Studying immune regulation and autoimmune disease in patient cohorts and model systems, focusing on the biology of clinical outcome.
The Smith laboratory combines genetics, genomics, immunology and clinical medicine, integrating detailed laboratory analysis of mechanisms of immune regulation with a prospective translational medicine programme in major autoimmune and inflammatory diseases.
The main focus of the group is investigation of the biology underlying clinical outcome in immune-mediated disease. Western medicine has focused on categorising disease into defined diagnostic categories, but what determines patient outcome is the long-term course the disease takes following diagnosis. Our group have investigated the factors driving long-term outcome by prospectively collecting patient cohorts, and then following them for over ten years. Genomic studies identified a CD8 T cell signature associated with clinical outcome and T cell exhaustion. Genetic studies examining factors driving prognosis in Crohn’s disease have led to the description of a new pathway controlling inflammation, and a genome-wide association study (GWAS) has found further variants that associated with outcome but not susceptibility. The major concept arising from these findings is that there is a tractable biology governing long-term outcome in autoimmune disease that is distinct from that associated with disease susceptibility. The group are also leaders in vasculitis genetics, performing the first GWAS in ANCA-associated vasculitis (AAV). This work is now focusing on larger GWAS powered to independently examine MPO-, PR3-, and Churg-Strauss vasculitis.
Other recent findings have been in the area of immune regulation and autoimmunity, with a focus on the germinal centre. They include the discovery of novel mechanisms of selection and tolerance in the germinal centre and the identification of a new cell type, the T-follicular regulatory cell. We have also uncovered many aspects of FcgammaRIIb biology, including the discovery that SLE-associated variants in FcgammaRIIb protect from malaria in mice and humans. Finally, clinical studies are performed in collaboration with both the Vasculitis and Gastroenterology services and have included the first study of B cell depletion therapy in vasculitis, leading to subsequent Phase III studies and drug registration.
Lee JC , … Smith KG; Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell 2013. DOI: 10.1016/j.cell.2013.08.034.
McKinney EF … Smith KG; T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 2015. DOI: 10.1038/nature14468.
Lee JC … Smith KG. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn’s disease. Nature Genetics 2017. DOI: 10.1038/ng.3755.
Lee JC … Smith KGC; A blood-based prognostic biomarker in inflammatory bowel disease. Gut 2019. DOI: 10.1101/535153.
Espeli M … Smith KGC; FcgRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human. Nature Communications 2019 In Press.