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Project description:Background & Aims: The precise mechanism underlying the attenuation of the antigen-specific B cell response induced by therapeutic vaccination during chronic HBV infection remains unclear. The development of vaccines or strategies targeting this impediment through rational design could potentially result in significant advancements in the treatment of chronic hepatitis B. Methods: A mouse model with a knock-in of a B cell receptor specific to the hepatitis B virus surface antigen was generated under the name E6F6-B. This model was utilized to investigate the temporal and spatial patterns of humoral responses induced by therapeutic vaccination in the presence of persistent antigen stimulation. Through the use of multiple transcriptome sequencing techniques, the differentiation trajectory of HBsAg-specific B cells post therapeutic vaccination during chronic hepatitis B infection was elucidated. Results: In light of the E6F6-B transfer model, a significant reduction in antibody secreting cells were observed two weeks after vaccination. Additionally, an atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138-) was identified as a consequence of persistent BCR signaling in the absence of CD40 co-stimulation. A therapeutic antibody-induced suppression of BCR signaling revitalized the HBsAg-specific B cell response.
2024-04-28 | GSE230862 | GEO
Project description:Background & Aims: The precise mechanism underlying the attenuation of the antigen-specific B cell response induced by therapeutic vaccination during chronic HBV infection remains unclear. The development of vaccines or strategies targeting this impediment through rational design could potentially result in significant advancements in the treatment of chronic hepatitis B. Methods: A mouse model with a knock-in of a B cell receptor specific to the hepatitis B virus surface antigen was generated under the name E6F6-B. This model was utilized to investigate the temporal and spatial patterns of humoral responses induced by therapeutic vaccination in the presence of persistent antigen stimulation. Through the use of multiple transcriptome sequencing techniques, the differentiation trajectory of HBsAg-specific B cells post therapeutic vaccination during chronic hepatitis B infection was elucidated. Results: In light of the E6F6-B transfer model, a significant reduction in antibody secreting cells were observed two weeks after vaccination. Additionally, an atypical pre-plasma cell population (BLIMP-1+ IRF4+ CD40- CD138-) was identified as a consequence of persistent BCR signaling in the absence of CD40 co-stimulation. A therapeutic antibody-induced suppression of BCR signaling revitalized the HBsAg-specific B cell response.
2024-04-28 | GSE230861 | GEO
Project description:Therapeutic vaccine induced plasma cell differentiation is defective upon persistent HBsAg stimulation
| PRJNA962873 | ENA
Project description:Therapeutic vaccine induced plasma cell differentiation is defective upon persistent HBsAg stimulation [bulkRNA]
| PRJNA962879 | ENA
Project description:Therapeutic vaccine induced plasma cell differentiation is defective upon persistent HBsAg stimulation [scRNA]
| PRJNA962880 | ENA
Project description: Not available
| S-EPMC8279091 | biostudies-literature
Project description:Introduction: Upon BMP-2 stimulation, the osteoblastic lineage commitment in C2C12 myoblasts is associated with a microenvironmental change that occurs over several days. How does BMP-2 operate a switch in adhesive machinery to adapt to the new microenvironment and to drive bone cell fate is not well understood. Here, we addressed this question for BMP-2 delivered either in solution or physically bound of a biomimetic film, to mimic its presentation to cells via the extracellular matrix (ECM). Methods: Biommetics films were prepared using a recently developed automated method that enable high content studies of cellular processes. Comparative gene expressions were done using RNA sequencing from the encyclopedia of the regulatory elements (ENCODE). Gene expressions of transcription factors, beta chain (1, 3, 5) integrins and cadherins (M, N, and Cad11) were studied using quantitative PCR. ECM proteins and adhesion receptor expressions were also quantified by Western blots and dot blots. Their spatial organization in and around cells was studied using immuno-stainings. The individual effect of each receptor on osteogenic transcription factors and alkaline phosphatase expression were studied using silencing RNA of each integrin and cadherin receptor. The organization of fibronectin was studied using immuno-staining and quantitative microscopic analysis. Results: Our findings highlight a switch of integrin and cadherin expression during muscle to bone transdifferentiation upon BMP-2 stimulation. This switch occurs no matter the presentation mode, for BMP-2 presented in solution or via the biomimetic film. While C2C12 muscle cells express M-cadherin and Laminin-specific integrins, the BMP-2-induced transdifferentiation into bone cells is associated with an increase in the expression of cadherin-11 and collagen-specific integrins. Biomimetic films presenting matrix-bound BMP-2 enable the revelation of specific roles of the adhesive receptors depending on the transcription factor. Discussion: While β3 integrin and cadherin-11 work in concert to control early pSMAD1,5,9 signaling, β1 integrin and Cadherin-11 control RunX2, ALP activity and fibronectin organization around the cells. In contrast, while β1 integrin is also important for osterix transcriptional activity, Cadherin-11 and β5 integrin act as negative osterix regulators. In addition, β5 integrin negatively regulates RunX2. Our results show that biomimetic films can be used to delinate the specific events associated with BMP-2-mediated muscle to bone transdifferentiation. Our study reveals how integrins and cadherins work together, while exerting distinct functions to drive osteogenic programming. Different sets of integrins and cadherins have complementary mechanical roles during the time window of this transdifferentiation.
| S-EPMC9846056 | biostudies-literature
Project description:An HBsAg-HBIG therapeutic vaccine (Yeast-derived Immune Complexes, YIC) for chronic hepatitis B (CHB) patients has undergone a series of clinical trials. The HBeAg sero-conversion rate of YIC varied from 21.9% to 14% depending on the immunization protocols from 6 to 12 injections. To analyze the immunological mechanisms exerted by 6 injections of YIC, 44 CHB patients were separately immunized with YIC, alum as adjuvant control or normal saline as blank control, with add on of antiviral drug Adefovir in all groups. Kinetic increase in Th1 and Th2 cells CD4+ T cell sub-populations with association in decrease in Treg cells and increase of Tc1 and Tc17 cells in CD8+ T cells were observed in YIC immunized group. No such changes were found in the other groups. By multifunctional analysis of cytokine profiles, significant increase of IL-2 levels was observed, both in CD4+ and CD8+ T cells in the YIC immunized group, accompanied by increase in IFN-gamma and decrease of inhibitory factors (IL-10, TGF-? and Foxp3) in CD4+ T cells. In the alum immunized group, slight increase of IL-10, TGF-? and Foxp3 in CD4+ T cells was found after the second injection, but decreased after more injections, suggesting that alum induced early inflammatory responses to a certain extent. Similar patterns of responses of IL-17A and TNF-? in CD8+T cells were shown between YIC and the saline group. Results indicate that add on of Adefovir, did not affect host specific immune responses.
| S-EPMC5612521 | biostudies-literature
Project description:Interaction between T follicular helper (Tfh) cells and B cells is complex and involves various pathways, including the production of IL-21 by the Tfh cells. Secretion of IL-21 results in B cell differentiation toward immunoglobulin-producing plasmablasts. In patients after kidney transplantation, the formation of alloantibodies produced by donor antigen-activated B cells are a major cause of organ failure. In this allogeneic response, the role of IL-21-producing Tfh cells that regulate B cell differentiation is unknown. Here, we tested, in an alloantigen-driven setting, whether Tfh cell help signals control B cell differentiation with its dependency on IL-21. Pre-transplantation patient PBMCs were sorted into pure CD4posCXCR5pos Tfh cells and CD19posCD27pos memory B cells and stimulated with donor antigen in the presence or absence of an IL-21 receptor (IL-21R) antagonist (αIL-21R). Donor antigen stimulation initiated expression of the activation markers inducible co-stimulator (ICOS) and programmed death 1 (PD-1) on Tfh cells and a shift toward a mixed Tfh2 and Tfh17 phenotype. The memory B cells underwent class switch recombination and differentiated toward IgM- and IgG-producing plasmablasts. In the presence of αIL-21R, a dose-dependent inhibition of STAT3 phosphorylation was measured in both T and B cells. Blockade of the IL-21R did not have an effect on PD-1 and ICOS expression on Tfh cells but significantly inhibited B cell differentiation. The proportion of plasmablasts decreased by 78% in the presence of αIL-21R. Moreover, secreted IgM and IgG2 levels were significantly lower in the presence of αIL-21R. In conclusion, our results demonstrate that IL-21 produced by alloantigen-activated Tfh cells controls B cell differentiation toward antibody producing plasmablasts. The IL-21R might, therefore, be a useful target in organ transplantation to prevent antigen-driven immune responses leading to graft failure.
| S-EPMC5357809 | biostudies-literature
Project description:Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These 'recovering' TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for TEX cell-targeted immunotherapies.
| S-EPMC8323971 | biostudies-literature