A5063277741- Salivary Gland Disorders and Functions
- Acute Myeloid Leukemia Research
- Immune cells in cancer
- Salivary Gland Tumors Diagnosis and Treatment
- Oral Health Pathology and Treatment
- Venous Thromboembolism Diagnosis and Management
- Cancer, Hypoxia, and Metabolism
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Protein Degradation and Inhibitors
- Single-cell and spatial transcriptomics
- Ubiquitin and proteasome pathways
- Blood Coagulation and Thrombosis Mechanisms
- Cell Adhesion Molecules Research
- Atherosclerosis and Cardiovascular Diseases
- T-cell and B-cell Immunology
- Lymphatic System and Diseases
- Radiomics and Machine Learning in Medical Imaging
- Hematopoietic Stem Cell Transplantation
- Medical Imaging Techniques and Applications
- Immune Cell Function and Interaction
- Platelet Disorders and Treatments
- Immunotherapy and Immune Responses
- Inflammasome and immune disorders
- Peptidase Inhibition and Analysis
- Chemokine receptors and signaling
University of Birmingham
2015-2024
Queen Mary University of London
2020-2024
Institute of Cancer Research
2024
Cancer Institute (WIA)
2023
Queen Elizabeth Hospital Birmingham
2015-2022
Versus Arthritis
2020
NIHR Birmingham Biomedical Research Centre
2019
University Hospitals Birmingham NHS Foundation Trust
2019
Centre for Inflammation Research
2014-2018
Centro Hospitalar Tondela-Viseu
2018
Significance Ectopic clusters of immune cells that mimic the structure and function secondary lymphoid organs are defined as tertiary (TLOs). They have been observed at sites chronic inflammation for decades, but their formation remained enigmatic. TLOs thought to contribute disease pathogenesis by promoting autoreactive lymphocyte survival autoantibody production. In this study we identify a novel role cytokine IL-22 in TLO development biology. We provide evidence expression within is...
Significance TLS, which are clusters of lymphocytes and stromal cells observed at sites chronic inflammation, play a key role in sustaining disease progression autoimmune conditions. While the these structures has been studied extensively, fibroblasts, nonhematopoietic cells, formation maintenance TLS not demonstrated. Here, we establish that, establishment, resident fibroblasts expand acquire immunological features process that is dependent on IL13 IL22. Interference with this or depletion...
The paradigmatic hematopoietic tree model is increasingly recognized to be limited, as it based on heterogeneous populations largely defined by non-homeostatic assays testing cell fate potentials. Here, we combine persistent labeling with time-series single-cell RNA sequencing build a real-time, quantitative of in vivo tissue dynamics for murine bone marrow hematopoiesis. We couple cascading expression patterns dynamic changes differentiation and growth speeds. resulting explicit linkage...
The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation the m6A reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion compromises acute myeloid leukemia. Here we investigate long-term impact YTHDF2 deletion on HSC maintenance multilineage We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial...
Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations inhibitor ibrutinib block CLEC-2-mediated activation and phosphorylation including Syk PLCγ2 in human platelets. Activation is also blocked patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence Btk. contrast, response to GPVI delayed presence XLA, preserved. A similar set results seen second-generation inhibitor, acalabrutinib. The...
Background The phosphatidylinositol 3-kinase delta isoform (PI3Kδ) belongs to an intracellular lipid kinase family that regulate lymphocyte metabolism, survival, proliferation, apoptosis and migration has been successfully targeted in B-cell malignancies. Primary Sjögren’s syndrome (pSS) is a chronic immune-mediated inflammatory disease characterised by exocrine gland lymphocytic infiltration hyperactivation which results systemic manifestations, autoantibody production loss of glandular...
Abstract Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to lymphatic vascular network during TLS development have not studied. Using a viral-induced, resolving model of formation salivary glands adult mice we demonstrate that expansion is tightly regulated. Lymphatic vessel occurs two distinct phases. The first wave dependent on IL-7. second phase, responsible for leukocyte exit...
The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a well-characterised role in the metabolism and activation of endogenous glucocorticoids (GCs). However, despite its potent upregulation at sites inflammation, peripheral action therapeutic GCs remains poorly understood. We investigated contribution 11β-HSD1 to anti-inflammatory properties active GC corticosterone, administered doses murine models polyarthritis.Using tumour necrosis factor-tg K/BxN serum-induced...
The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche undefined. Here, we show fibroblastic reticular cells (FRCs) an component of the LN niche. Genetic ablation FRCs caused rapid loss macrophages monocytes from LNs across two in vivo models. Macrophages co-localized with human LNs, murine single-cell RNA-sequencing revealed FRC subsets broadly expressed master regulator CSF1. Functional...
SS is an autoimmune condition characterized by systemic B-cell activation, autoantibody production and ectopic germinal centres' formation within the salivary gland (SG). The extent of SG infiltrate has been proposed as a biomarker disease severity. Plasma levels CXCL13 correlate with activity in animal models severity SS, suggesting its potential use surrogate serum marker to monitor local activation. aim this study was evaluate role pathology two independent cohorts.109 patients were...
Abstract Identification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic patients' outcomes and, using clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) a therapeutic vulnerability AML models vitro vivo. Multiomic analysis demonstrates SCDi...
Abstract Atherosclerosis is a complex inflammatory disease characterized by the accumulation of lipids and immune cells in arterial wall, leading to narrowing stiffening blood vessels. The involvement both innate adaptive immunity pathogenesis human atherosclerosis increasingly recognised. However, spatial organization specific roles during various stages progression remain poorly understood, underscoring necessity for additional research elucidate their functions throughout course. A better...
Abstract Background: Head and neck cancer (HNC) encompasses a diverse group of malignancies originating from the mucosal surfaces upper aerodigestive tract. The tumor microenvironment (TME) in HNC is marked by immune cells, stromal extracellular matrix components. Hypoxia, key feature TME, drives growth, invasion, metastasis modulating gene expression related to angiogenesis, cell survival, metabolism. Understanding interplay between hypoxia infiltrates TME essential for developing new...
Abstract Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property this population, dependent on inducible T-cell co-stimulator ligand and its (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T inducing LTα3 production...
The commitment of stem and progenitor cells toward specific hematopoietic lineages is tightly controlled by a number transcription factors that regulate differentiation programs via the expression lineage restricting genes. Nuclear factor one (NFI) are important in regulating hematopoiesis here we report an physiological role NFIX B- myeloid differentiation. We demonstrate acts as regulator specification haematopoietic system Nfix was transcriptionally downregulated B commit differentiate,...
Abstract Deep vein thrombosis is a life-threatening development of blood clots in deep veins. Immobility and flow stagnancy are typical risk factors indicating that fluid dynamics play an important role the initiation venous clots. However, roles physical parameters valves conditions have not been fully understood. Here, we describe microfluidics vitro method enabled us to explore valve elasticity using situ fabrication characterisation. In our experimental model stiffness each leaflet can...
Platelets play a key role in the development, progression and resolution of inflammatory response during sterile inflammation infection, although mechanism is not well understood. Here we show that platelet CLEC-2 reduces tissue by regulating macrophage activation trafficking from inflamed tissues. The immune regulatory function depends on expression its ligand, podoplanin, upregulated macrophages independent secretion. Mechanistically, also recombinant CLEC-2-Fc accelerates actin...
BackgroundPlatelet endothelial aggregation receptor 1 (PEAR1) is a single-transmembrane orphan primarily expressed on platelets and cells. Genetic variants of PEAR1 have repeatedly independently been identified to be associated with cardiovascular diseases, including coronary artery disease.ObjectivesWe sulfated fucoidans their mimetics as ligands for proposed that its endogenous ligand proteoglycan. The aim this study was test hypothesis.MethodsA heparin proteoglycan-mimetic (HPGM) created...