The ultimate aim of my work is to devise more effective therapies for immune-mediated glomerular disease, based on better understanding of pathogenesis. It concentrates on focal necrotizing glomerulonephritis (FNGN) associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA), and in particular on the contribution to pathogenesis of autoantibodies to lysosome membrane protein-2 (LAMP-2).
We have shown these autoantibodies are highly prevalent in ANCA-associated FNGN, correlate with disease activity and commonly recognised an epitope shared with the bacterial adhesin FimH; and that rats immunised with FimH develop anti-LAMP-2 antibodies, demonstrating the molecular mimicry between the two proteins and confirming their pathogenicity.
We are now trying to elucidate the role of molecular mimicry in patients with FNGN, and its mechanisms in transgenic mice that express human LAMP-2; and to characterise cellular consequences of antibody-induced disruption to LAMP-2’s physiological function, especially macro- and chaperone mediated autophagy, and antigen presentation. The research techniques used include clinical studies, morphology and ultrastructural approaches, molecular cell biology, and studying of T cell responses.