Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8
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ABSTRACT:
PROVIDER: PRJNA817174 | ENA |
REPOSITORIES: ENA
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Project description:DOCK8 is required for T cell-dependent gut IgA by maintaining plasma cell metabolic fitness
2024-01-10 | GSE198847 | GEO
Project description:Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer’s patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.
2022-07-13 | GSE160732 | GEO
Project description:Immunoglobulin A (IgA) is the most abundant antibody in the intestinal tract. Recent studies show that discrete subsets of gut human plasma cells (PCs) release IgA, which contributes to the maintenance of gut homeostasis. To better characterize the properties of these PC subsets, we performed global transcriptome analysis in naïve B cells as well as immature CD19+IgA+CD138- PCs, mature CD19+IgA+CD138+ PCs and late CD19-IgA+CD138+ PCs after their purification from human colon samples.
2020-03-29 | GSE141005 | GEO
Project description:Immunoglobulin A (IgA)-producing plasma cells derived from conventional B cells in the gut play an important role in maintaining the homeostasis of gut flora. Both T cell-dependent and T cell-independent IgA class switching occurs in the lymphoid structures in the gut, whose formation depends on lymphoid tissue inducers (LTis), a subset of innate lymphoid cells (ILCs). However, our knowledge on the functions of ILCs, the innate counter parts of CD4 T helper cells, in promoting IgA production is still limited. By cell adoptive transfer and utilizing a unique mouse strain, we demonstrated that the generation of IgA-producing plasma cells from B cells in the gut occurred efficiently in the absence of both T cells and ILCs and without engaging TGFβ signaling. Nevertheless, B cell recruitment and/or retention in the gut required NKp46-CCR6+ LTis. Therefore, while ILCs contribute to the accumulation of B cells in the gut through inducing lymphoid structure formation, they are not essential for the T cell-independent generation of IgA-producing plasma cells.
2021-06-28 | GSE167188 | GEO
Project description:Plasma cell gene expression is driven both by isotype and tissue location. In this series we examine gene expression of bone marrow IgA, IgM and IgG plasma cells as well as IgA plasma cells from small intestine lamina propria. To validate tissue specific gene expression we also include gene expression from lamina propria IgA-/- plasma cells. All plasma cell samples are from Blimp1+/GFP reporter animals and splenic follicular and marginal zone B cell gene expression have been added as reference populations.
2021-11-30 | GSE189410 | GEO
Project description:Krüppel-like factor 2 controls IgA plasma cell compartmentalization and IgA responses
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Project description:Gut-educated IgA-secreting plasma cells that disseminate beyond the mucosa and into systemic tissues can help prevent disease in several contexts. Here we show, the commensal bacteria Bacteroides fragilis (Bf), is an efficient inducer of systemic IgA responses. The generation of bone marrow IgA plasma cells and high levels of serum IgA specific to Bf requires robust intestinal colonization. Bf-specific IgA responses were severely diminished in mice lacking Peyer’s patches, but not mice lacking a cecal patch. Colonization resulted in few changes in the host transcriptional profile in the gut, suggesting a commensal relationship. High levels of Bf-specific serum IgA, but not IgG, provided protection from peritoneal abscess formation in a bowel perforation model of Bf dissemination. These findings demonstrate a critical role for bacterial colonization and Peyer’s patches in the induction of robust systemic IgA responses that confer protection from bacterial dissemination originating from the gut.
2024-07-25 | GSE272717 | GEO
Project description:In order to provide information on the peptide sequence of the IgA glycopeptides, a proteomics analysis was run on LC-MS/MS data of N-glycosidase F-digested IgA samples, in which the N-glycans had been released. The samples included IgA (isolated) from: 1) the saliva samples from two healthy donors, 2) a pooled-plasma standard from a minimum of 20 human donors (VisuCon-F Frozen Normal Control Plasma; Affinity Biologicals, Ancaster, Canada), 3) 10 μg of a human plasma-derived IgA standard (Lee Biosolutions, Maryland Heights, MO), and 4) a human colostrum-derived SIgA standard (Athens Research and Technology, Athens, GA).
2018-11-09 | PXD011228 | Pride
Project description:Background: DOCK8 deficiency is an autosomal recessive form of hyperimmunoglobulinemia E syndrome (HIES). Severe atopic dermatitis (AD) shares with DOCK8 deficiency some clinical symptoms, including eczema, eosinophilia, and increased serum IgE levels. The deficiency of DOCK8 protein is potentially a life-threatening autosomal recessive HIES and only curable with bone marrow transplantation. Despite identified metabolomics and cytokine biomarkers, novel proteomics biomarkers need to be identified, as the connecting networks are critical to our understanding of this disease. Hence we performed serum proteomics profiling using LC-MSE SynaptG2. Method: Label-free untargeted proteomics analysis was used to identify potentially reliable, sensitive, and specific protein biomarkers in serum collected from DOCK8 (n=10), AD (n=9) patients, which were compared to ctrls (n=5). Results: From a total of 275 quantifiable proteins, binary comparisons between AD vs. Ctrl, DOCK8 vs. Ctrl, and DOCK8 vs. AD revealed 109, 105 and 85 dysregulated proteins, respectively. 24 among 85 proteins were specific potential biomarkers among the DOCK8 and AD groups. The sensitivity and specificity of few proteins like Claspin, Immunoglobulin kappa and heavy, complement components as potential biomarkers to distinguish between DOCK8 and AD patients were evaluated using the receiver operating characteristic curve. DOCK8 deficiency and AD groups' profiling revealed a shared role of ERK1/2 among the commonly dysregulated proteins. Conclusion: In this study, we have identified potential proteomics biomarkers and profile to distinguish between DOCK8 and AD, with possible diagnostic and therapeutic applications to help create effective interventions for managing these diseases. Further studies to confirm these associations in prospective cohorts are warranted.
2022-05-17 | PXD029052 | Pride
Project description:T follicular helper (Tfh) cell migration into germinal centers (GC) is essential for the generation of GC B cells and antibody responses to T dependent (TD) antigens. This process requires interactions between LFA-1 on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells have impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they develop normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8 deficient T cells into GCs is defective. Following TCR/CD3 ligation, DOCK8 deficient T cells have impaired LFA-1 activation and reduced binding to ICAM-1. DOCK8 is important for LFA1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.
2020-07-23 | GSE154897 | GEO