Similar Datasets
Project description:CD11c+ atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single cell dataset. We identified CD11c+ B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation. Furthermore, ZEB2 haplo-insufficient Mowat Wilson syndrome (MWS) patients have decreased circulating ABCs in the blood. In Cd23Cre/+Zeb2fl/fl mice with impaired ABC formation, ABCs were dispensable for efficient humoral responses after Plasmodium sporozoite immunization but were required to control recrudescent blood-stage malaria. Immune phenotyping revealed that ABCs drive optimal T follicular helper (Tfh) cell formation and germinal center (GC) responses and they reside at the red/white pulp border likely permitting better access to pathogen antigens for presentation. Collectively, our study shows that ABC formation is dependent upon Zeb2, and these cells can limit recrudescent infection by sustaining GC reactions.
2024-02-09 | GSE213194 | GEO
Project description:CD11c+ atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single cell dataset. We identified CD11c+ B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation. Furthermore, ZEB2 haplo-insufficient Mowat Wilson syndrome (MWS) patients have decreased circulating ABCs in the blood. In Cd23Cre/+Zeb2fl/fl mice with impaired ABC formation, ABCs were dispensable for efficient humoral responses after Plasmodium sporozoite immunization but were required to control recrudescent blood-stage malaria. Immune phenotyping revealed that ABCs drive optimal T follicular helper (Tfh) cell formation and germinal center (GC) responses and they reside at the red/white pulp border likely permitting better access to pathogen antigens for presentation. Collectively, our study shows that ABC formation is dependent upon Zeb2, and these cells can limit recrudescent infection by sustaining GC reactions.
2024-02-09 | GSE213186 | GEO
Project description:Germinal centers (GC) are important sites for high-affinity and long-lived antibody induction. Tight regulation of GC responses is critical for maintaining self-tolerance. Here, we show that Galectin-3 (Gal-3) is involved in GC development. Compared with WT mice, Gal-3 KO mice have more GC B cells and T follicular helper cells, increased percentages of antibody-secreting cells and higher concentrations of immunoglobulins and IFN-? in serum, and develop a lupus-like disease. IFN-? blockade in Gal-3 KO mice reduces spontaneous GC formation, class-switch recombination, autoantibody production and renal pathology, demonstrating that IFN-? overproduction sustains autoimmunity. The results from chimeric mice show that intrinsic Gal-3 signaling in B cells controls spontaneous GC formation. Taken together, our data provide evidence that Gal-3 acts directly on B cells to regulate GC responses via IFN-? and implicate the potential of Gal-3 as a therapeutic target in autoimmunity.
| S-EPMC5915532 | biostudies-literature
Project description:Following infection or immunization, memory B cells (MBCs) and long-lived plasma cells provide humoral immunity that can last for decades. Most principles of MBC biology have been determined with hapten-protein carrier models or fluorescent protein immunizations. Here, we examine the temporal dynamics of the germinal center (GC) B cell and MBC response following mouse influenza A virus infection. We find that antiviral B cell responses within the lung-draining mediastinal lymph node (mLN) and the spleen are distinct in regard to duration, enrichment for antigen-binding cells, and class switching dynamics. While splenic GCs dissolve after 6 weeks post-infection, mLN hemagglutinin-specific (HA+) GCs can persist for 22 weeks. Persistent GCs continuously differentiate MBCs, with "peak" and "late" GCs contributing equal numbers of HA+ MBCs to the long-lived compartment. Our findings highlight critical aspects of persistent GC responses and MBC differentiation following respiratory virus infection with direct implications for developing effective vaccination strategies.
| S-EPMC7612942 | biostudies-literature
Project description:Antibodies are essential molecules for the defense of organisms against infections. Understanding the mechanisms by which B lymphocytes produce them is essential to enhance immune responses to infections and prevent the development of autoimmune diseases. Gal-3 appears as a molecule capable of regulating multiple biological functions, among them, influencing the immune response.
2018-03-08 | E-MTAB-6053 | biostudies-arrayexpress
Project description:Atypical Salmonella Enteritidis persistent infection
| PRJEB2566 | ENA
Project description:Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites.
| S-EPMC7062533 | biostudies-literature
Project description:Germinal centers (GCs) are the primary sites of clonal B cell expansion and affinity maturation, directing the production of high-affinity antibodies. This response is a central driver of pathogenesis in autoimmune diseases, such as systemic lupus erythematosus (SLE), but the natural history of autoreactive GCs remains unclear. Here, we present a novel mouse model where the presence of a single autoreactive B cell clone drives the TLR7-dependent activation, expansion, and differentiation of other autoreactive B cells in spontaneous GCs. Once tolerance was broken for one self-antigen, autoreactive GCs generated B cells targeting other self-antigens. GCs became independent of the initial clone and evolved toward dominance of individual clonal lineages, indicating affinity maturation. This process produced serum autoantibodies to a breadth of self-antigens, leading to antibody deposition in the kidneys. Our data provide insight into the maturation of the self-reactive B cell response, contextualizing the epitope spreading observed in autoimmune disease.
| S-EPMC5784431 | biostudies-literature
Project description:Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-alpha (IFN-alpha) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFN-alpha produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P(1) chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells.
| S-EPMC3249418 | biostudies-literature
Project description:Germinal centers (GCs) are sites of intense B cell proliferation and are central for T cell-dependent antibody responses. However, the role of c-Myc, a key cell-cycle regulator, in this process has been questioned. Here we identified c-Myc(+) B cell subpopulations in immature and mature GCs and found, by genetic ablation of Myc, that they had indispensable roles in the formation and maintenance of GCs. The identification of these functionally critical cellular subsets has implications for human B cell lymphomagenesis, which originates mostly from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the c-Myc(+) GC subpopulations may be at a particularly high risk for malignant transformation.
| S-EPMC4132664 | biostudies-literature