NIHRDataInsights/HRCSData huggingface dataset:
Title: Tissue-resident CD8+ memory T cell and fibroblast cross-talk in juvenile idiopathic arthritis
Funder: Medical Research Council

Abstract: The majority of children with juvenile idiopathic arthritis (JIA) do not achieve remission despite years of treatment, resulting in joint damage and long-term disability. In murine models, a long-lived tissue-resident CD8+ memory T cell (TRM) population has been identified that resides in the joint during remission and mediates inflammatory flares. Clonally-expanded TRM-like cells are enriched in the synovial fluid of patients with JIA. In other contexts, fibroblast subsets have been shown to produce maintenance factors, metabolically re-programme and enhance CD8+ T cell survival. Therefore, I aim to explore whether persistence of inflammation in JIA is driven by cross-talk between fibroblast subsets and TRM, enhancing TRM retention, survival and longevity. My objectives include functionally characterising TRM and fibroblast subsets of the inflamed tissue from patients with JIA at diagnosis; determining how differences in these populations relate to disease trajectory and assessing the functional importance of interactions between these subsets in the inflamed joint. I will analyse synovial biopsies and synovial fluid from children with JIA using multi-omics platforms and immunofluorescence imaging, characterising the transcriptomic and proteomic profiles of cellular subsets at a single cell level of resolution. Independent datasets of bulk-RNA sequenced synovial fluid will be used to verify findings. Murine models of antigen-induced arthritis in transgenic mice will enable investigation of selective depletion or transfer of the cellular subsets. TRM are not currently directly targeted by any of the available treatments. Fibroblast-targeting therapies are under development for arthritis in adults, but further characterisation of fibroblasts in JIA is needed to determine the likely efficacy in children. Understanding the mechanisms mediating persistence of inflammation in joints is critical for achieving sustained clinical remission and cure of arthritis


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Unravelling the role of fibroblasts in giant cell arteritis and establishing their contribution in the promotion of inflammation and disease relapse.
Funder: Chief Scientist Office, Scotland

Abstract: Giant cell arteritis is a common inflammatory condition of old age that affects the large arteries of the body. Untreated, patients can suffer blindness or sudden death. Historically steroids have been the mainstay of treatment. While they can help avoid significant disease complications in the short term, they are associated with serious side effects. Furthermore, inflammation persists in many patients despite steroid treatment, reflected by the fact that often when we stop these drugs the disease commonly returns. This study seeks to investigate the cells which are responsible for the persistent inflammation and relapsing symptoms. Firstly, I will use tissue which has been previously collected to begin to identify the precise cells which are implicated in the inflammation observed in giant cell arteritis. Second, I will collect fresh samples from relapsing patients and will apply state of the art laboratory technologies to evaluate the function and importance of these particular cells


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: ARCHERY Project: Ai to Revolutionise the patient Care pathway in Hip and knEe aRthroplastY.
Funder: Chief Scientist Office, Scotland

Abstract: The project will determine whether Artificial intelligence (AI) can help General Practitioners’ (GPs) decision-making about which patients with arthritis are referred for hip or knee replacement surgery. More than 1 in 10 people over the age of 45 have arthritis. This can be associated with significant pain and inability to perform normal activities such as walking, getting dressed or going to the shops. Some have described living with the condition as a state “worse than death”. Surgery provides an excellent solution but is not a suitable option for all patients. Currently GPs often have difficulty deciding which patients with arthritis might benefit from an operation. This leads to many referrals for orthopaedic input and prolonged waiting times for surgery. Planned AI analysis of routinely collected health information about patients with end stage hip and knee arthritis will allow for development of a tool that helps predict who is likely to undergo surgery. Use of such a tool will help improve future referral pathways, ensuring those likely to benefit from surgery are seen promptly and efficiently. This should see reduced waiting times that helps those needing surgery to get back on their feet again quickly


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Towards a Predictive Molecular Taxonomy for Psoriatic Arthritis
Funder: Chief Scientist Office, Scotland

Abstract: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with significant comorbidity and reduced life expectancy. Despite recent improvements, current therapeutic strategies still lead to generally disappointing results. Patients often have dichotomous treatment responses, suggesting that discrete inflammatory pathways may operate across different tissue compartments. The marked clinical heterogeneity and broad spectrum of target tissue involvement in PsA represents arguably the major challenge in improving treatment and thus addressing unmet need. Herein we will test the hypothesis that a molecular signature can be derived from a combination of genomic and transcriptomic sequence analysis that will predict the phenotypic evolution in early PsA, with implications for intervention and stratification. Patients with new and recent onset PsA will be carefully phenotyped and baseline samples collected and sequenced. All participants will be reassessed at 6 and 12 months. This study builds on the success, collaboration and infrastructure of our established SERA study.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing an adoptive regulatory T cell therapy for the treatment of rheumatoid arthritis
Funder: Chief Scientist Office, Scotland

Abstract: The immune system contains a balance of cells that turn responses ‘on’ and those that turn it ‘off’. When this balance breaks down, inappropriate immune responses can attack healthy tissues causing autoimmune disease, such as rheumatoid arthritis. We have developed an approach that directs regulatory cells, responsible for switching off the immune system, to sites of autoimmunity. This process is based on genetically modifying regulatory cells to express disease-targeting receptors. Notably, this approach completely ameliorates disease in an animal model of rheumatoid arthritis. Here we propose to translate this to treat patients with rheumatoid arthritis. This includes validating receptors that enable targeting of the rheumatoid arthritis joint; and defining the safest and most effective cell preparation approaches to generate the therapeutic cell product. This work is part of an exciting new wave of personalised therapy and would contribute to Scotland being at the forefront of this type of therapy


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Delineating disease-relevant T cell subsets in rheumatoid arthritis: potential biomarkers of therapeutic response.
Funder: Chief Scientist Office, Scotland

Abstract: Rheumatoid arthritis (RA) is an immune-mediated disease leading to joint pain, disability, and reduced quality-of-life. Currently, we have a wide range of drugs available, but they do not work in all individuals and in those for whom there is a response, this is often partial. Treatment must also be given life-long with the risk of side-effects. Ideally, each individual would receive the medicine that has the highest chance of success and lowest risk of toxicity. We recently found a cell type in blood that seems to be present in people with RA who do not benefit from their current treatment. Here, we will investigate how these cells can be used as a test to inform future response to treatment. This study has the potential to reveal new biological markers of treatment response in RA. It also has the potential to find new targets for the development of more effective medicines.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The Immunology of Alopecia Areata: How do Macrophages Contribute to Maintaining Hair Loss?
Funder: Chief Scientist Office, Scotland

Abstract: Alopecia areata (AA) is a common condition in which the immune system, which normally protects against infection, kills cells at the base of hair follicles. This causes patchy hair loss, which can progress to affect the entire scalp or the whole body. Available treatments for AA may be effective for those with patchy hair loss, but are rarely effective for severe disease, although clinical trials are now testing drugs that supress the immune system. To investigate AA we established a dedicated research clinic, in association with the charity Alopecia UK. This clinic provides samples that are used in my laboratory, however the majority of samples are stored in a Biobank and are accessible to other researchers. Using the samples from volunteers with AA we have shown that the immune system in the entire body is changed in people with AA. Our most recent results show that, in AA skin, immune cells called macrophages function differently than macrophages in healthy skin. These macrophages are located around the hair follicle, very close to the other immune cells that have previously been shown to contribute to AA. Because macrophages are important for controlling normal hair growth, and because they are known to control other immune cells, we here aim to investigate AA macrophages in more detail. By targeting the macrophages that control the hair-damaging immune response, we hope to develop new strategies for treating AA


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Targeting follicular helper T cells across multiple autoimmune diseases
Funder: Versus Arthritis

Abstract: There are more than 80 different autoimmune conditions and often people develop more than one at a time. They can affect people of any age and last a life-time, potentially resulting in decades of ill health and medical costs. On the face of it, these diseases seem very different from one another, with completely different symptoms affecting distinct parts of the body. However at a mechanistic level, when we try to unpick the early events that trigger the development of these diseases we can find common ground. Long before any symptoms develop, there are changes in how cells of the immune system behave. White blood cells called T cells play an important role in determining whether an immune response takes place – either against a part of our own body (an auto-immune response) or against an infection. T cells that have the potential to cause autoimmune disease exist in all of us, but are normally tightly regulated so they don’t become activated – in particular they are prevented from interacting with another type of white blood cells, B cells. Data from our lab and others suggests that when regulation starts to fail, one of the first things that happens is that T cells start to collaborate with B cells and immune responses begin to develop. These interactions trigger autoantibodies to be produced – soluble proteins in the blood that can be measured clinically to test if someone is developing a particular condition. In type 1 diabetes, the presence of islet autoantibodies precedes the development of overt diabetes by many years. The T cells that collaborate with B cells are called follicular helper T cells, or Tfh. Interestingly, the number and appearance of Tfh starts to change early on in multiple different autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, lupus, multiple sclerosis and many more. Data from animal models suggest that Tfh may be important in driving disease. Approaches to target these cells would be a novel way of intervening in relevant to multiple different conditions. One problem is that there is no single marker that identifies Tfh so they are difficult to selectively target with drugs. To overcome this, we have brought together 2 different scientific disciplines (cellular immunology and organic chemistry) to try and tackle this in a new way. Using a new chemical approach, we can target 2 markers on a cell at the same time, opening up the possibility to deliver a toxic drug just to the Tfh cells. We plan to test whether this approach can kill Tfh cells in plastic dishes and also in live animals (in 2 different mouse models of autoimmune disease). We also plan to start making the human equivalent of the drug and testing it on human cells in the lab. Ultimately our goal is to deploy this as a new way to intervene across multiple autoimmune settings, early in disease and potentially prior to symptom development.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Metabolic reprogramming of human neutrophils during inflammation
Funder: Versus Arthritis

Abstract: Neutrophils contribute to pathology in inflammatory diseases including rheumatoid arthritis (RA), lupus and vasculitis. We have shown that neutrophil gene expression in RA is dramatically different from that of healthy individuals. Neutrophil activation in RA induces rapid release of tissue-damaging proteases and reactive oxygen species (ROS), secretion of inflammatory cytokines/chemokines, and exposure of auto-antigens on neutrophil extracellular traps (NETs). We are beginning to understand how metabolism is regulated during inflammation and in inflammatory disease (immunometabolism), e.g. how metabolism is regulated during hypoxia or during cell differentiation. Metabolic regulation may be as important as (and indeed a direct controller of) gene expression during inflammation and inflammatory disease. We have recently developed protocols for the study of intracellular metabolism in human neutrophils and have preliminary data showing the intracellular metabolite profile of RA neutrophils is significantly altered compared to that of healthy individuals. This project will investigate metabolic regulation of neutrophil activation in RA to (1) generate new understanding of basic neutrophil biology during in vitro and in vivo inflammation, and (2) identify metabolic pathways that could be targeted by existing or novel therapeutics for the treatment of RA. We will use NMR metabolomics and assays of cellular metabolism alongside functional neutrophil assays to study the regulation of neutrophil activation by specific inflammatory metabolites, such as citrate and succinate, and by specific metabolic pathways (e.g. glycolysis). We will do this using both healthy control and RA neutrophils to study the way that neutrophil metabolism and activation is dysregulated in RA. Our hypothesis is that altered neutrophil metabolism represents a novel therapeutic target in inflammatory diseases such as RA. This project will identify potential metabolic targets, either for the development of novel therapeutics or the re-purposing of existing therapies to treat RA, and will provide excellent training in both project-specific and transferrable skills.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating cytokine control of lymphoid-rich joint inflammation – a determinant of disease progression and response to therapy in inflammatory arthritis
Funder: Versus Arthritis

Abstract: Disease remission is the ultimate objective for the treatment of patients with inflammatory arthritis (e.g., rheumatoid arthritis and psoriatic arthritis). Biological therapies for inflammatory arthritis aim to reduce inflammation. These include cytokine-targeting biologics, such as anti-TNF therapies. While these drugs benefit a considerable proportion of patients, many (~40-44%) remain unresponsive. This problem is compounded by the fact that conditions like rheumatoid arthritis (RA) are considered heterogeneous. Patients present with varying forms of synovitis that can ultimately affect their response to therapy. My lab addresses the following key questions: • What are the immune mechanisms that determine why patients with inflammatory arthritis develop different forms of synovitis? • Can an improved understanding of the mechanisms that determine different forms of synovial pathology inform the diagnosis and treatment of patients with early arthritis? With investment from the School of Cellular and Molecular Medicine and established collaborations with academic, clinical and industrial partners, my ambition is to deliver a new research programme at the University of Bristol that provides fundamental insight into synovial ectopic lymphoid structure (ELS) regulation and improves the clinical management of patients with inflammatory arthritis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How does one-carbon metabolism in germinal centre B cells promote autoimmunity and lymphoma?
Funder: Versus Arthritis

Abstract: Background The metabolic state of immune cells has profound effects on their biological properties through multiple mechanisms, including epigenetic regulation. The germinal centre (GC) reaction is of central importance to antibody-mediated autoimmune diseases and is the origin of most lymphoma. However, the metabolic phenotype of GC B cells is essentially unknown. We hypothesize that a GC_x0002_dependent metabolic program is imprinted on GC-derived lymphoma, and that this is shared with normal and autoimmune GC B cells. We have identified one-carbon (1C) metabolism as upregulated in GC B cells, and much of this pathway is supplied by glucose, through the serine synthesis pathway (SSP). This pathway may represent a common point of intervention in autoimmunity and lymphoma. Aims In this work, we will define the role of 1C metabolism and the de novo serine synthesis pathway in normal GC physiology, then extend our examination to understand their differential regulation in autoimmune GCs and in GC-derived diffuse large B cell lymphoma (DLBCL). Methods We will use in vivo stable isotope-resolved metabolomics to trace the flow of carbon from glucose and serine into normal and autoimmune GC B cells. We will conditionally delete the first component of the SSP (Phgdh) in GC B cells and examine their phenotype, including their epigenetic landscape. We will compare the activity of the SSP in GC and non-GC-derived DLBCL cell lines, and extend this to DLBCL patient biopsies. We will explore the dependence of DLBCL on the SSP via deletion of pathway genes and pharmacologic inhibition. How the results of this research will be used. This research will provide the first systematic exploration of the 1C pathway in the GC, using advanced in vivo metabolomic techniques to provide maximum biological fidelity, and with specific genetic deletion of a key SSP pathway gene. It will also be the first to examine autoimmune GCs with the potential to rationalise SSP inhibitors as therapeutic agents in diseases such as SLE. This work will provide insight into the underpinnings of DLBCL by exploration of the metabolism of their cell of origin, carrying through these findings into interventional models which have the capacity to also inform new treatment approaches in lymphoma.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Restoring order to the joint: identifying the cellular drivers of treatment refractory rheumatoid arthritis
Funder: Versus Arthritis

Abstract: The immune mechanisms underlying treatment refractory rheumatoid arthritis (RA) are completely unknown. We have recently demonstrated the ability of synovial tissue macrophages to negatively regulate joint inflammation though the induction of a repair phenotype in inflammatory synovial fibroblasts. Critically, this cellular immune checkpoint promotes the resolution of joint inflammation. In this project we propose that the induction of an epigenetically imprinted, inflammatory phenotype in specific subsets of synovial fibroblasts leads to the failure of this immune checkpoint though the inability of joint fibroblasts to respond to negative regulation. The early induction of these epigenetically imprinted, fibroblast phenotypes could determine poor treatment response and an early refractory disease trajectory. We propose that therapeutic strategies should be employed that aim to re-establish this synovial immune checkpoint in patients with refractory RA. We have recently defined the functional diversity of synovial macrophages and fibroblasts, identifying distinct cellular subsets with non-overlapping effector functions that differentially regulate processes of inflammation and tissue damage. In RA, expansion and differentiation of immune-modulatory synovial fibroblasts (THY1+ CD34+) is driven by inductive NOTCH-3 signalling from the vascular endothelium and these fibroblasts, lose their immune-protective functions and instead amplify inflammation, producing pathogenic levels of chemokines and cytokines that drive leucocyte accumulation. We hypothesize that a refractory disease endotype results from an epigenetically imprinted change in the phenotype of THY1+ CD34+ fibroblasts that maintains these cells in a persistent pathogenic state, leading to their failure to respond to negative regulation by MerTK+ tissue macrophages. As a result, joint haemostasis cannot be re-established and inflammation persists. To test this hypothesis, we will determine the heterogeneity of synovial tissue fibroblasts and macrophages associated with a refractory disease endotype and establish the gene regulatory pathways responsible for the maintenance of specific pathogenic cell phenotypes and determine how these changes impact on fibroblast-macrophage cross-talk.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM