Project ID CM-HD2024_22


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Department of Inflammation BiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Additional Supervisor Prof Miraz Rahman

Pathogenic mast cells in chronic inflammatory diseases

Mast cells (MCs) abound in all barrier tissues and play an important role in pathogenesis of many chronic inflammatory diseases including urticaria, asthma, polyposis and food allergy. We studied immune cells obtained from nasal polyps and found increased percentages of MC expressing IL-17RB (receptor for IL-25), identifying a potentially novel “pathogenic“ MC subpopulation. Our aim is to use an unbiased approach to confirm features of IL-17RB+ MCs and to comprehensively evaluate MC heterogeneity at the single cell transcriptomic and epigenetic levels. Identified MC subpopulations will be further researched using already obtained transcriptional data from chronic urticaria patients, healthy controls and other available datasets of patients with chronic inflammatory diseases. To characterise functions of IL-17RB+ MCs a model of human MCs overexpressing IL-17RB has been established and will be used to study the role of IL-25/IL17RB in MC activation. Although there are many therapies targeting immune cells, there are no current treatments that specifically target MCs or MC specific pathways.
Year 1: the student will use experimental techniques for analysis of human MC lines and primary MCs isolated from polyp tissues, including tissue digestion, cell culture and flow cytometry. Subpopulations will be quantified, phenotyped and cell sorted for single cell analysis (Chromium Single Cell Multiome ATAC + Gene Expression).
Year 2: the student will evaluate airway MC heterogeneity at the single cell transcriptomic and chromatin levels in nasal polyps (single cell data analysis, confirmation of findings in primary MC cells using flow cytometry, cell signalling, cell culture).
Year 3: identified MC subpopulations will be further studied at functional level using recombinant models and human primary cells in context of chronic inflammatory diseases.

Representative Publications

Epithelial coxsackievirus adenovirus receptor promotes house dust mite-induced lung inflammation. Ortiz-Zapater E, Bagley DC, Hernandez VL, Roberts LB, Maguire TJA, Voss F, Mertins P, Kirchner M, Peset-Martin I, Woszczek G, Rosenblatt J, Gotthardt M, Santis G, Parsons M. Nat Commun. 2022 Oct 27;13(1):6407. doi: 10.1038/s41467-022-33882-w. Prostaglandin D2 receptors in human mast cells. Xia J, Abdu S, Maguire TJA, Hopkins C, Till SJ, Woszczek G. Allergy. 2020 Jun;75(6):1477-1480. doi: 10.1111/all.14161. Leukotriene E4 is a full functional agonist for human cysteinyl leukotriene type 1 receptor-dependent gene expression. Foster HR, Fuerst E, Branchett W, Lee TH, Cousins DJ, Woszczek G.Sci Rep. 2016 Feb 2;6:20461. doi: 10.1038/srep20461.
Basophils from Cancer Patients Respond to Immune Stimuli and Predict Clinical Outcome. Bax HJ, Chauhan J, Stavraka C, Khiabany A, Nakamura M, Pellizzari G, Ilieva KM, Lombardi S, Gould HJ, Corrigan CJ, Till SJ, Katugampola S, Jones PS, Barton C, Winship A, Ghosh S, Montes A, Josephs DH, Spicer JF, Karagiannis SN.Cells. 2020 Jul 7;9(7):1631. doi: 10.3390/cells9071631. Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms. Slovick A, Douiri A, Muir R, Guerra A, Tsioulos K, Hay E, Lam EPS, Kelly J, Peacock JL, Ying S, Shamji MH, Cousins DJ, Durham SR, Till SJ.J Allergy Clin Immunol. 2017 Jun;139(6):1830-1839.e13. doi: 10.1016/j.jaci.2016.09.024. IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa. Lam EP, Kariyawasam HH, Rana BM, Durham SR, McKenzie AN, Powell N, Orban N, Lennartz-Walker M, Hopkins C, Ying S, Rimmer J, Lund VJ, Cousins DJ, Till SJ.J Allergy Clin Immunol. 2016 May;137(5):1514-24. doi: 10.1016/j.jaci.2015.10.019.