A5051662657- Immune Cell Function and Interaction
- Asthma and respiratory diseases
- T-cell and B-cell Immunology
- Cytokine Signaling Pathways and Interactions
- Epigenetics and DNA Methylation
- IL-33, ST2, and ILC Pathways
- Estrogen and related hormone effects
- Immune Response and Inflammation
- Adrenal Hormones and Disorders
- Complement system in diseases
- NF-κB Signaling Pathways
- Receptor Mechanisms and Signaling
- Stress Responses and Cortisol
- Vitamin D Research Studies
- MicroRNA in disease regulation
- Hormonal Regulation and Hypertension
- Renin-Angiotensin System Studies
- Kruppel-like factors research
- RNA Interference and Gene Delivery
- Protein Degradation and Inhibitors
- Retinoids in leukemia and cellular processes
- Ion channel regulation and function
- Cancer-related molecular mechanisms research
- Regulation of Appetite and Obesity
- Cancer-related gene regulation
King's College London
2016-2025
Asthma UK
2015-2025
Guy's Hospital
2007-2022
Van Andel Institute
2022
Medical Research Council
2007-2018
Guy's and St Thomas' NHS Foundation Trust
2018
King's College - North Carolina
2016
ENT and Allergy
2000-2011
St Thomas' Hospital
2004
The Gurdon Institute
1996-1999
We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence dexamethasone and calcitriol (vitamin D3). now show following stimulation by allergen, IL-10-secreting inhibit cytokine secretion allergen-specific Th2 cells an IL-10-dependent manner. A proportion patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, their is characterized as resistant (SR, abbreviation derived from "steroid resistant")....
The renin-angiotensin system is a powerful pressor with major influence on salt and water homeostasis. Angiotensinogen (also called renin substrate) key component of this system; it cleaved by to yield angiotensin I, which then angiotensin-converting enzyme II. observation that plasma angiotensinogen levels correlate blood pressure track through families suggests may have role in essential hypertension. We therefore investigated whether there linkage between the gene chromosome 1q42-43
Expansion and acquisition of Th1 cell effector function requires metabolic reprogramming; however, the signals instructing these adaptations remain poorly defined. Here we found that in activated human T cells, autocrine stimulation complement receptor CD46, specifically its intracellular domain CYT-1, was required for induction amino acid (AA) transporter LAT1 enhanced expression glucose GLUT1. Furthermore, CD46 activation simultaneously drove LAMTOR5, which mediated assembly AA-sensing...
The renin-angiotensin system regulates blood pressure and sodium balance. angiotensinogen gene which encodes the key substrate within this has been linked to essential hypertension in White Europeans. It suggested that people of West African ancestry may have a different genetic basis for hypertension. In study we tested whether there is linkage Caribbeans from St. Vincent Grenadines. DNA 63 affected sibling pairs with was by analyzing excess allele sharing among siblings genotyped using an...
Phenotypic modulation of airway smooth muscle (ASM) is an important feature remodeling in asthma that characterized by enhanced proliferation and secretion pro-inflammatory chemokines. These activities are regulated the concentration free Ca(2+) cytosol ([Ca(2+)](i)). A rise [Ca(2+)](i) normalized rapid reuptake into sarcoplasmic reticulum (SR) stores sarco/endoplasmic (SERCA) pump. We examined whether increased proliferative secretory responses ASM from asthmatics result reduced SERCA...
Abstract The mechanisms controlling CD4 + T cell switching from an effector to anti-inflammatory (IL-10 ) phenotype play important role in the persistence of chronic inflammatory diseases. Here, we identify cholesterol biosynthesis pathway as a key regulator this process. Pathway analysis cultured cytokine-producing human cells reveals significant association between IL-10 and metabolism gene expression. Inhibition with atorvastatin or 25-hydroxycholesterol during IFNγ shows specific block...
Abstract The induction of human CD4 + Th1 cells requires autocrine stimulation the complement receptor CD46 in direct crosstalk with a T cell-intrinsic NLRP3 inflammasome. However, it is unclear whether cytotoxic CD8 cell (CTL) responses also rely on an intrinsic complement-inflammasome axis. Here we show, using CTLs from patients deficiency or constitutively-active NLRP3, that delivers co-stimulatory signals for optimal CTL activity by augmenting nutrient-influx and fatty acid synthesis....
Sepsis is life-threatening organ dysfunction due to dysregulated host responses infection. Current knowledge of human B-cell alterations in sepsis sparse. We tested the hypothesis that loss involves distinct subpopulations B cells and investigated mechanisms depletion.Prospective cohort study.Critical care units.Adult patients without any documented immune comorbidity.None.B-cell subsets were quantified by flow cytometry; annexin-V status identified apoptotic phosphorylation intracellular...
Using Northern blotting with a human genomic DNA probe for the pro-opiomelanocortin (POMC) gene, we have shown specific mRNA in normal peripheral mononuclear cells (PBMC); presence of was also observed T lymphocyte cell line derived from patient lymphoma. We then demonstrated that PBMC translate message into protein. Thus, using radioimmunoassay an antibody ACTH, median 29 pg ACTH-like immunoreactivity (ACTH-LIR) found 10(7) PBMC. ACTH-LIR detected seven different lines patients lymphoid and...
The glucocorticoid receptor (GR) is a hormone-inducible transcription factor which activates of specific genes by binding to DNA sequence present in the promoters inducible genes. These response elements (GREs) have conserved palindromic sequence. Each half-GRE palindrome binds one subunit GR. We assessed relative affinity GR monomers and homodimers for GRE determined whether homodimer formation rate-limiting high binding. vitro was approximately 2 x 10(-10) M, whereas it 1 nM monomers....
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition neutrophils. While a pathological effect on neutrophils acknowledged, impact ANCA monocyte function less well understood. Using IgG from patients we investigated these found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 IL-6 secretion response LPS. This reduction depended Fc receptors enzymatic was...
An alternatively spliced transcript of the human insulin-like growth factor-I (IGF-I) gene is described. The was identified in liver RNA by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. It contained IGF-I exons 3 4, 49 basepairs exon 5, then 6 (exon 4-5-6). 5'-donor site at 5-6 junction a cryptic splice (IGF633). 3'-acceptor usual intron-exon junction. A second pair primers across 5-exon used to confirm presence reaction. Cloning sequencing this fragment confirmed...
SUMMARY Accurate differential diagnosis of the precise cause Cushing's syndrome can be difficult, and conventional tests such as those based on use dexamethasone may misleading. We have therefore studied cortisol ACTH responses to ovine corticotrophin‐releasing factor (CRF‐41) in 28 consecutive patients with syndrome, compared diagnostic value this test that high‐dose suppression (8 mg/day for 48 h). Of 20 confirmed disease (pituitary‐dependent syndrome), only 16 (80%) showed expected 50% or...
Greater clinical benefit in controlling the symptoms of asthma is frequently observed through combining moderate doses inhaled glucocorticoids together with long-acting beta(2)-agonists, as compared increasing glucocorticoid dosage alone. To address vitro whether plus alone, have greater inhibitory activity on CD4+ T cell responses to allergen, peripheral blood allergen were presence or absence fluticasone proprionate and short- beta(2)-agonists salbutamol salmeterol, respectively....
Highlights•Th1 genes and Th2 are associated with RNA pol II in the alternative lineage•T-bet acts to recruit Mediator SEC activate Th1 eRNAs•T-bet NF-κB-dependent P-TEFb recruitment pathways converge at enhancers•P-TEFb inhibition silences T-bet target abrogates uveitis vivoSummaryThe transcription factor directs cell differentiation, but molecular mechanisms that underlie this lineage-specific gene regulation not completely understood. Here, we show through enhancers allow of form super...