Photo of Dr Helen Wright

Dr Helen Wright PhD, BSc

Career Development Fellow Versus Arthritis / Tenure Track Fellow Musculoskeletal Biology I

Research

NEUTROPHIL-DERIVED MOLECULAR BIOMARKERS IN INFLAMMATORY DISEASE
Complex role of neutrophils in the pathogenesis of inflammatory disease (taken from Seminars in Immunology, Volume 28, Issue 2, pp.159-173)
Complex role of neutrophils in the pathogenesis of inflammatory disease (taken from Seminars in Immunology, Volume 28, Issue 2, pp.159-173)

The major theme of my research is investigating the role of neutrophils in the pathophysiology of inflammatory diseases such as rheumatoid arthritis (RA), including identification of neutrophil-derived molecular biomarkers of response to therapy and novel targets for the development of new therapies and understanding the molecular effects of therapeutics (anti-TNF therapy, anti-IL17A therapy, JAK inhibitors) on neutrophil function in inflammatory disease. My research combines functional laboratory assays on freshly-isolated peripheral blood neutrophils from patients and healthy controls stimulated in vitro with relevant agonists, and RNA-Seq to understand the phenotype of inflammatory neutrophils. As an Arthritis Research UK Foundation Fellow at the University of Liverpool I made a significant contribution to the understanding of neutrophil gene expression during inflammation, including publishing the first RNA-seq analysis of primary human neutrophils, cells which are notoriously difficult to work with in vitro, including making two datasets available to the public (GSE40548, GSE70068). I also published the first analysis of neutrophils from RA patients using RNA-Seq, identifying signalling pathways that correlate with disease activity. During my Fellowship I identified a panel of gene biomarkers of response and non-response to TNF inhibitors in RA. I have now secured the patent on these genes and am now in discussion with industrial partners to validate the panel as part of a multi-centre clinical trial, and develop a diagnostic assay. Recent funding has allowed me to extend my molecular study of RA neutrophils using quantitative proteomics (Wellcome Trust Seed Award) and 1H NMR metabolomics (Pfizer Aspire grant).

Current funding: Career Development Fellowship Versus Arthritis, Illix R&D Ltd, Wellcome Trust ISSF

REGULATION OF NEUTROPHIL EXTRACELLULAR TRAP FORMATION
NETs from a patient with rheumatoid arthritis (DNA, blue; myeloperoxidase, red; elastase, green; overlay, yellow)
NETs from a patient with rheumatoid arthritis (DNA, blue; myeloperoxidase, red; elastase, green; overlay, yellow)

Neutrophil extracellular traps (NETs) kill pathogens via the release of chromatin and anti-microbial granule enzymes in an extracellular mesh or “net”. NET release represents a novel form of cell death (NETosis), distinct from apoptosis and necrosis, that can be induced by inflammatory agents (LPS, TNFα, IFNα) and micro-organisms. During NETosis, ROS production and protein-arginine deiminase (PAD)-4 activation induces histone citrullination, chromatin disruption and disintegration of the nuclear membrane. Granule enzymes are released from membrane-bound organelles into the cytoplasm, whereupon they mix with histones and decondensed chromatin, before the protein-loaded DNA is released via disruptions in the cell membrane. NETs may also a source of autoantigens in autoimmune diseases such as systemic lupus erythematosus (SLE) where they contribute to organ damage and nephritis. Emerging evidence also implicates NETs in RA as a source of citrullinated neoepitopes that can lead to loss of immune tolerance and development of antibodies to citrullinated proteins (ACPA), a hallmark of severe RA. This new evidence creates new avenues for understanding the role of neutrophils in RA. Serum autoantibody profiles in SLE and RA are different: the former typically have high titres of anti-dsDNA and anti-nuclear protein antibodies, while the latter have high ACPA. This suggests that either the molecular properties of NETs produced in SLE and RA are different and expose distinct autoantigens, or the host immune response to NETs in SLE and RA is different. This project is combining quantitative proteomics and immune-fluorescent staining to determine the molecular properties of NETs in RA and SLE.

NEUTROPHIL METABOLOMICS
High resolution (EM) image of a neutrophil from a patient with rheumatoid arthritis
High resolution (EM) image of a neutrophil from a patient with rheumatoid arthritis

Neutrophils are phagocytic innate immune cells that play essential roles in host defence, but are also implicated in inflammatory diseases such as rheumatoid arthritis (RA) where they contribute to systemic inflammation and joint damage. Transcriptomic analysis of neutrophils has revealed significant changes in gene expression in neutrophils activated in vitro by cytokines and in vivo during inflammation in RA. However, there are no reports on the global metabolomic changes that occur during neutrophil activation. We are using 1H NMR spectrometry to investigate the intracellular changes in the neutrophil metabolome during in vitro and in vivo inflammation. In particular, we are interested in the changes to the metabolome which take place in RA patients during treatment with therapies such as JAK inhibitors.

Current funding: PhD scholarship from Versus Arthritis and the Masonic Charitable Foundation (Mr Michele Fresneda Alarcon).

Research Grants

Computational modelling and functional investigation of neutrophil activation and plasticity in inflammatory disease

ARTHRITIS RESEARCH UK

June 2017 - May 2022

Evaluation of novel mechanisms for inhibiting rheumatoid arthritis

AINTREE ARTHRITIS TRUST (UK)

October 2017 - September 2020

Biomarkers in inflammation

ILLIX LIMITED (UK)

May 2018 - May 2020

Multi-modal high resolution preclinical PET+SPECT+CT scanner

WELLCOME TRUST (UK)

October 2017 - October 2022

The effect of JAK inhibition on neutrophil killing, NETosis and metabolism in rheumatoid arthritis

PFIZER LTD (UK)

October 2016 - July 2017

Molecular properties of neutrophil extracellular traps (NETs) in rheumatoid arthritis (RA)

WELLCOME TRUST (UK)

June 2016 - May 2018

Secukinumab, neutrophils and vitamin D in Psoriatic Arthritis

NOVARTIS PHARMACEUTICALS UK LTD (UK)

May 2015 - December 2019

Role of neutrophils in inflammation induced liver cancer following liver fluke infection

DEPARTMENT FOR BUSINESS, ENERGY AND INDUSTRIAL STRATEGY (BEIS) (UK)

April 2016 - June 2017

Bridging and accelerating the translation of novel scientific findings for health and wealth gain

MEDICAL RESEARCH COUNCIL (MRC)

March 2014 - August 2015

Changes in neutrophil gene expression during active and resolved inflammation

ARTHRITIS RESEARCH UK

December 2010 - April 2014

Research Collaborations

Prof Robert Moots

Project: Adult Rheumatology
Internal

Clinical collaboration in adult rheumatology

Prof Rob Beynon

Project: Proteomics analysis of NETs
Internal

Proteomics

Dr Marie Phelan

Project: Neutrophil metabolomics
Internal

Metabolomics

Dr Angela Midgley

Project: Pediatric neutrophil transcriptomics
Internal

Paediatric Rheumatology