Our group seeks to understand how a break down in our our immune system can generate undesirable immune responses that lead to life threatening conditions such as autoimmune and chronic inflammatory diseases. Our research employs structural biology to examine, at the molecular level, critical events in in the pathogenesis of these diseases. Specifically, we examine the interaction between the T cell antigen receptor (TCR) and peptide autoantigens bound to the antigen-presenting molecule, Major Histocompatibility Complex Class II (peptide-MHC-II). The structural information is complemented by data generated using a set of techniques that have been developed in the laboratory over many years in the areas of molecular biology, biochemistry, biophysics and cellular immunology. Revealing the 3D picture of the engagement of the TCR with peptide-MHC-II enables us to generate a complete picture of the events triggering the T cell immune response. To assist in our understanding of these events comprehensively, that is, across the whole immune response to a given peptide-MHC-II, we have also developed technologies that enables production of peptide-MHC-II in fluorescently labelled tetrameric forms. These peptide-MHC-II tetramer reagents provide us with invaluable tools to examine the immune repertoire in disease settings. We are able to estimate the diversity of the T cell receptor repertoire displayed by antigen specific T cells directly from biopsy material from patients as we have demonstrated in celiac disease and rheumatoid arthritis. This in turn allows us to determine the structural bases for the recognition of peptide-MHC-II by a broad group of responding T cells which is crucial for understanding initial triggers for autoimmune disease. For a particular disease, this information allows us to understand how the TCR repertoire, and any biased TRAV/TRBV gene usage within it, is selected. This provides vital information on the role of a given autoantigen in driving disease pathogenesis.
Projects underway in the lab are focused on understanding disease pathogenesis in a number of autoimmune and inflammatory conditions including: rheumatoid arthritis, type 1 diabetes, coeliac disease, multiple sclerosis and Goodpasture’s disease. We are particularly interested in examining the influence that post-translational modifications of autoantigens have on the pathogenesis of these diseases. We are also comparing the structural basis for activation of regulatory T cells versus T effector cells for the same peptide-MHC-II to see how this governs the outcome of the the immune response to a given autoantigen.
Ultimately our goal is to help drive our basic research towards translational outcomes.
Hence, we aim to contribute to the development of better therapeutics as well as clinical testing reagents for autoimmune and chronic inflammatory diseases.