Ontology highlight
ABSTRACT:
PROVIDER: PRJNA857425 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20073486.fastq.gz | Fastqsanger.gz | |||
| SRR20073487.fastq.gz | Fastqsanger.gz | |||
| SRR20073488_1.fastq.gz | Fastqsanger.gz | |||
| SRR20073488_2.fastq.gz | Fastqsanger.gz | |||
| SRR20073489_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Immune responses in hemophilia A patients to replacement factor VIII can be either tolerogenic or immunogenic, the latter resulting in induction of non-neutralizing anti-factor VIII antibodies or neutralizing antibodies called inhibitors. Since these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them are of top priority in disease management. The extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) is an approved therapy for hemophilia A patients. In addition, it has been reported that rFVIIIFc can induce tolerance to FVIII in hemophilia A patients that have developed inhibitors. Given that the IgG1 Fc region has the potential to interact with immune cells expressing Fc receptors and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both Fc receptors and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages towards an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-Fc receptor interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc.
2018-11-20 | GSE118157 | GEO
Project description:We compared scRNA expression analysis of 3 populations of regulatory CD4+ T cells induced in oral tolerance to factor VIII in a mouse model of hemophilia: FoxP3+LAP-, FoxP3+LAP+, FoxP3-LAP+
2023-09-16 | GSE242919 | GEO
Project description:The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) remains the most serious complication in the treatment of hemophilia A. While immune tolerance induction (ITI) is the standard strategy to eliminate these antibodies, it fails in approximately 30% of patients with severe hemophilia A, underscoring the need for innovative approaches to promote FVIII-specific tolerance. To address this challenge, we generated fusion proteins composed of A2, A3-C1-C2 (light chain, LCh), and C2 domains of FVIII linked to Annexin A5 (AnxA5), a protein that binds phosphatidylserine (PS), a hallmark of apoptotic cells. ELISA confirmed high-affinity binding of all fusion proteins to immobilized PS. To model PS exposure in vitro, red blood cells (RBCs) were treated with phorbol 12-myristate 13-acetate (PMA), leading to the release of PS-exposing microvesicles. Flow cytometry showed that FVIII-AnxA5 fusion proteins selectively bound to PS-exposing microvesicles but not to intact RBCs. Using mass spectrometry-based immunopeptidomics, we demonstrated that macrophages pulsed with FVIII-AnxA5 fusion proteins efficiently processed and presented FVIII-derived peptides on HLA-DR molecules. These findings suggest that FVIII-AnxA5 fusion proteins can engage apoptotic cell clearance pathways to facilitate antigen presentation in a potentially tolerogenic context. This strategy may offer a novel means of inducing immune tolerance to FVIII in hemophilia A.
2025-10-20 | PXD068424 | Pride
Project description:Background: The main complication in hemophilia A treatment is the development of inhibitory antibodies against factor (F)VIII. Immune tolerance induction, the gold standard for eradicating anti-FVIII antibodies, is efficient in only 60% to 80% of cases. This underscores the need for more efficient induction of tolerance in patients with hemophilia A with FVIII inhibitors. Objectives: In this study, we explored whether red blood cells (RBCs) can be utilized as antigen delivery system to modulate the immune response against FVIII. Methods: Two promiscuously HLA-DR–presented peptides derived from the A2 and C1 domains of FVIII were fused to the TAT cell-penetrating peptide and incubated with RBCs. Results: Biotinylated TAT-A2 and TAT-C1 peptides were found to interact with RBCs as shown by flow cytometry and imaging flow cytometry. Moreover, macrophages efficiently phagocytosed TAT-FVIII peptide–treated RBCs. Using mass spectrometry– based immunopeptidomics we established that TAT-FVIII peptides were presented on major histocompatibility complex class II of macrophages that phagocytosed TAT peptide–pulsed RBCs. Specifically, the TAT-A2 peptide exhibited efficient processing and presentation on HLA-DR molecules. Importantly, incubation of TAT-C1 peptide– treated RBCs-loaded macrophages with a FVIII-specific T-cell hybridoma led to a significant increase in IL-2 production, suggesting functional presentation of TAT-C1– derived peptides by macrophages. Conclusion: Our findings indicate that RBCs can serve as effective vehicle for the delivery of FVIII-derived peptides to antigen-presenting cells. The successful display of T-cell epitopes on antigen-presenting cell using ex vivo–loaded RBC may be potentially utilized to modulate pathogenic immune responses such as observed in a subset of patients with hemophilia A.
2025-10-02 | PXD069058 | Pride
Project description:<p>Rare individuals are highly resistant to infection with human immunodeficiency virus (HIV). Studies of candidate genes resulted in the discovery of a 32bp deletion in the CC-chemokine receptor 5 gene (CCR5Δ32), which rendered this critical co-receptor for primary HIV infection to be non-functional. Pharmacologic and vaccine-induced blockade of CCR5 is being pursued to treat and prevent HIV infection and other conditions.</p> <p>The allele frequency of CCR5Δ32 among persons of European ancestry is approximately 10%. CCR5Δ32/Δ32 homozygotes are almost totally resistant to HIV infection. People with severe hemophilia A require frequent replacement with clotting Factor VIII (FVIII) to control hemorrhage. Prior to the discovery of HIV in 1984 and licensure of recombinant FVIII in the late 1980s, people with severe hemophilia A were treated with plasma-derived FVIII and thus were intensively exposed to HIV. Only 5% of such patients were not infected with HIV. Of these, approximately 1/3 were CCR5Δ32/Δ32 homozygotes. The remaining 2/3 of these people who were highly resistant to HIV remain unexplained. This project seeks to discover genome variations among people who are highly resistant to HIV infection. Such variation is likely to serve as a target for reducing the morbidity and incidence of HIV. </p>
| phs000445 | dbGaP
Project description:Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct a 140 kb int1h inversion frequently found in patients diagnosed with Hemophilia A. With the use of directed molecular evolution, we developed a linked heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from int1h patient derived iPSCs, resulted in prominent correction of the inversion and restored Factor VIII mRNA expression. Our data suggest that the development of designer-recombinases represent an efficient and specific mean towards treatment of large gene inversions causing monogenic diseases.
2021-12-31 | GSE159492 | GEO
Project description:Gut dysbiosis modulates the immune response to factor VIIII in murine hemophilia A
| PRJNA575698 | ENA
Project description:von Willebrand factor (VWF) is the protective carrier of procoagulant factor VIII (FVIII) in the shear forces of the circulation, prolonging its half‐life and delivering it to the developing thrombus. VWF∙FVIII complex formation is characterized by catch‐bond behavior in which force first decelerates then accelerates bond dissociation. Patients with mutations in VWF at the FVIII binding site phenocopies hemophilia A and the most common mutations involve cysteine residues of multiple disulfides. Thirteen VWF disulfide bonds at the FVIII binding site exist in formed and unformed states, and binding of FVIII results in partial formation of 12 of the VWF bonds. The VWF∙FVIII bond stiffens in response to force and this property is ablated when VWF disulfide bonds are prevented from forming, resulting in slip‐bond behavior. These findings demonstrate that FVIII binding to VWF involves dynamic changes in the covalent states of several VWF disulfides that are required for productive interaction.
2023-07-20 | PXD034866 | Pride
Project description:Recombinant and plasma-derived Factor VIII products induce distinct splenic cytokine microenvironments in hemophilia A
| PRJNA116721 | ENA
Project description:Hemophilia B, or the 'Royal Disease', arises from mutations in the Coagulation Factor IX (F9) gene. Mutations within the F9 promoter are associated with a remarkable form of the disease, termed Hemophilia B Leyden, in which symptoms ameliorate after puberty. Mutations at the -5/-6 site account for the majority of Leyden cases, and have been postulated to disrupt the binding of a transcriptional activator, the identity of which has remained elusive for more than twenty years. Here we show that the ONECUT transcription factors (ONECUT1/HNF6 and ONECUT2/HNF6B) bind to the -5/-6 site. The various Hemophilia B Leyden mutations that have been reported in this site inhibit ONECUT binding to varying degrees that correlate well with their associated clinical severities. In addition, expression of F9 is crucially dependent on ONECUT factors in vivo and as such, mice that are deficient in either ONECUT1, ONECUT2 or both, exhibit depleted levels of F9. Taken together, our findings establish the ONECUT transcription factors as the missing regulators of Hemophilia B Leyden that operate through the -5/-6 site.
2013-03-06 | E-MTAB-890 | biostudies-arrayexpress