NIHRDataInsights/HRCSData huggingface dataset:
Title: Where fibroblasts go bad: rebalancing immune checkpoints in RA by targeting the synovial microenvironment
Funder: Versus Arthritis

Abstract: Joint inflammation is a naturally self-limiting process. In contrast, rheumatoid arthritis (RA) is defined by inappropriate, persistent joint inflammation. We identified one way in which immune checkpoints designed to resolve inflammation fail in people who develop RA. We found that signals from the microenvironment, which trigger inflammation intended to restore homeostasis following tissue injury, are not switched off in RA joints. We developed therapeutic monoclonal antibodies that prevent disease progression in arthritis models by blocking toll-like receptor 4 activation by the extracellular matrix molecule tenascin-C. Absent from healthy human joints, tenascin-C accumulates in inflamed joints early in RA development, before disease is clinically apparent. High tenascin-C levels associate with difficult-to-treat disease, and predict people whose pain will not be improved by anti-TNF treatment. This new class of immunomodulatory drug offers the potential for early disease modification in RA, without engendering global immune suppression. However, progressing these antibodies to the clinic requires better understanding at the cellular level of how improved disease outcome is achieved. In the RA synovium, an anatomically complex tissue inhabited by diverse, functionally specialized cell subpopulations, tenascin-C is restricted to two specific niches; surrounding immunomodulatory fibroblast subsets in the sublining layer, and underneath blood vessels at sites of immune cell infiltration. Aim 1 of this project will identify which cell subsets within these niches are potential targets for tenascin-C. Aim 2 will investigate the mechanisms by which different synovial fibroblast subsets sense and respond to tenascin-C, and test the hypothesis that tenascin-C blockade ameliorates joint disease by preventing prolonged activation of immunomodulatory fibroblasts. Our goal is to understand the mode of action of anti-tenascin-C antibodies; specifically how they modulate the architecture and phenotype of pathogenic synovial cell networks during different disease stages, to inform the design of clinical trials of these antibodies in people with RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The pathogenic role of interleukin-36 in Systemic Lupus Erythematosus
Funder: Versus Arthritis

Abstract: Systemic lupus erythematosus (SLE) is an incapacitating autoimmune condition, which presents with fatigue, arthritis, scarring skin rashes and, in the most severe cases, life-threatening nephritis. While it has long been established that the disease is mediated by the activation of autoreactive B cells, the mechanisms underlying this phenomenon remain poorly understood. Thus, treatment mostly relies on broad immune modulators associated with significant side effects. Interleukin (IL)-36 is an IL-1 family cytokine that is up-regulated in the serum of individuals with SLE. We have recently demonstrated that IL-36 potentiates IFN-α production by plasmacytoid dendritic cells (pDCs), a process that is crucial to SLE pathogenesis. We also observed that the IL-36 receptor receptor is abundantly expressed in pDCs and B lymphocytes. Thus we propose that IL-36 contributes to SLE by promoting the activation of these cell types. To validate this disease model, we will: Investigate the effects of IL-36 on the pDC and B cell transcriptional networks that are de-regulated in SLE. This will be achieved through the analysis of single-cell RNA-sequencing data that is being generated by the group. Determine the effects of IL-36 stimulation and IL-36 blockade on B cell activation. We will isolate B cells from the blood of healthy donors and affected individuals. We will then characterise the effects of IL-36 by flow-cytometry. Assess the correlation between serum IL-36 levels, B cell activation, IFN-α upregulation and SLE severity. We have already collected serum and characterised B cell immune phenotypes in 94 affected individuals. We will build on this dataset to measure SLE activity, IL-36 production and signatures of IFN-α activation. Taken together, these experiments are expected to validate IL-36 as novel biomarker and therapeutic target in SLE. Given that two IL-36 blockers are currently in clinical development, our findings will have significant translational implications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Health outcomes in people with rare autoimmune rheumatic diseases during the COVID-19 pandemic: a whole population study in England.
Funder: Versus Arthritis

Abstract: Background People with rare autoimmune rheumatic diseases (RAIRD) have been shown to have a larger increase in all-cause mortality during COVID than the general population(5). My research during the first wave of the pandemic has confirmed an increased rate of COVID-19 infection and a higher age-adjusted COVID-19-related mortality rate in people with RAIRD compared to the general population. Key goals In people with RAIRD in England: Calculate the rates of COVID-19 infection, hospitalisation and death during the second wave of the pandemic, and compare to the general population. Quantify the effect of: age, sex, ethnicity, socioeconomic status, co-morbidities. Quantify the effect of corticosteroids, immunosuppression, and the relationship with shielding status, on COVID-19 outcomes. Quantify the effectiveness of vaccination in preventing COVID-19 infection, hospitalisation and death compared to the general population. Study design We have identified 168,691 people living in England with a diagnostic ICD-10 code for RAIRD. Using NCARDRS’ legal permissions, I will access HES data in patient-identifiable format, allowing linkage of data on admissions, diagnostic coding, Office for National Statistics mortality, COVID-19 PCR testing, shielding status, the National Immunisation Service, and NHS Prescription Services. I will calculate COVID-19 infection and hospitalisation rates, and crude, age-specific and age-standardised mortality rates. I will add covariates for corticosteroids, immunosuppressive medication and shielding, and use Cox regression to quantify their influence on outcomes. I will compare rates of confirmed COVID-19 infection following vaccination between people with RAIRD and the general population. I will compare markers of disease activity and damage (corticosteroid prescriptions, CKD diagnoses) at the start of the pandemic and 12 months later. Application This work will quantify COVID-19 outcomes among people with RAIRD and examine the effect of modifiable risk factors. The results will inform clinical guidelines and health policy on shielding and vaccination schedules.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the role of androgen receptor modulation in the pathogenesis of juvenile systemic lupus erythematosus
Funder: Versus Arthritis

Abstract: Paediatric-onset juvenile systemic lupus erythematosus (JSLE) is associated with increased morbidity and mortality compared to adult-onset disease, suggesting an unmet need for better patient stratification and selection of therapies. JSLE in more common in girls and starts at the time of puberty, implying a link between female sexual maturity and JSLE development. Research in animal models has shown that androgens and androgen receptor (AR) modulation exert suppressive effects on development and activation of B-cells that can be protective against immunity. Using our unique adolescent biobank resource, we have shown that healthy adolescent males and females have distinct immune cell signatures, which are lost if they develop JSLE, suggesting a sex-biased phenotypic switch potentially implicated in the pathogenesis of JSLE. In this proposal, the PhD student will test the hypothesis that puberty determinants (defined as pubertal state, sex hormone levels and number of X-chromosomes) influence AR expression and function on B-cell subsets or cause defects in the AR signalling processing that contribute to JSLE pathogenesis. The project will have 3 key goals: 1. Investigate the impact of puberty determinants on B-cell phenotypic profiling in JSLE. 2. Analyse gene expression profiling in sorted CD19+ B-cells from JSLE patients compared to healthy controls and explore the impact of puberty determinants on target gene expression. 3. Test whether modulation of AR in vitro can alter B-cell function and explore its potential relevance for JSLE pathogenesis. The project includes basic mechanistic investigations and translation potential, using a well-phenotyped pre- and post-pubertal JSLE cohort and a unique experimental group, including young people with gender dysphoria and Turner and Klinefelter’s syndromes. This research has translational potential as it could reveal puberty and gender related unique immune signatures that will help us stratify JSLE patients, or AR signalling abnormalities that can be targeted by the available AR modulators.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: A functional investigation of the inducible nitric oxide synthase (NOS2) association with Ankylosing Spondylitis
Funder: Versus Arthritis

Abstract: Ankylosing spondylitis (AS) has a complex polygenic aetiology with >100 genes significantly associated, including two independent associations with NOS2 (inducible nitric oxide synthase) for which the most significant single nucleotide polymorphisms (SNP) are rs2531875 (p=1.2x10-10) and rs2297518 (p=6.3x10-7). We will fine map all the primary NOS2 SNP association(s) and then establish the causal functional mechanisms for this to identify potential new drug targets for AS. We have already explored several AS-associated NOS2 SNPs for evidence of functional effects. For example, we investigated rs2531864, another plausible functional candidate and showed that the risk and protective alleles exhibited differential binding of nuclear extracts from monocytes and lymphocytes. This polymorphism lies in a putative enhancer 5’ of NOS2 and influences differential lymphocyte count. We will use detailed conditional analysis of the ongoing International Genetics of AS (IGAS) consortium genome-wide association data to fine map the NOS2 associations before conducting targeted functional studies to characterise the likely influence of individual SNPs in AS. These experiments will evaluate effects on transcription factor binding (Electrophoretic Mobility Shift Assays), gene promoter/enhancer activity (Luciferase Reporter Assays), effects on chromatin organisation (Chromosome Conformation Capture) and physical interactions (DNA pull-down/Mass Spectrometry). The focus of the project will be: 1) To fine map the genetic association at this locus and identify the NOS2 SNPs primarily associated with AS. 2) To investigate the functional effects of rs2531875 and other AS-associated polymorphisms in relevant cell types (especially CD8+ T-cells, monocytes and macrophages). 3) To identify differentially binding transcription factors and other DNA regulatory elements at NOS2 4) To define the physical interactions of NOS2 regulatory elements at the local and genome-wide level and to define their effects on transcriptional activity From these experiments we expect to identify cell-type specific biological pathways that will be informative for the identification of drug targets for AS.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Using multi-omic signatures and artificial intelligence (AI)/machine learning (ML) to predict long-term prognosis of patients with juvenile systemic lupus erythematosus
Funder: Versus Arthritis

Abstract: Juvenile-onset systemic lupus erythematosus (JSLE) accounts for 15%-20% of all cases and starts in childhood or adolescence. JSLE has a more aggressive disease presentation compared to adult disease; there are no licensed treatments for JSLE and no cure. We investigated the potential immunological processes driving JSLE pathogenesis using machine learning (ML) techniques applied to immunophenotype data and longitudinal clinical data for patient stratification and prognosis. The immunological architecture of JSLE patients was significantly disrupted compared to matched healthy controls characterised by defects in CD8+T-cell, CD19+B-cell and CD14+monocyte populations. Furthermore, we identified a distinct CD8+T-cell immunological signature that predicted a more active disease outcome at 5-year follow-up (Lancet Rheumatology https://doi.org/10.1016/s2665-9913(20)30168-5). We now hypothesise that ML approaches applied to multi-omics (immunophenotyping, proteomic, metabolomic and transcriptomic data) and clinical data from JSLE patients can identify predictive signatures for precision diagnosis and personalised therapy. Our key goals are: Aim-1: Stratify JSLE patients into clinically meaningful groups (clusters) based on immune signatures identified and validated by our established ML analysis pipelines (published data): investigate the proteomic/metabolomic and transcriptomic signatures associated with each cluster. Aim-2: Establish long-term disease trajectories of each disease cluster and investigate the predictive value of the signatures’’ defined in Aim-1. Aim-3: Define the functional characteristics of immune cells from JSLE patients stratified using multi-omic signatures and assess the in vitro impact of pharmacological inhibition e.g. cytokine/signaling inhibitors. Outcomes: This project will Identify and validate immune/transcriptomic/proteomic/metabolomic biomarkers with predictive value which can inform treatment decisions in JSLE (e.g. stopping treatment in JSLE patients with sustained low disease activity or improved selection of B-cell and other targeted therapies). This research has translational potential and could reveal new JSLE molecular abnormalities potentially targetable by new/repurposed treatments. The project will provide research training opportunities in ML and multi-omic analysis, cell culture and flow cytometry techniques.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of co-receptors in T cell signaling and activation
Funder: Wellcome Trust

Abstract: T cells patrol the human body for signs of infection and cancer. We generally divide them into two different types depending on what surface molecules they express and what functions they have: CD8+ T cells directly kill infected cells and CD4+ T cells help and talk to other immune cells. The CD4 and CD8 molecules are also known as ‘co-receptors’ as they help integrate and enhance signaling through the main T cell receptor in its search for danger signals – but how they help is not well understood. Our aim is to investigate the functions and features of these ‘co-receptors’ that allow them to enhance our immune responses so potently. We will do this through state-of-the-art biophysical measurements and super-resolution microscopy. The results of this study will help explain how T cells are activated in response to foreign threats, which is critical to refining our understanding of T cells in order to harness them therapeutically.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of CD101+ Tregs for adoptive cell therapies in systemic lupus erythemasosus
Funder: Wellcome Trust

Abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder primarily affecting women of childbearing age. Characteristic for SLE is the dysregulation of the immune system leading to inflammation. Regulatory T cells (Tregs) which suppress excessive immune responses lose their abilitiy to appropriately suppress other immune cells. Analysis of the profile of active genes (transcriptional signature) in Tregs helped to identify potential proteins that might be involved in disease progression. The surface protein CD101 is present on highly suppressive Tregs in mouse models and patients with active SLE exhibit a loss of this subpopulation. With this project, we propose a multi-faceted approach of phenotypic and functional characterisation of CD101+ Tregs in established cell culture assays and mouse models to validate their suitability for potential therapies. High-dimensional analysis will provide a personalised deep-phenotypic and transcriptomic signature of immune cells and correlate these data to disease progression. Thus, delivering a detailed profile of the subset distribution of Tregs and other cell types affected by the loss of Treg function in SLE. Thereby, we aim to provide detailed insights into the pathophysiology of this heterogeneous disease and identify potential diagnostic markers that facilitate patient-specific therapeutic decisions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: How does impaired FAMIN activity affect dendritic cell function?
Funder: Wellcome Trust

Abstract: Inflammatory bowel disease (IBD) is a major problem in the developed world and prevalence is increasing in newly industrialised countries. Genome-wide association studies (GWAS) have identified more than 200 IBD risk loci, however functional insight is lacking. A single nucleotide polymorphism (SNP) in FAMIN, present in 30 % of most populations, increases risk of Crohn’s disease (CD) and leprosy. A missense mutation is linked to early-onset CD. Previous work in the Kaser laboratory identified FAMIN as being a key player at the intersection of metabolism and immunity, affecting cellular energy homeostasis and immunological function. Thus far, studies in the Kaser laboratory have focussed on macrophages – innate immune sentinels that are heavily impaired by lost FAMIN activity. I am interested in dendritic cells (DCs), the go-between of the innate and adaptive immune systems and the importance of whose metabolic regulation has increasingly come into focus. Intriguingly, preliminary data indicates impaired FAMIN function boosts DC priming of T cells. I will use reductionist, physiologically relevant murine DC (co-)culture models and LC-MS techniques to study fatty acid metabolism and the effects of lost FAMIN activity in DCs. This work will provide valuable mechanistic insight into how metabolic patterns direct DC immunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the impact of the local inflammatory environment on CD4+ T cell metabolism and function
Funder: Wellcome Trust

Abstract: In inflammatory diseases such as rheumatoid arthritis (RA), T cells (a type of white blood cell) take on multiple different forms. These forms, known as subsets, can contribute to disease or help to resolve it. To develop new drugs for inflammatory diseases, we need to understand how these subsets of T cells are made and maintained. “Metabolism” describes the chemical processes cells use to break down nutrients. It is the basis of all changes in cells, even determining what subset they become. Importantly, metabolism can be targeted with drugs. Whether T cell metabolism changes in inflammatory disease is not yet fully understood. We will investigate this, try to understand the processes involved and test if changing the metabolism of inflammatory T cells influences their subset. To do this, we will compare the metabolism of T cells from RA patients with those from healthy people. We will also investigate the role of cytokines –signals released by immune cells to communicate with each other. These are increased in RA and alter metabolism in other cell types, but their effects on T cells is not known. Together, this research will help us to better understand RA and aid the development of new treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: B cell receptor repertoire alterations in immunity and autoimmunity
Funder: Wellcome Trust

Abstract: Rheumatoid arthritis (RA) is a chronic, incurable autoimmune condition that affects more than 400,000 people in the UK and can cause severe disability. The contribution of B cells to pathogenesis in RA has long been recognised but the exact mechanisms by which they influence the inflammatory process are incompletely understood. Large-scale next-generation sequencing (NGS) projects have already begun to elevate our knowledge of the role of B cells in a wide range of diseases, by characterising expressed immunoglobulin (Ig) repertoires. New NGS methods focusing on individual cells, including single-cell RNA sequencing, are incredibly powerful at revealing heterogeneity in immune cell populations. A subset of B cells showing a distinct signature of hypomutated antibody, or IgG, has recently been identified in RA. By combining transcriptomic and antigen receptor repertoire data at a single cell level, I aim to understand the origin and role of this cell population. To do so, I will determine the transcriptional heterogeneity of peripheral B cells in RA, characterise gene expression signatures associated with the production of hypomutated IgG, and develop tools to improve analysis pipelines. This work will help clarify the involvement of B cell subsets in RA and may provide targets for more directed therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of TIGIT in immune regulation of autoimmune diseases
Funder: Wellcome Trust

Abstract: The adaptive immune system provides the host with a vast receptor repertoire of immune cells that facilitate protection from a broad range of pathogens1. One consequence of this incredible diversity is the development of immune cells specific for self-tissues, which could lead to the development of autoimmune diseases2. To counteract this auto-reactivity, the immune system uses a number of mechanisms to reinforce the state of tolerance to an individual’s own antigens3. This includes a dominant role for co-inhibitory receptors, such as T cell Ig and ITIM domain (TIGIT), which acts as a brake that determines the balance between activating and inhibitory signals4. While much has been learned recently about which co-inhibitory receptors are expressed in various immunological settings, little is known about how they actually function. We aim to use specific monoclonal antibodies that either block or boost the function of TIGIT and investigate the impact on T cell responses. We will use genetically manipulated mouse models that will provide insight into the role of TIGIT in immune regulation. Data obtained from this study can pave the way for future validation in humans, which will provide novel targets for the treatment of chronic infectious diseases, cancer, allergic and autoimmune diseases.


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