G S Ogg

NIHR Oxford Biomedical Research, Oxford, England, United Kingdom

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Publications (187)1256.95 Total impact

  • [Show abstract] [Hide abstract]
    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, and although many soluble factors such as cytokines and lipid mediators can influence ILC2, direct interaction of these cells with the microenvironment and other cells has been less explored. Natural cytotoxicity receptors are expressed by subsets of group 1 ILC and group 3 ILC and thought to be important for their effector function, but they have not been shown to be expressed by ILC2. Therefore, we sought to investigate the expression and functional properties of the natural cytotoxicity receptor NKp30 on human ILC2. A subset of ex vivo and cultured ILC2 express NKp30 that upon interaction with its cognate activatory ligand B7-H6 induces rapid production of type 2 cytokines. This interaction can be blocked by NKp30 blocking Ab and an inhibitory ligand, galectin-3. Higher expression of B7-H6 was observed in lesional skin biopsies of patients with atopic dermatitis, and incubation of keratinocytes with proinflammatory and type 2 cytokines upregulated B7-H6, leading to increased ILC2 cytokine production. NKp30-B7-H6 interaction is a novel cell contact mechanism that mediates activation of ILC2 and identifies a potential target for the development of novel therapeutics for atopic dermatitis and other atopic diseases.
    The Journal of Immunology 11/2015; DOI:10.4049/jimmunol.1501102 · 4.92 Impact Factor
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    ABSTRACT: The role of CD1a-reactive T cells in human allergic disease is unknown. We have previously shown that circulating CD1a-reactive T cells recognise neolipid antigens generated by bee and wasp venom phospholipase, and here tested the hypothesis that venom-responsive CD1a-reactive T cells associate with venom allergy. Circulating T cells from bee and wasp venom allergic individuals, before and during immunotherapy, were exposed to CD1a-transfected K562 cells in the presence of wasp or bee venom. T-cell response was evaluated based on IFNγ, GM-CSF and IL-13 cytokine production. Venom allergic individuals showed significantly higher frequencies of IFN-γ, GM-CSF and IL-13 producing CD1a-reactive T cells responsive to venom and venom derived phospholipase than healthy individuals. Venom-responsive CD1a-reactive T cells were cross-responsive between wasp and bee suggesting shared pathways of allergenicity. Frequencies of CD1a-reactive T cells were initially induced during subcutaneous immunotherapy, peaking by weeks 5, but then reduced despite escalation of antigen dose. Our current understanding of venom allergy and immunotherapy is largely based on peptide and protein-specific T cell and antibody responses. Here, we show that lipid antigens and CD1a-reactive T cells associate with the allergic response. These data have implications for mechanisms of allergy and approaches to immunotherapy. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 10/2015; DOI:10.1002/eji.201545869 · 4.03 Impact Factor
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    Gathsaurie Malavige · Graham Ogg ·

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    ABSTRACT: Atopic dermatitis (AD) is an inflammatory skin condition that can occur in early life, predisposing to asthma development in a phenomenon known as the atopic march. Although genetic and environmental factors are known to contribute to AD and asthma, the mechanisms underlying the atopic march remain poorly understood. Filaggrin loss-of-function mutations are a major genetic predisposer for the development of AD and progression to AD-associated asthma. We sought to experimentally address whether filaggrin mutations in mice lead to the development of spontaneous eczematous inflammation and address the aberrant immunologic milieu arising in a mouse model of filaggrin deficiency. Filaggrin mutant mice were generated on the proallergic BALB/c background, creating a novel model for the assessment of spontaneous AD-like inflammation. Independently recruited AD case collections were analyzed to define associations between filaggrin mutations and immunologic phenotypes. Filaggrin-deficient mice on a BALB/c background had profound spontaneous AD-like inflammation with progression to compromised pulmonary function with age, reflecting the atopic march in patients with AD. Strikingly, skin inflammation occurs independently of adaptive immunity and is associated with cutaneous expansion of IL-5-producing type 2 innate lymphoid cells. Furthermore, subjects with filaggrin mutations have an increased frequency of type 2 innate lymphoid cells in the skin in comparison with control subjects. This study provides new insights into our understanding of the atopic march, with innate immunity initiating dermatitis and the adaptive immunity required for subsequent development of compromised lung function. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    The Journal of allergy and clinical immunology 08/2015; DOI:10.1016/j.jaci.2015.06.045 · 11.48 Impact Factor
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    ABSTRACT: Although antibody responses to dengue virus (DENV) in naturally infected individuals have been extensively studied, the functionality of DENV specific memory T cell responses in relation to clinical disease severity is incompletely understood. Using ex vivo IFNγ ELISpot assays, and by determining cytokines produced in ELISpot supernatants, we investigated the functionality of DENV-specific memory T cell responses in a large cohort of individuals from Sri Lanka (n=338), who were naturally infected and were either hospitalized due to dengue or had mild or sub clinical dengue infection. We found that T cells of individuals with both past mild or sub clinical dengue infection and who were hospitalized produced multiple cytokines when stimulated with DENV-NS3 peptides. However, while DENV-NS3 specific T cells of those with mild/sub clinical dengue infection were more likely to produce only granzyme B (p=0.02), those who were hospitalized were more likely to produce both TNFα and IFNγ (p=0.03) or TNFα alone. We have also investigated the usefulness of a novel T cell based assay, which can be used to determine the past infecting DENV serotype. 92.4% of DENV seropositive individuals responded to at least one DENV serotype of this assay and none of the seronegatives responded. Individuals who were seronegative, but had received the Japanese encephalitis vaccine too made no responses, suggesting that the peptides used in this assay did not cross react with the Japanese encephalitis virus. The types of cytokines produced by DENV-specific memory T cells appear to influence the outcome of clinical disease severity. The novel T cell based assay, is likely to be useful in determining the past infecting DENV serotype in immune-epidemiological studies and also in dengue vaccine trials.
    PLoS Neglected Tropical Diseases 04/2015; 9(4). DOI:10.1371/journal.pntd.0003673 · 4.45 Impact Factor
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    ABSTRACT: The varicella-zoster virus (VZV) re-activation increases during ageing. Although the effects of VZV re-activation are observed in the skin (shingles) the number or functional capacity of cutaneous VZV specific T cells have not been investigated. The numbers of circulating IFN-γ secreting VZV specific CD4(+) T cells are significantly decreased in old subjects however other measures of VZV-specific CD4(+) T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4(+) T cells with a MHC class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin resident T cells. VZV-specific CD4(+) T cells were significantly increased in the skin compared to the blood in young and old subjects and their function was similar in both age groups. In contrast the number of Foxp3(+) regulatory T cells (Tregs) and expression of the inhibitory receptor PD-1 on CD4(+) T cells were significantly increased in the skin of older humans. Therefore VZV-specific CD4(+) T cells in the skin of older individuals are functionally competent. However their activity may be restricted by multiple inhibitory influences in situ.Journal of Investigative Dermatology accepted article preview online, 03 March 2015. doi:10.1038/jid.2015.63.
    Journal of Investigative Dermatology 03/2015; 135(7). DOI:10.1038/jid.2015.63 · 7.22 Impact Factor
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    ABSTRACT: Venoms frequently co-opt host immune responses, so study of their mode of 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, we show that venoms activate human T cells via CD1a proteins. Whereas CD1 proteins typically present lipids, chromatographic separation of venoms unexpectedly showed that stimulatory factors partition into protein-containing fractions. This finding was explained by demonstrating that bee venom-derived phospholipase A2 (PLA2) activates T cells through generation of small neoantigens, such as free fatty acids and lysophospholipids, from common phosphodiacylglycerides. Patient studies showed that injected PLA2 generates lysophospholipids within human skin in vivo, and polyclonal T cell responses are dependent on CD1a protein and PLA2. These findings support a previously unknown skin immune response based on T cell recognition of CD1a proteins and lipid neoantigen generated in vivo by phospholipases. The findings have implications for skin barrier sensing by T cells and mechanisms underlying phospholipase-dependent inflammatory skin disease. © 2015 Bourgeois et al.
    Journal of Experimental Medicine 02/2015; 212(2). DOI:10.1084/jem.20141505 · 12.52 Impact Factor
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    ABSTRACT: Although plasma leakage is the hallmark of severe dengue infections, the factors that cause increased vascular permeability have not been identified. As platelet activating factor (PAF) is associated with an increase in vascular permeability in other diseases, we set out to investigate its role in acute dengue infection. PAF levels were initially assessed in 25 patients with acute dengue infection to determine if they were increased in acute dengue. For investigation of the kinetics of PAF, serial PAF values were assessed in 36 patients. The effect of dengue serum on tight junction protein ZO-1 was determined by using human endothelial cell lines (HUVECs). The effect of dengue serum on and trans-endothelial resistance (TEER) was also measured on HUVECs. PAF levels were significantly higher in patients with acute dengue (n = 25; p = 0.001) when compared to healthy individuals (n = 12). In further investigation of the kinetics of PAF in serial blood samples of patients (n = 36), PAF levels rose just before the onset of the critical phase. PAF levels were significantly higher in patients with evidence of vascular leak throughout the course of the illness when compared to those with milder disease. Serum from patients with dengue significantly down-regulated expression of tight junction protein, ZO-1 (p = 0.004), HUVECs. This was significantly inhibited (p = 0.004) by use of a PAF receptor (PAFR) blocker. Serum from dengue patients also significantly reduced TEER and this reduction was also significantly (p = 0.02) inhibited by prior incubation with the PAFR blocker. Our results suggest the PAF is likely to be playing a significant role in inducing vascular leak in acute dengue infection which offers a potential target for therapeutic intervention.
    PLoS Neglected Tropical Diseases 02/2015; 9(2):e0003459. DOI:10.1371/journal.pntd.0003459 · 4.45 Impact Factor
  • K. Adelmann · A. N. Hegazy · G. Ogg · F. Powrie ·

    Immunology 12/2014; 143:175-175. · 3.80 Impact Factor
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    Maryam Salimi · Graham Ogg ·
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    ABSTRACT: Innate lymphoid cells are an emerging family of effector cells that contribute to lymphoid organogenesis, metabolism, tissue remodelling and protection against infections. They maintain homeostatic immunity at barrier surfaces such as lung, skin and gut (Nature 464:1367-1371, 2010, Nat Rev Immunol 13: 145-149, 2013). Several human and mouse studies suggest a role for innate lymphoid cells in inflammatory skin conditions including atopic eczema and psoriasis. Here we review the innate lymphoid cell family and discuss their function in the skin and during inflammation.
    BMC Dermatology 11/2014; 14(1):18. DOI:10.1186/1471-5945-14-18
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    ABSTRACT: Vascular leak is the hallmark of severe dengue infections and leads to complications such as shock and multi-organ failure. Although many mediators have been implicated in the vascular leak in dengue, the role of sphingosine 1-phosphate (S1P) has not been investigated. As S1P has been shown to be important in barrier integrity, we assessed the S1P levels in 28 patients with acute dengue and 12 healthy individuals. The S1P levels were significantly lower in patients with acute dengue (p = 0.002) and the levels in patients with grade IV dengue haemorrhagic fever (DHF) were significantly lower than those with dengue fever (p = 0.005). We then investigated the kinetics of S1P levels throughout the course of the illness in another 32 patients in serum samples obtained twice a day. We found that S1P levels were low throughout the course of illness and S1P levels were <0.5 µM in 12/23 patients with DHF when compared to 1/9 with DF. As S1P has shown to be important in the endothelial barrier integrity and increases transendothelial resistance, low levels of S1P in acute dengue infection are likely to contribute to increased vascular permeability.
    PLoS ONE 11/2014; 9(11):e113394. DOI:10.1371/journal.pone.0113394 · 3.23 Impact Factor
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    ABSTRACT: Background Early detection of complications significantly reduces dengue associated mortality and morbidity. We set out to determine if the NS1 rapid antigen detection test could be used as a point of care test to predict severe disease.Methods186 adult patients with confirmed dengue were enrolled during day 3¿8 of illness. Clinical and laboratory parameters were recorded during the course of the illness and NS1 antigen levels were determined using both the Panbio dengue early ELISA (Panbio, Australia) and a NS1 rapid antigen detection kit (SD Bioline, South Korea).Results59.1% of patients presented to hospital on day 5¿6 of illness when NS1 antigen positivity was significantly (p¿=¿0.008) associated with severe dengue (odds ratio 3.0, 95% CI 1.39 to 6.47) and the NS1 antigen levels were significantly higher (p¿=¿0.03) in those who went on to develop shock. Serum NS1 antigen levels significantly (p¿<¿0.0001) and inversely correlated with the total white cell counts and lymphocyte counts. The bedside NS1 test showed comparable sensitivity (97.4%) and specificity (93.7%) to the laboratory NS1 test in our setting and cohort.ConclusionNS1 antigen positivity is associated with a higher risk of developing severe dengue especially when positive beyond day 5 of illness in our cohort, and while further validation studies are required, the test can therefore potentially be used as a bedside point of care test as a warning sign of severe dengue.
    BMC Infectious Diseases 10/2014; 14(1):570. DOI:10.1186/s12879-014-0570-8 · 2.61 Impact Factor
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    ABSTRACT: Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications.
    Journal of Allergy and Clinical Immunology 10/2014; 135(5). DOI:10.1016/j.jaci.2014.09.006 · 11.48 Impact Factor
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    ABSTRACT: Background: The role of epidermal barrier genes in the pathogenesis of atopic skin inflammation has recently been highlighted. Cytokines that are abundant in the skin during inflammation have been shown to exert various effects on the expression of barrier genes, although the role of histamine in this area of skin biology is not yet fully understood. Objective: To assess the effect of stimulation with histamine on keratinocytes by analysis of the pathways involved in epidermal barrier integrity. Material and Methods: We performed a gene expression analysis of histamine-stimulated keratinocytes. Functional changes were tested using the dye penetration assay. Differential changes in filaggrin and the filaggrin-processing enzyme bleomycin hydrolase (BLMH) were validated at the protein level, and expression was also assessed in filaggrin knock-down keratinocytes. Results: Histamine altered expression of multiple barrier genes. Expression of filaggrin was downregulated, as was that of other markers, thus suggesting the presence of delayed/aberrant keratinocyte differentiation. Expression of genes involved in cellular adhesiveness and genes of protease expression was dysregulated, but expression of protease inhibitors was increased. BLMH was upregulated in keratinocytes subjected to histamine and filaggrin knockdown. Conclusions: Histamine exerts a dual effect on epidermal barrier genes; it suppresses keratinocyte differentiation and dysregulates genes of cellular adhesiveness, although it induces genes contributing to stratum corneum function. Upregulation of BLMH and protease inhibitors could support maintenance of the permeability barrier by enhanced generation of moisturizing compounds and suppressed desquamation. In contrast, in the case of stratum corneum damage, histamine could enhance transcutaneous sensitization.
    Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología 09/2014; 24(4):231-9. · 2.60 Impact Factor
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    ABSTRACT: Group 2 innate lymphoid cells (ILC2s) release interleukin-13 (IL-13) during protective immunity to helminth infection and detrimentally during allergy and asthma. Using two mouse models to deplete ILC2s in vivo, we demonstrate that T helper 2 (Th2) cell responses are impaired in the absence of ILC2s. We show that MHCII-expressing ILC2s interact with antigen-specific T cells to instigate a dialog in which IL-2 production from T cells promotes ILC2 proliferation and IL-13 production. Deletion of MHCII renders IL-13-expressing ILC2s incapable of efficiently inducing Nippostrongylus brasiliensis expulsion. Thus, during transition to adaptive T cell-mediated immunity, the ILC2 and T cell crosstalk contributes to their mutual maintenance, expansion and cytokine production. This interaction appears to augment dendritic-cell-induced T cell activation and identifies a previously unappreciated pathway in the regulation of type-2 immunity.
    Immunity 07/2014; 41(2). DOI:10.1016/j.immuni.2014.06.016 · 21.56 Impact Factor
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    ABSTRACT: Background Histamine is an abundant mediator accumulating in the skin of atopic patients, where it is thought to be derived from immune cells. While keratinocytes express histidine decarboxylase (HDC), levels of the enzyme in normal or diseased epidermis and factors that influence its expression in human keratinocytes are not known. Objectives To assess levels of HDC in inflammatory skin diseases and factors influencing its expression. Methods Normal and filaggrin-insufficient human keratinocytes, organotypic epidermal models and skin samples were investigated for the expression of HDC. The effect of cytokines, bacterial and allergen stimuli exposure and functional changes in differentiation were evaluated in vitro. ResultsWe detected abundant expression of the HDC protein in all models studied; expression was increased in atopic skin samples. Filaggrin-insufficient keratinocytes maintained HDC levels, but exposure of keratinocytes to thymic stromal lymphopoietin, tumour necrosis factor-, lipopolysaccharide (LPS) and house dust mite (HDM) extract increased HDC expression in vitro. Furthermore, filaggrin expression in cultured keratinocytes increased following histamine depletion. Conclusions Keratinocytes express abundant HDC protein, and the levels increase in atopic skin. LPS, HDM and cytokines, which are implicated in allergic inflammation, promote the expression of the enzyme and upregulate histamine levels in keratinocytes. Actively produced histamine influences keratinocyte differentiation, suggesting functional relevance of the axis to atopic dermatitis. The findings therefore identify a new point of therapeutic intervention.
    British Journal of Dermatology 06/2014; 171(4). DOI:10.1111/bjd.13199 · 4.28 Impact Factor
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    International Journal of Infectious Diseases 04/2014; 21. DOI:10.1016/j.ijid.2014.03.1101 · 1.86 Impact Factor

  • Clinical Immunology 04/2014; 153(1). DOI:10.1016/j.clim.2014.04.011 · 3.67 Impact Factor
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    ABSTRACT: The role of the epidermis in the immune response is well known. While multiple cytokines are implicated in keratinocyte-mediated infection clearance and wound healing, little is known about the involvement of keratinocytes in promoting resolution of inflammation. To assess effects of histamine stimulation on keratinocyte function. We performed a combined microarray/Gene Ontology analysis of histamine-stimulated keratinocytes. Functional changes were tested by apoptosis assessment and scratch assays. Histamine receptor involvement was also assessed by blocking wound closure with specific antagonists. Histamine treatment had extensive effects on keratinocytes, including effects on proinflammatory responses and cellular functions promoting wound healing. At the functional level, there was reduced apoptosis and enhancement of wound healing in vitro. At the receptor level, we identified involvement of all keratinocyte-expressed histamine receptors (HRHs), with HRH1 blockage resulting in the most prominent effect. Histamine activates wound healing and infection clearance-related functions of keratinocytes. While enhancement of histamine-mediated wound healing is mediated predominantly via the HRH1 receptor, other keratinocyte-expressed receptors are also involved. These effects could promote resolution of skin inflammation caused by infection or superficial injury.
    Clinical and Experimental Dermatology 01/2014; 39(2). DOI:10.1111/ced.12256 · 1.09 Impact Factor

Publication Stats

16k Citations
1,256.95 Total Impact Points


  • 2010-2015
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 1998-2015
    • University of Oxford
      • MRC Human Immunology Unit
      Oxford, England, United Kingdom
    • University of Lausanne
      • Department of Biochemistry
      Lausanne, Vaud, Switzerland
    • University Hospital of Lausanne
      Lausanne, Vaud, Switzerland
  • 1989-2014
    • Oxford University Hospitals NHS Trust
      • Nuffield Department of Medicine
      Oxford, England, United Kingdom
  • 2012
    • The Institute for Molecular Medicine
      Huntington Beach, California, United States
    • University of Sri Jayewardenepura
      • Department of Microbiology
      Columbo, Western, Sri Lanka
  • 2002-2009
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • MRC Cognition and Brain Sciences Unit
      Cambridge, England, United Kingdom
  • 2006
    • J. David Gladstone Institutes
      San Francisco, California, United States
  • 2002-2004
    • University College London
      Londinium, England, United Kingdom
  • 2000-2001
    • The Rockefeller University
      • Laboratory of Cellular Physiology and Immunology
      New York City, New York, United States