH) cells, which we designated as TFH2 cells, are generated from conventional TH2 cells by antigen sensitization. TFH2 cells have a unique cytokine profile (IL-4+IL-5-IL-13+IL-21+) and co-express the TFH and TH2 master transcriptional regulators, BCL-6 and GATA3.

2019-09-26 | GSE137970 | GEO

Distinct roles of FOXA2 and FOXA3 in allergic airway disease

Project description:Allergen challenge induced mucus metaplasia modify the expression of two transcription factors belonging to the FOXA family: FOXA2 and FOXA3. Foxa2 expression is decreased during allergic airway disease whereas, Foxa3 expression is increased by allergen. Therefore, we asked whether persistent expression of Foxa2 prevents mucus and whether absence of Foxa3 affects mucus or other features asociated with allergic airway disease. We analyzed the effects of these changes in FOXA transcription factor expression using Foxa2 transgenic mice and Foxa3-/- mice. We found that persistent expression of FOXA2 reduced mucus but the absence of FOXA3 had no effect on mucus production induced by allergen challenge. However, the absence of FOXA3 decreased airway hyperreactivity and increased IgE production and eosinophilic inflammation but none of these features were affected by persistent expression of FOXA2. These results indicate that FOXA3 has functions distinct from those of FOXA2 in the allergic response. Keywords: gene expression comparison between Foxa3-/- and littermate control mice both challenged with OVA DNA miocroarrays were used to analyze lung mRNA expression of Foxa3 KO and littermate control mice challenged with saline or OVA. The experiment incorporated a 1 color design and used Agilent arrays that contained roughly 44,000 60mer probes that provide complete coverage of the mouse genome. 11 arrays were hybridized and represent 3 lung samples for groups WT saline, WT OVA and KO OVA. There are 2 lung samples for the KO saline group.

2010-04-03 | E-GEOD-13382 | biostudies-arrayexpress

IgE-binding monocytes upregulate the coagulation cascade in allergic horses

Project description:IgE-binding monocytes are a rare peripheral immune cell type involved in the allergic response through binding of IgE on their surface. IgE-binding monocytes are present in both healthy and allergic individuals. We performed RNA sequencing to ask how the function of IgE-binding monocytes differs in the context of allergy. Using a large animal model of allergy, equine Culicoides hypersensitivity, we compared the transcriptome of IgE-binding monocytes in allergic and non-allergic horses at two seasonal timepoints: (i) when allergic animals were clinical healthy, in the winter “Remission Phase”, and (ii) during chronic disease, in the summer “Clinical Phase”. Most transcriptional differences between allergic and non-allergic horses occurred only during the “Remission Phase”, suggesting principal differences in monocyte function even in the absence of allergen exposure. F13A1, a subunit of fibrinoligase, was significantly upregulated at both timepoints in allergic horses. This suggested a role for increased fibrin deposition in the coagulation cascade to promote allergic inflammation. IgE-binding monocytes also downregulated CCR10 expression in allergic horses during the “Clinical Phase”, suggesting a defect in maintenance of skin homeostasis, which further promotes allergic inflammation. Together, this transcriptional analysis provides valuable clues into the mechanisms used by IgE-binding monocytes in allergic individuals.

2023-05-15 | GSE231427 | GEO

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