NIHRDataInsights/HRCSData huggingface dataset:
Title: Decoding heterogeneity and specialisation of interstitial synovial macrophages: what, where and how
Funder: Wellcome Trust

Abstract: Rheumatoid arthritis is an autoinflammatory condition that mainly affects the joints. Increased permeability of the blood vessels and recruitment of immune cells into the joint likely play a role at the onset of this disease. For immune cells to enter the joint, a signal sent by joint tissue-resident cells is required. A specific subtype of tissue-resident immune cells, called synovial macrophages are suspected to be the source of this initial signal. It has been shown that synovial macrophages consist of different macrophage populations with unclear functions within the joint and during arthritis development. Exploration of synovial macrophages via computational methods, namely single-cell RNA sequencing, revealed a subpopulation of macrophages defined by high gene expression of aquaporin 1(AQP1). This population was not previously defined in the literature and the overall role of AQP1 in macrophages is unknown. Furthermore, AQP1-positive macrophages expressed high levels of genes associated with bioactive lipid signalling previously shown to influence the inflammation in animal arthritis models. In my project, I aim to characterize the AQP1-positive macrophages, define their function and position within the joint, and finally identify the contribution of these cells in bioactive lipid signalling and induction of inflammatory arthritis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissecting the ILC-Stromal axis in Health and Disease
Funder: Wellcome Trust

Abstract: Innate lymphoid cells (ILC) are rare immune cells enriched in barrier tissues such as the gut or lung, and within lymph nodes, that are important regulators of tissue immunity and wound healing. Whilst some of the interactions that occur between ILC and other cells are understood, many are poorly defined, especially within the context of inflammation and tissue remodelling. A better understanding of the interactions between ILC and stromal cells may reveal therapeutic targets and therefore enable the design of better therapeutics that can be used in cases of chronic disease that ILC mediate. Therefore, to better define how ILC communicate with other cells and what signals are involved in regulating their localisation both in health and disease I will firstly use bioinformatic tools to assess whether there are novel cell-cell interactions between ILC and other cells. I will then image ILC over the time-course of an infection using imaging mass cytometry. This work will help us understand how ILC communicate with other cells and give new insights into cues that regulate ILC localisation in both health, and throughout infection, and in turn, how ILC modulate the adaptive and innate immune response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding the aetiology and stratification of Immune Mediated Inflammatory Diseases using AI
Funder: Wellcome Trust

Abstract: Our goal is to use Artificial Intelligence (AI) to better understand the biology of immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis, psoriasis, lupus, and Sjögren’s syndrome. Despite being common conditions, the mechanisms which explain how IMIDs work are poorly understood. We consider there must be key cellular mechanisms underlying IMIDs and that studying the differences between them will provide clues as to their origin and development. This project will focus on studying interferon signalling, a central mechanism for control of inflammation, known to influence IMID development and drug response. Using genomic data from a range of IMIDs, we will build networks explaining the relation between the different components of interferon signalling. We will also integrate patient clinical information, genomic and imaging data to find sub-groups of patients whose disease and response to treatment progresses in a similar manner. Finally, we will use this research to identify pharmaceutical drugs, already on the market and in use for different conditions, which might be effective in the treatment of IMIDs because their mechanism of action indicates they would affect important areas of IMID biology. This could also lead to identifying areas of interest for future IMID drug development research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the determinants of B cell activation, differentiation, and function in Psoriatic Arthritis and related human autoimmune diseases
Funder: Wellcome Trust

Abstract: B cells are key players of the immune system through the secretion of antibodies, antigen presentation and through cell-cell signalling. The fine balance of B cell activation and regulation is key to both protecting us from infection, whilst staying tolerant to our own self. Different tolerance mechanisms are essential in shaping the human B cell repertoire by elimination of autoreactive B cells at different stages of B cell development. Dysregulation in the tolerant B cell compartment is characteristic of many autoimmune diseases, but in Psoriatic Arthritis (PsA), the role of B cells remains unknown. I will firstly investigate mechanisms of B cell tolerance in health and infection, and then apply this knowledge to PsA to determine if tolerance is broken in this context and the functional implications of this in disease pathogenesis. I will determine if auto-reactivity is a feature of PsA and role of synovial B cells. Understanding underlying mechanisms that contribute to fine balance of B cell activation and regulation could allow us to better understand processes involved in autoimmune diseases. These studies will hopefully decipher new layers of PsA pathology, that could translate into novel therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Improving pain outcomes in rheumatoid arthritis; detecting the contribution of central pain mechanisms
Funder: Versus Arthritis

Abstract: Background: DMARDs reduce joint inflammation but persistent pain remains RA’s most important symptom. Persistent RA pain is associated with central sensitisation, which may remain unresponsive to the reduction of inflammation. We have developed a simple, new questionnaire measuring Central Aspects of Pain in people with Knee pain (CAP-Knee) which we will refine and validate for use in people with RA. This tool will be used to predict and stratify for treatments aiming to improve pain prognosis. Objectives: Refine and validate the new questionnaire (CAP-RA) identifying people with active RA whose pain is augmented by central sensitisation, and who are destined to have poor pain outcome despite csDMARD or bDMARD therapy. Derive CAP-RA scoring recommendations for patient stratification in clinical trials and clinical practice, identifying those who might benefit from adjunctive treatments aiming to reduce central sensitisation. Methodology: CAP-RA will be developed from our CAP-Knee questionnaire, and qualitatively and quantitatively validated in 250 people followed for 12 weeks after recruitment with active RA. Measurement properties and optimal scoring methods will be determined through Rasch analysis, and test-retest reliability by intra-class correlation. External validity as an index of central sensitisation will be tested using quantitative sensory testing. CAP-RA cut offs for clinically-important central sensitisation will be derived by ROC analysis to predict persistent pain. Impact: CAP-RA will identify those with high central sensitisation destined to have persistent pain despite DMARD treatment for active RA. A stratification algorithm will be generated that will identify people who are most likely to benefit from adjunctive treatments targeting central pain mechanisms, for subsequent implementation in clinical trials and practice aiming to reduce the burden of RA pain.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the T cell signature of REmiSsion and mechanisms of ToleRAnce IN patients with Rheumatoid Arthritis treated with anti-TNF (RESTRAIN-RA)
Funder: Versus Arthritis

Abstract: Remission in rheumatoid arthritis (RA) is frequently achieved using therapies such as anti-tumour necrosis factor (anti-TNF) biologics. Whilst some patients remain in sustained remission even on tapering anti-TNF, up to two-thirds experience flares, suggesting a wide variation in immune states associated with remission. Regulatory T cell (Treg) function is disturbed in RA but their function and number can be enhanced by anti-TNF. My pilot data suggests that Treg may aid in the maintenance of remission, and their frequency in peripheral blood could predict flares during anti-TNF tapering. I hypothesise that Treg, through suppression of aberrant T effector cell (Teff) responses, determines whether remission is achieved and maintained. Treg-Teff balance is important for immune homeostasis. Abnormalities in Teff subsets may explain their resistance to Treg suppression and contribute to persisting inflammation. My pilot data suggests a higher proportion of senescent (aged) Teff in patients who have persistent disease activity despite treatment with anti-TNF compared to patients in remission. Senescent T cells are pro-inflammatory and may be resistant to Treg suppression. I will compare Treg and Teff subsets and functions between remission and non-remission RA patients on anti-TNF. I will also study a cohort of RA patients in remission who taper their anti-TNF, which is an increasingly practised therapeutic strategy, to understand mechanisms of tolerance and identify potential predictors of sustained remission. Goals: 1. Identify a T cell signature associated with anti-TNF induced remission in RA. 2. Investigate the role of T cell senescence and its relationship with Treg in preventing remission in RA. 3. Investigate the role of Treg and T cell senescence in maintaining remission upon anti-TNF tapering. The long-term aim is to understand how remission is achieved and maintained to aid therapeutic decision-making, including when tapering therapy, and inform current knowledge for defining remission.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing a theory-informed behaviour change intervention to improve pain assessment and communication by healthcare professionals managing children and young people with Juvenile Idiopathic Arthritis
Funder: Versus Arthritis

Abstract: Pain is one of the most challenging and burdensome features of Juvenile Idiopathic Arthritis (JIA) for children and young people and for a significant proportion of patients, pain will persist even when the disease appears well managed. Self-reported, multi-dimensional assessment is critical for informing optimal management of pain in JIA. However, there are considerable challenges for healthcare professionals (HCPs) when communicating about pain in youth with JIA. My PhD research found many reasons contributing to this communication barrier, such as; time pressures to discuss pain complaints limited resources to address pain if it is reported lack of education on the role and nature of pain attitudinal barriers about pain perception and reporting in these patients Reducing pain is a priority for those with JIA but in addition, just having the opportunity to communicate about pain symptoms with HCPs is known to improve patients’ well-being even if complete relief is not possible. We now have multi-dimensional tools available to assess and communicate about pain, such as My Pain Tracker which helps children structure, understand and verbalise pain issues. However the capabilities, opportunities and motivation for HCPs’ to engage in these pain discussions still needs to be better understood and enhanced. The aim of this three year foundation fellowship project is to apply behaviour change theory to develop an acceptable and feasible behaviour change intervention to improve pain assessment and communication in HCPs managing JIA. I am a strong fellowship candidate given my strengths in qualitative research and my background in health psychology, pain and rheumatology research. I also have experience of leading pain and mHealth related research with children and young people, families and HCPs within the Centre for Epidemiology Versus Arthritis at The University of Manchester.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Validating granulocyte-colony stimulating factor (GM-CSF) as a novel therapeutic target in axial spondyloarthropathy (SpA): The GM-CSF Signa-SpA study
Funder: Versus Arthritis

Abstract: Background: Axial spondyloarthritis (SpA) is a common inflammatory arthritis primarily affecting spinal and sacroiliac joints. Patients’ physical abilities and quality of life can be severely impacted by the disease. Only two immune pathways are currently targeted by licenced therapies; these include inhibitors of tumour necrosis factor (TNF)-alpha and interleukin (IL)-17A. Only about one third of SpA patients achieve disease remission with anti-TNF agents; illustrating the significant clinical need for novel therapies for this disease. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a haematopoietic growth factor and immuno-modulatory cytokine. Neutralisation of the GM-CSF pathway has significant anti-inflammatory and analgesic effects in experimental models of inflammatory arthritis and in phase II clinical trials in rheumatoid arthritis (RA). Preclinical characterisation of the immuno-biology in SpA suggests that GM-CSF mediated inflammation may be more pathogenic in SpA than in RA; GM-CSF blockade should therefore be explored as a novel therapeutic pathway in axial SpA. Aims and objectives: I wish to determine if there is a distinct GM-CSF signature in the blood of SpA patients; and to ask if it is reversed by anti-GM-CSF treatment and correlates with clinical response to biologic therapies. This work will deepen our understanding of SpA pathogenesis and will refute or strengthen the scientific rationale for further developing GM-CSF targeted therapy in axial SpA. Identifying GM-CSF-specific biomarkers and immunological phenotypes could also be of value in characterising those patients most likely to benefit from GM-CSF inhibition prior to- or soon after commencing therapy. I will study patients recruited to an investigator-initiated, double blind, randomised, placebo-controlled, first in-disease, phase II clinical trial of a GM-CSF neutralising monoclonal antibody (namilumab) in axial SpA (NAMASTE trial). SpA patients starting anti-TNF-alpha and anti-IL17A agents as part of their routine NHS care will act as comparators.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Characterising the Centralised Pain Phenotype in Chronic Rheumatic Disease - A Stride Towards Personalised Analgesia
Funder: Versus Arthritis

Abstract: Pain is pervasive, burdensome and challenging to manage across all chronic rheumatic diseases, even treatable inflammatory disorders. For example, many patients with psoriatic arthritis (PsA) continue to report significant pain despite excellent control of their inflammation with modern immunosuppressive therapies. A central thesis to our proposed study is that this disparity between inflammation and pain typically results when dysfunctional central nervous system (CNS) processes are superimposed upon peripheral inflammatory mechanisms. We use the term “Centralised Pain” to refer to this phenomenon. Most importantly, this type of CNS pain needs entirely different treatments than those that are effective in treating inflammation. Currently no valid clinical measures of centralised pain exist. Since fibromyalgia (FM) is considered the prototypical centralised pain disorder, its diagnostic criteria may serve as a reliable proxy measure for this construct. PsA patients with the highest FM criteria scores would therefore be expected to exhibit features of CNS dysfunction in keeping with centralised pain and we would anticipate that this score will be highly predictive of non-response to peripherally targeted immunosuppressive therapies. We will test these hypotheses using data collected in the UK PsA registry and by recruiting PsA patients who will be deeply characterised using non-invasive investigations of the CNS. If we are correct, these studies will immediately substantiate the existence of centralised pain in PsA and will lend support to the use of FM criteria as a putative measure of centralised pain. Should we confirm our hypotheses in this current proposal, we will next submit an application to support the integration of our data with ongoing studies in other rheumatic populations with view to developing a generic point of care tool. Such a measure will transform clinicians' capacity to better diagnose pain according to mechanism, in turn leading to a personalised approach to pain management.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Development of a measuring app for finger lesions as an outcome measure for systemic sclerosis-related digital ulceration (SALVE: Scleroderma App for Lesion VErification)’
Funder: Versus Arthritis

Abstract: In order to support these aims, the funders have agreed to support a UK Centre that will:


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of DRG inflammation in the Passive Transfer Model of Fibromyalgia
Funder: Versus Arthritis

Abstract: Fibromyalgia syndrome (FMS) is a devastating common chronic pain condition. The severe pain and fatigue have a lasting impact on patients’ function and quality of life, affecting 2% of the population. The lack of a disease mechanism has hampered treatment, indeed, there are no disease modifying therapies to improve pain or function. In a paradigm shift, it was shown that pain-sensitising IgG serum-autoantibodies may cause FMS. FMS-IgG injected into mice, consistently elicits mechanical hyperalgesia mimicking donor-patients’ symptoms. Serum from healthy controls (HC) never caused hypersensitivity. C-fibre sensitisation also occurs. Little is known yet about these autoantibodies, however, immunohistochemistry shows that FMS-IgG locates to the satellite glial cells in the dorsal root ganglia (DRG). How they cause pain is unknown. My work has demonstrated localised DRG cytokine changes in this model. DRG, but not paw, IL-10 concentrations were significantly increased in FMS-IgG compared with HC-IgG treated mice. IL-6 was also increased. IL-10 likely represents a response to inflammation. Here, the macrophage is a key candidate based on transcriptome and macrophage knockout data. Cytokines are involved in several neuropathic models, particularly IL-10 and IL-6. Understanding these changes and their role in the pro-nociceptive FMS phenotype may unearth disease mechanisms modifiable by immunotherapy and diagnostic signatures. We aim to understand the mechanism of autoimmunity in FMS investigating the inflammatory changes in the DRG passive transfer model. Long term, we hope to develop diagnostic tests and therapies. We hypothesise that FMS autoantibodies generate localised DRG inflammation and that macrophages orchestrate this response. To test this, we will measure the changes in DRG inflammatory mediator concentrations, measure DRG macrophage proliferation and activation using fluorescence-activated cell sorting (FACS) and then measure cytokine transcription and production in these macrophages. Using a selective macrophage knock-down model we may also test the necessity of the macrophage in FMS development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of the Gut Microbiome in the development of Rheumatoid Arthritis in individuals positive for Anti-Cyclic Citrullinated Protein Antibody. (GMiRA study)
Funder: Versus Arthritis

Abstract: The aim of my fellowship is to investigate the role of the gut microbiome as a trigger for development of rheumatoid arthritis (RA) across a spectrum of at-risk individuals. Through a nationwide primary care initiative, we recruit individuals with non-specific muscle-skeletal (MSK) pain who are Anti-Cyclic Citrullinated Peptide Antibody (ACPA) positive, but without a diagnosis of an autoimmune disease. My pilot work, utilising a prospective at-risk cohort, has shown a gut dysbiosis in the at-risk population, and that the gut microbiome of both palindromic and pre-RA patients cluster, based on similarity of bacterial taxa regardless of ACPA titre. I will explore this relationship further using: Cross-sectional analysis.Individuals undergo baseline clinical, radiological and serological assessment placing them into high, medium or low risk of progression to RA. Stool samples, will be collected for 16S rRNA analysis. A total of 78 samples have been collected to date, with the aim of 40 samples per risk group. A healthy control comparative group of 25 individuals will be recruited. Longitudinal analysis.16S rRNA analysis of 25 patients from each risk group, at 0, 3, 6, 9 and 12 months, will investigate if progression along the preclinical disease continuum (from systemic autoimmunity to palindromic rheumatism and established disease) is associated with a gut dysbiosis that is, at each step, distinct from individuals who do not progress. Functional analysis.Using shotgun whole genome sequencing in a subset of disease progressors (n=10) to elucidate the species-specific members and infer pre-RA microbiome function. I will investigate the development of RA through microbial dysbiosis, a major break though in the understanding of RA development. It will also provide an archetypal profile informing risk stratification models for RA development, and provide niche microbial targets to develop new therapeutics with the potential to improve outcomes for those suffering from RA.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The immunogenetics of LGI1- and CASPR2-antibody encephalitis: towards aetiology
Funder: Wellcome Trust

Abstract: Inflammation of the brain, known as encephalitis, causes symptoms of seizures, confusion and worsening memory, and may be due to infection or autoimmune causes. Autoimmune means a person’s immune system reacts against their own body, instead of nature’s intended targets of bacteria and viruses. So, if the immune system reacts in this way against the brain, it results in encephalitis. We know that treatments which dampen down the immune system can help limit the symptoms of autoimmune encephalitis, but our current medications are only partially successful, particularly for long-term effects on important aspects like memory, mood, and quality of life. If we could understand the root cause of autoimmune encephalitis in more detail, it would help us plan effective clinical trials and treatments. Recently, research by our group and others discovered certain molecules involved in infection and immunity, termed Human Leucocyte Antigens (HLA), are linked to autoimmune encephalitis risk. Specific HLA genetic variants are more frequent in patients with autoimmune encephalitis. Now, we aim to expand on these findings by studying more patients and other genes. These genes might influence whether a person gets the disease, make side effects from drugs more likely, or increase risk of longer-term problems.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM