A5102750867- IL-33, ST2, and ILC Pathways
- Eosinophilic Esophagitis
- Dermatology and Skin Diseases
- Immune Cell Function and Interaction
- Asthma and respiratory diseases
- Allergic Rhinitis and Sensitization
- Malaria Research and Control
- Viral Infections and Vectors
- Mosquito-borne diseases and control
- Food Allergy and Anaphylaxis Research
- Immunotherapy and Immune Responses
- Lymphoma Diagnosis and Treatment
- Psoriasis: Treatment and Pathogenesis
- T-cell and Retrovirus Studies
- Mast cells and histamine
- Cutaneous lymphoproliferative disorders research
- T-cell and B-cell Immunology
- Toxin Mechanisms and Immunotoxins
- Contact Dermatitis and Allergies
- melanin and skin pigmentation
- Pediatric health and respiratory diseases
- Vibrio bacteria research studies
- Healthcare and Venom Research
- Immune Response and Inflammation
University of Oxford
2013-2024
MRC Weatherall Institute of Molecular Medicine
2022-2024
MRC Human Immunology Unit
2011-2022
Medical Research Council
2013-2019
National Institute for Health Research
2013-2019
John Radcliffe Hospital
2011-2018
Oxford BioMedica (United Kingdom)
2015
Institute of Molecular Medicine
2012-2015
Type 2 innate lymphoid cells (ILC2s, nuocytes, NHC) require RORA and GATA3 for their development. We show that human ILC2s express skin homing receptors infiltrate the after allergen challenge, where they produce type cytokines IL-5 IL-13. Skin-derived IL-33 receptor ST2, which is up-regulated during activation, are enriched in lesional biopsies from atopic patients. Signaling via induces cytokine amphiregulin expression, increases ILC2 migration. Furthermore, we demonstrate E-cadherin...
BackgroundActivation of the group 2 innate lymphoid cell (ILC2) population leads to production classical type cytokines, thus promoting immunity. Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2), is by human ILC2s. However, function CRTH2 in these unclear.ObjectivesWe sought determine role PGD2 and ILC2s compare it with that established ILC2 activators IL-25 IL-33.MethodsThe effects PGD2, IL-25, IL-33 migration, cytokine...
Psoriasis is a chronic inflammatory skin disease associated with T helper 17 response. Yet, it has proved challenging to identify relevant peptide-based cell antigens. Antigen-presenting Langerhans cells show differential migration phenotype in psoriatic lesions and express constitutively high levels of CD1a, which presents lipid antigens cells. In addition, phospholipase A2 (PLA2) highly expressed known generate neolipid for recognition by CD1a-reactive this study, we observed expression...
Atopic eczema and psoriasis are common skin diseases. While it is well established that the pathogenesis of these diseases varies, both characterized by impairment in epidermal barrier function abnormal IL-17 expression peripheral blood. Recent findings indicated filaggrin essential during formation its insufficiency underlies atopic eczema. Filaggrin downregulation has also been reported psoriasis. It clear Th1/Th2 bias influences protein, but an analysis effects interleukin-17 (IL-17) on...
The identification of filaggrin mutations has contributed towards our understanding hereditary factors associated with epidermal dysfunction observed in individuals atopic eczema (AE). However, that predispose to acquired modulation are not well understood. Interleukin (IL)-22 is upregulated lesional AE tissue, but its effects on expression and genes function have yet been comprehensively addressed.To investigate the IL-22 encoding proteins relevant function.Microarray analysis was performed...
Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development a phenomenon known as the atopic march. Although genetic and environmental factors are contribute AD asthma, mechanisms underlying march remain poorly understood. Filaggrin loss-of-function mutations major predisposer for of progression AD-associated asthma.We sought experimentally address whether filaggrin mice lead spontaneous eczematous inflammation aberrant...
BackgroundGroup 2 innate lymphoid cells (ILC2s) are a potential source of type cytokines in the pathogenesis allergic conditions. Epithelial (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) mast cell mediators (prostaglandin D2 [PGD2]) critical activators ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C4, LTD4, LTE4, metabolites arachidonic acid mediate inflammatory responses. Their role human ILC2s is still poorly understood.ObjectivesWe sought to determine cysLTs...
Venoms frequently co-opt host immune responses, so study of their mode action can provide insight into novel inflammatory pathways. Using bee and wasp venom responses as a model system, we investigated whether venoms contain CD1-presented antigens. Here, show that activate human T cells via CD1a proteins. Whereas CD1 proteins typically present lipids, chromatographic separation unexpectedly showed stimulatory factors partition protein-containing fractions. This finding was explained by...
Innate lymphoid cells (ILC) are part of a heterogeneous family haematopoietic effector which lack re-arranged antigen-specific receptors. They promote host defense and contribute to tissue metabolic homeostasis, wound healing immune surveillance. Their role in human cancer immunity is less defined, therefore we aimed identify the frequency phenotype distinct ILC groups various types cancer.Tissue samples peripheral blood were collected from patients undergoing surgical resection...
Lack of the skin barrier protein filaggrin worsens atopic dermatitis by allergenic activation CD1a-reactive T cells.
The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and immune factors. Existing published data are not consistent, in part related relatively small sample sizes. We set out determine possible associations virus (DEN-V) NS3 specific T cells cytokine chemokine levels pathogenesis severe disease large cohort individuals with DHF.By using ex vivo IFNγ ELISpot assays we determined DENV-NS3 responses patients varying...
Several studies have shown that serum IL-10, IFNγ and MIF are elevated in patients severe dengue (SD) could be used as potential biomarkers. We proceeded to determine if these cytokines biomarkers a large cohort of adult with varying severity infection.Serum IL-10 levels were determined 259 whom 40 had infection. Serum IFNα done 78 65 acute Clinical features laboratory investigations undertaken during the febrile critical phase.We found significantly higher (p = 0.001) SD, when compared...
Abstract Group 2 innate lymphoid cells (ILC2) are important in effector functions for eliciting allergic inflammation, parasite defense, epithelial repair, and lipid homeostasis. ILC2 lack rearranged Ag-specific receptors, although many soluble factors such as cytokines mediators can influence ILC2, direct interaction of these with the microenvironment other has been less explored. Natural cytotoxicity receptors expressed by subsets group 1 ILC 3 thought to be their function, but they have...
Human skin–derived ILC2 express CD1a and present endogenous PLA2G4A-dependent antigens to T cells.
BackgroundProstaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 cysLTs (notably leukotriene E4 [LTE4]) enhances cytokine production. However, the synergistic interaction with in promoting cell activation is still poorly understood. receptors for these drug targets treatment allergic diseases, hence understanding their likely to have clinical implications.ObjectiveWe aimed comprehensively...
Background Elevated IL-10 has been shown to be associated with severe dengue infection (DI). We proceeded investigate the role of in pathogenesis acute DI. Materials and methods Ex vivo cultured IFNγ ELISpot assays for virus (DENV) NS3 protein non viral proteins were carried out 26 patients DI (16 haemorrhagic fever) 12 healthy seropositive individuals from Sri Lanka. DENV serotype specific (SS) responses determined by using a panel SS peptides. Results Serum level significantly higher (p =...
Summary Both dengue NS1 antigen and serum interleukin (IL)-10 levels have been shown to associate with severe clinical disease in acute infection, IL-10 has also suppress dengue-specific T cell responses. Therefore, we proceeded investigate the mechanisms by which contributes pathogenesis if it is associated altered production. Serum were assessed serially 36 adult Sri Lankan individuals infection. We found that correlated positively (Spearman's r = 0·47, P < 0·0001), annexin V...
Human type-2 CD8+ T cells are a cell population with potentially important roles in allergic disease. We investigated this the context of severe asthma persistent airway eosinophilia—a phenotype associated high exacerbation risk and responsiveness to cytokine-targeted therapies. In two independent cohorts we show that, contrast Th2 cells, cytokine-secreting CD8+CRTH2+ (Tc2) enriched blood airways eosinophilic asthma. Concentrations prostaglandin D2 (PGD2) cysteinyl leukotriene E4 (LTE4) also...
Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) and are traditionally defined as being BDCA-2+CD123+. pDCs not readily detectable in healthy human skin, but have been suggested to accumulate wounds. Here, we describe a CD1a-bearing BDCA-2+CD123int DC subset that rapidly infiltrates skin wounds comprises major population. Using single-cell RNA sequencing, show these largely activated DCs acquiring features compatible with lymph node homing antigen presentation,...
Abstract Mast cell products and high levels of type 2 cytokines are associated with severe dengue disease. Group innate lymphoid cells (ILC2) type-2 cytokine-producing that activated by epithelial mast cell-derived lipid mediators. Through ex vivo RNAseq analysis, we observed ILC2 during acute viral infection, show an impaired I-IFN signature in We circulating permissive for virus infection vitro, particularly when through prostaglandin D (PGD ). underwent productive which was inhibited...
Background Although antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell relation clinical disease severity is incompletely understood. Methodology/Principal findings Using ex vivo IFNγ ELISpot assays, and by determining cytokines produced supernatants, we investigated DENV-specific a large cohort from Sri Lanka (n=338), who were either hospitalized due or had mild sub infection. We found...
Summary Determining previous infecting dengue virus (DENV) serotypes has been difficult due to highly cross-reactive immune responses from DENV infections. the correlates of serotype-specific would be crucial in understanding transmission community and also help determine protective responses. Therefore, we set out define conserved, regions DENVs. Serotype-specific conserved four were identified using Basic Local Alignment Search Tool (BLAST) searches custom perl scripts. Using ex-vivo...
Atopic dermatitis (AD) is a common inflammatory skin disorder, characterized by barrier defects and enhanced allergen priming. Null mutations in the filaggrin gene (FLG) are strongly associated with moderate to severe AD, but pathways linking dysfunction cutaneous inflammation still largely unknown.To assess alteration of endogenous cysteine protease activity FLG-deficient keratinocytes, determine whether affects epidermal function protein expression.We established stable FLG knockdown cell...