Research Themes
ANCA-Associated Vasculitis, Clinical Trials, Secondary Immunodeficiency, Autoimmune disease
Research Activity
The group has been at the forefront of research defining the molecular pathogenesis of vasculitis with a particular emphasis on the role of pathogenic autoantibodies.
Our group has identified how autoantibodies against neutrophil cytoplasm components develop in patients with vasculitis, bind to neutrophil membrane components and trigger signal transduction pathways that lead to aberrant neutrophil activation. We have shown that the local inflammatory milieu is important in attracting and priming neutrophils for activation by ANCA. This is relevant to pathogenesis because accumulating evidence from our clinical studies, in vitro models and animal models, indicates that the aberrant autoantibody-driven neutrophil activation leads directly to initiation of endothelial and vascular damage. The impact of dysregulated neutrophil activation on effector responses is investigated in vitro using models of neutrophil-endothelial cell interactions under flow and intravital microscopy, while effects on the kidney glomerular and interstitial environment is studied using multi-staining immunohistochemistry and confocal microscopy in association with in vitro responses of isolated, cultured glomerular and tubular cells.
Our clinical research is designed to improve the long term survival of these patients by reducing disease and treatment associated morbidity and mortality by understanding the way that both the disease and its treatment affect the immune system. Clinical trials in collaboration with the European Vasculitis Study Group (EUVAS) have focused on optimising the short to medium term use of intensive immunosuppression for acute disease.
Clinical studies have targeted the adverse events, especially infection, associated with long term immunosuppressant use by identifying predictors of infection, investigating the role of secondary immunodeficiency, and investigating vaccine responses. We are also interested in the way that chronic viral infections modulate immune responses. Our studies suggest that CMV infection, probably in combination with immunosuppression, leads to profound changes in the T cell repertoire conferring an increased risk of infection and mortality which may be amenable to pharmacological intervention. We have recently demonstrated that cardiovascular disease risk is also significantly increased in vasculitis patients and we are examining the inflammatory mechanisms underpinning this with a view to introducing new risk reduction treatments. Improving quality of life for patients with chronic inflammatory and renal disease is also important to us and we are currently investigating the factors underlying the severe chronic fatigue experienced by many patients.