NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of monocytes in the pathogenesis of class IV-G lupus nephritis.
Funder: Arthritis Research UK

Abstract: Lupus nephritis is a major cause of morbidity and mortality in systemic lupus erythematosus (SLE). Therapy of lupus nephritis remains unacceptably empiric, with significant associated side effects. Diagnosis is often delayed as there are few predictive markers to identify lupus patients at high risk of developing future nephritis. Patients with class IV-G nephritis exhibit greater immune complex deposition and glomerular monocytes than patients with class IV-S nephritis. CD16+ monocytes may act as effector cells in class IV-G lupus nephritis, as a result of their FcγR-dependent and TLR-dependent activation by immune-complexes containing nucleic acids, by producing inflammatory cytokines or cytotoxic molecules resulting in endothelial damage in genetically predisposed individuals. We aim to confirm our hypothesis that different pathogenic mechanisms result in distinct forms of lupus nephritis (class IV-G and class IV-S), examine the role of genetic polymorphisms uncovered in recent Genome Wide Association Studies (GWAS) studies in the development of class IV-G nephritis and in monocyte activation, and investigate the mechanisms of endothelial cytotoxicity by monocytes. Understanding the pathophysiology of class IV-G lupus nephritis will allow prospective testing of the predictive value of risk factors for the development of lupus nephritis in patients and to develop personalized/customized therapies in susceptible individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Exploring novel molecular mechanisms and targets to improve treatment and outcomes in patients with the antiphospholipid syndrome
Funder: Arthritis Research UK

Abstract: The antiphospholipid syndrome (APS) is a major cause of thrombosis, miscarriage and strokes especially in patients with autoimmune rheumatic diseases. APS is caused by antiphospholipid antibodies (aPL) which bind to beta-2-glycoprotein I (beta-2-GPI). The aPL/beta-2-GPI complexes act on target cells including monocytes, endothelial cells and trophoblast to trigger intracellular signalling mechanisms and altered cell function leading to development of thrombosis and/or miscarriages. Current methods for diagnosis and treatment of APS are limited and unsatisfactory. Blood tests to detect aPL are not specific enough for APS to predict accurately the risk of developing thrombosis or miscarriage. The only treatment currently proven to prevent recurrent thrombosis in patients with APS is long-term anticoagulation with warfarin which can have serious adverse effects. Our programme of research aims to improve diagnosis and treatment of APS by achieving the following goals_x000D_ _x000D_ 1) Develop new blood tests which identify people with a high risk of developing APS more accurately than current tests._x000D_ _x000D_ 2) Develop a new drug treatment that stops aPL from binding to beta-2-GPI and hence blocks the actions of aPL on target cells._x000D_ _x000D_ 3) Achieve a detailed understanding of changes in signalling and function inside cells that are triggered by surface interaction with aPL.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Scleroderma pathogenesis: fibroblast-dependent dysregulated connective tissue repair
Funder: Arthritis Research UK

Abstract: Scleroderma is a life-threatening rheumatic disease where three linked pathophysiological processes; vasculopathy, inflammation, and tissue remodelling underlie key clinical manifestations. Although vascular and immune activation are early and potentially primary events in scleroderma, they inevitably lead to progressive and excessive scarring of affected tissues and organs. Whilst recent evidence paints an emerging picture of increased complexity with distinct cell activities (endothelial, pericytes, macrophages, neutrophils, B/T cells) prominent at specific stages of disease development, it is the fundamental re-programming of the tissue fibroblast which causes the major pathological sequelae of abnormal tissue repair and replacement fibrosis (Figure 1.). We aim to significantly refine our understanding of the molecular mechanisms driving the fibroblasts to deposit and remodel scar tissue by; 1. Performing novel in vitro experimental therapeutic studies with scleroderma fibroblasts increasing our precision delineating regulatory pathways activated in established disease; 2. Executing a longitudinal contemporaneous prospective study, to delineate for the first time, the cell and molecular mechanisms that underpin each subset and disease stage to inform disease susceptibility and progression, and 3. Developing new, novel and more informative in vivo models, to robustly test fibroblast-specific gene modulation and fibroblast ablation on diseases pathogenesis and to explore therapeutic targets and strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Evaluation of the roles of TPL-2 kinase and ABIN-2 ubiquitin-binding protein in arthritis
Funder: Arthritis Research UK

Abstract: Analyses of Tpl2-/- mice have suggested that the MAP 3-kinase TPL-2 is a critical regulator of inflammatory responses, controlling the production of both tumour necrosis factor and interleukin-1β. However, Tpl2-/- cells are also deficient in the ubiquitin-binding protein ABIN-2, with which TPL-2 associates. It is therefore uncertain whether the described phenotypes of Tpl2-/- mice are due to the lack of TPL-2, ABIN-2 or both. To develop a better model for TPL-2 in inflammation, we have generated a new Tpl2 knock-in mouse strain that expresses a kinase-inactive mutant of TPL-2, and normal levels of ABIN-2. This mouse strain will be used to determine whether inhibition of TPL-2 kinase activity has beneficial effects on the development of collagen-induced and antigen-induced arthritis. Our proposed experiments are an important step in the evaluation of TPL-2 kinase as a potential drug target in rheumatoid arthritis. We will also test the development of arthritis in a novel Abin2 knock-in mouse strain, in which the ubiquitin-binding activity of ABIN-2 is blocked. These complementary experiments will establish whether ABIN-2 could also be a potential drug target for arthritis treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Changes in neutrophil gene expression during active and resolved inflammation
Funder: Arthritis Research UK

Abstract: During my PhD I studied changes in the function of neutrophils in active rheumatoid arthritis (RA) and during anti-TNF therapy. I showed abnormal autocrine TNF signalling in these cells that returned to normal, baseline levels during successful therapy. I collected and stored RNA and protein samples of 20 RA patients pre-therapy and at 4-and 12-weeks post therapy (plus healthy controls). My experiments predicted global changes in gene expression that I could explore further with the tools and resources available to me at that time. The purpose of this Fellowship is to receive training in the emerging new technology of digital transcriptomics that offers considerable advantages over existing methodologies to examine global changes in gene expression. I will also receive first rate training in bioinformatics to analyse and interpret the data, and evaluate its biological significance. This will provide fundamental new insights into the molecular pathology of acute inflammation that should have benefits for patient care and could lead to new therapeutic approaches to treatment. The Fellowship will also provide me with first rate training in state of the art post-genomic technologies that will enable me to develop as an independent researcher working at the scientific/clinical interface.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Shedding light on the cause of systemic sclerosis: Can non-invasive imaging techniques elucidate pathogenesis and measure disease?
Funder: Arthritis Research UK

Abstract: Background: Systemic sclerosis (SSc) is a rare multisystem connective tissue disease. It often affects young people and has the highest mortality of all rheumatological disorders. Ischaemia, hypoxia and oxidative stress are all believed to play a key pathogenic role. However, their inter-relationships with fibrosis, particularly the skin fibrosis which characterises SSc, are not fully understood. Goals: The aims of this study are to validate novel, light-based, non-invasive imaging techniques as markers for SSc; to investigate the relationships between skin thickening (reflecting fibrosis), blood flow, oxygenation and oxidative stress; and to elucidate the pathogenesis of digital ulceration, calcinosis, and telangiectases, three key cutaneous clinical features of SSc associated with significant pain, disability and/or distress. Methods: Imaging techniques will be applied in longitudinal studies including studies of reproducibility and in cross-sectional studies of patients and healthy controls, examining areas of involved/uninvolved skin in early/late disease and in studies of digital ulcers, calcinosis, and telangiectases. Conclusions: Validating markers for SSc will facilitate studies of disease severity, progression and treatment response. Understanding how fibrosis, perfusion, oxygenation and oxidative stress interconnect will clarify pathogenesis and may inform new approaches to treatment. These imaging techniques are likely to significantly impact upon future SSc-related research.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of the interaction of mast cells, T cells and dendritic cells in inflammatory arthritis
Funder: Arthritis Research UK

Abstract: Mast cells play key roles in the pathology associated with host defence and a variety of inflammatory diseases. They are a potent source of enzymes, cytokines and possess costimulatory and antigen presenting capacity. Recent studies implicate mast cells in inflammatory arthritis pathogenesis. However such studies have focussed mainly on innate immune mechanisms elucidated via immune complex driven models and leave many unanswered questions that preclude optimal therapeutic targeting. We will determine how mast cells, dendritic cells and T cells interact during the development of synovitis and thereafter evaluate the role mast cells play in the induction and perpetuation of the inflammatory response therein. Specifically, we will test the hypothesis that mast cells, either directly or indirectly, regulate the onset of synovitis via effects on antigen presentation, costimulation and T cell / APC activation and trafficking. Confirmation of this will directly inform the design of optimal MC targeting therapeutic strategies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Interactions between IgM, apoptotic cells and infection to modulate inflammatory arthritis and systemic lupus erythematosus
Funder: Arthritis Research UK

Abstract: Understanding how the immune system is controlled to avoid tissue destruction will yield insight into disease mechanisms and more effective treatments. Efficient clearance of apoptotic cells is not only key to preventing systemic lupus erythematosus (SLE), but can also switch off inflammatory arthritis. Secreted IgM facilitates the removal of apoptotic cells and its absence can promote autoimmunity. We have found that the ability of apoptotic cells to suppress inflammatory arthritis is dependent on the presence of secreted IgM. This proposal will dissect the mechanisms that underpin the actions of secreted IgM and its interactions with apoptotic cells to suppress both SLE and inflammatory arthritis. Recent evidence has revealed that the response to infected apoptotic cells is to promote, rather than resolve inflammation. Given the putative role of infection in autoimmune rheumatic disease, we will compare the impact of resting and infected apoptotic cells on inflammatory arthritis and lupus autoimmunity. Our aim is to unravel key cellular interactions that are engaged by apoptotic cells and help in the identification of new regulatory pathways. These findings will also shed new light on the interaction between infection, inflammatory arthritis and SLE in the context of cell death.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of CREB in limiting inflammation
Funder: Arthritis Research UK

Abstract: Appropriate regulation of pro-inflammatroy cytokine production by innate immune cells is essential for the normal function of the immune system, however excess production of pro-inflammatory cytokines by these cells is a contributing factor to many autoimmune or auto-inflammatory diseases. Cytokine production is precisely regulated by positive and negative mechanisms While much progress has been made in understanding the signaling promoting the induction of pro-inflammatory cytokines, the negative regulatory pathways are not fully understood. Recently, in work funded by a previous Arthritis Research UK grant, we have found that the kinases MSK1 and MSK2 play an important role in limiting pro-inflammatory cytokine production downstream of TLRs (Nat. Immunol., 2008, 9, 1026-36, Biochem J. 2010, 425, 595-602). How MSK does this is unclear, however one possibility is that MSKs act via the phosphorylation of the transcription factors CREB and ATF1 to induce genes that limit TLR signaling or encode anti-inflammatory proteins. In this work we will examine the role of CREB and ATF1 in mediating the effects of MSKs, and determine the target genes they regulate that are responsible for limiting inflammation. Additionally the possibility that CREB and ATF1 act to integrate anti-inflammatory signals downstream of other pathways will also be investigated.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Identification and defining the role of pathogenic B lymphocytes in patients with lupus
Funder: Arthritis Research UK

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune inflammatory disease influenced by defective regulation of B-lymphocyte leading to hyperactivity and the production of pathogenic auto-antibodies. Studies carried out in our laboratory have identified defects in key signaling pathways in B-lymphocyte from patients with SLE. These signaling defects are associated with altered regulation of CD45, an important membrane phosphatase that regulates antigen and cytokine receptor-mediated signaling. A sub-set of B-lymphocytes that expresses reduced membrane CD45RB and CD5 and manifest characteristic signaling defects, hyper responsiveness and produce auto-antibodies has been identified as significantly increased in the blood of patients with SLE. In this study we propose to confirm the role of this B-lymphocyte subset in lupus disease pathology. We aim to achieve this by relating the frequency and responses of this subset of cells to disease activity and response of patients to therapy. In particular, we wish to relate the frequency and functions such as proliferation cytokine production and micro RNA levels of these cells with depleting anti-B-lymphocyte therapy (Rituximab). Further, we will explore the existence of unique features in these cells to facilitate targeting them for therapy. The study could have profound benefits for the treatment of patients with SLE.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Does PKC theta contribute to T cell survival in the inflamed joint?
Funder: Arthritis Research UK

Abstract: In the inflamed rheumatoid synovium the microenvironment delays the removal of T cells by apoptosis. Since we first described this observation, investigating the underlying mechanism has been a priority area for our work. In our studies of the role of the PKC family of signalling molecules in the regulation of T cell apoptosis we recently showed that activation of PKC theta in T cells is a survival signal of such a magnitude that it can overcome the proapoptotic effects of other members of the PKC family such as PKC delta. In this study, we also observed an unexpectedly high level of activation of PKC theta on T cells in the inflamed synovium. We hypothesize that PKC theta activation contributes to the extended life-span of T cells in the rheumatoid synovium. In the PhD project proposed here, we plan to quantify the level of PKC theta activation, and to investigate the signals leading to its activation in T cells infiltrating the rheumatoid synovial fluid and tissue. Furthermore, we will use inhibition assays to examine the role of PKC theta activation in synovial T cell survival. The proposed research will eventually help to determine whether this survival signal could be exploited therapeutically.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Does strength of T-cell receptor signalling regulate Th17 responses in autoimmune arthritis?
Funder: Arthritis Research UK

Abstract: T helper (Th)17 cells play a key role in the pathogenesis of rheumatoid arthritis (RA) and other autoimmune diseases. Therefore, it is important to understand how Th17 responses are regulated and how they can be switched off. We have recently demonstrated that T-cell receptor (TCR) signal strength determines Th17 cell development in vitro, providing new avenues for targeting Th17 cells. We propose to investigate the role of TCR signal strength in regulating Th17 development in vivo, using transgenic mice expressing a TCR specific for aggrecan, a candidate autoantigen for RA. The contribution of TCR ligand affinity and density to Th17 development will be determined by designing altered peptide ligands with high or low affinity for the aggrecan-TCR and by performing extensive dose titrations, respectively. Furthermore, as the duration of TCR-peptide-MHC II binding also determines strength of T-cell activation, the effect of shortening this interaction will also be investigated. Finally, we will investigate whether established Th17 responses in arthritic mice can be inhibited by altering TCR signal strength. This work will provide novel insights into the mechanism(s) regulating Th17 development in vivo, potentially leading to the design of novel therapeutic strategies for RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Examining the interplay between serum and membrane lipids in driving lupus T cell dysfunction
Funder: Arthritis Research UK

Abstract: Recent advances in the treatment of patients with systemic lupus eyrthematosus (SLE) has extended the lives of many but revealed a new and serious complication of the disease, premature atherosclerosis. This increased risk is associated with, amongst other factors, abnormal serum lipid profiles. The role of serum cholesterol in atherosclerosis, in particular the role of low density lipoprotein (LDL), high density lipoprotein (HDL) and their oxidised forms, is well described. Signals generated by HDL and LDL can influence cellular lipid homeostasis, although their effect on lymphocyte activation is less well known. Previously we have demonstrated lymphocyte dysfunction associated with altered levels of plasma membrane cholesterol and glycosphingolipids (GSL) in patients with SLE. Here, we propose to characterise the effects of cellular and serum dyslipidaemia on T cell function in lupus patients compared with healthy volunteers and patients with rheumatoid arthritis and Sjogren’s Syndrome as disease controls. Specifically, we aim to phenotypically and functionally characterise the T cell plasma membrane and serum lipid profile, and to evaluate the effect that dysregulated lipid expression has on T cell function and explore how any abnormal interactions can be modified.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Imaging normal and abnormal HLA-B27 in cell lines and in Ankylosing Spondylitis patients
Funder: Arthritis Research UK

Abstract: Possession of the Human Leukocyte Antigen (HLA) class I molecule B27 is strongly associated with Ankylosing Spondylitis (AS), but its pathogenic role is unknown. B27 can adopt different forms, and we have proposed that an abnormal dimeric form causes inflammation in AS when expressed at the cell surface. Others have highlighted the importance of abnormal B27 forms expressed in the endoplasmic reticulum. We will use FACS, confocal microscopy, image stream and DySCo to determine which cells express B27 dimers, where in the cell and how B27 dimers form. By using existing antibodies together with a novel B27-dimer-specific monoclonal antibody, we will also quantify B27 dimer expression on different AS patient cells within blood and synovial fluid, and ask if B27 dimer expression correlates with disease activity in AS patients followed over time.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM
Title: Innovative approaches to improving the safety and efficacy of glucocorticoids
Funder: Arthritis Research UK

Abstract: Glucocorticoids (GCs) can cooperate with pro-inflammatory stimuli to increase or prolong the expression of genes such as DUSP1, A20 and TTP, which are involved in the negative feedback control of inflammatory responses. We hypothesise that this unexpected cooperative gene regulation is responsible for many of the anti-inflammatory effects of GCs. If correct, there are very important implications for how we should understand both the successes and failures of GCs in the rheumatology clinic, and how we should try to improve both the safety and efficacy of these extremely useful but problematic drugs._x000D_ _x000D_ In this programme we will determine how much DUSP1, A20 and TTP contribute to anti-inflammatory actions of GC; identify other negative regulators of inflammation that are also cooperatively regulated by GCs and pro-inflammatory stimuli; determine the mechanism(s) underlying cooperative regulation; and formally test the hypothesis that activation of transcription by GCs is necessary for the effective suppression of inflammation. In the course of the programme we will also generate tools that could later be used for drug discovery, based on the principle that enhancing the expression of negative feedback genes is likely to inhibit inflammatory responses.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM