Immune regulation, autoimmune disease and infection
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 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.
Key papers
Thomas DC, Clare S, Sowerby JM, Pardo M, Juss JK, Goulding DA, van der Weyden L, Storisteanu D, Prakash A, Espéli M, Flint S, Lee JC, Hoenderdos K, Kane L, Harcourt K, Mukhopadhyay S, Umrania Y, Antrobus R, Nathan JA, Adams DJ, Bateman A, Choudhary JS, Lyons PA, Condliffe AM, Chilvers ER, Dougan G and Smith KGC. Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity. J Exp Med. 214(4):1111-1128. doi: 10.1084/jem.20161382 (2017)
Lee JC, Biasci D, Roberts R, Gearry RB, Mansfield JC, Ahmad T, Prescott NJ, Satsangi J, Wilson DC, Jostins L, Anderson CA; UK IBD Genetics Consortium., Traherne JA, Lyons PA, Parkes M and Smith KGC. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nat Genet. 49(2):262-268. doi: 10.1038/ng.3755 (2017)
Peters JE, Lyons PA, Lee JC, Richard AC, Fortune MD, Newcombe PJ, Richardson S and Smith KG. Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease. PLoS Genet. 12(3):e1005908. doi: 10.1371/journal.pgen.1005908 (2016)
McKinney EF, Lee, JC, Jayne DRW, Lyons PA and Smith KGC. T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection. Nature 523, 612-616 (2015). doi: 10.1038/nature14468.
Linterman, MA, Denton, AE, Divekar, DP, Zvetkova, I, Kane, L, Ferreira, C, Veldhoen, M, Clare, S, Dougan G, Espéli, M, and Smith, KGC. CD28 expression is required after T cell priming for helper T cell responses and protective immunity to infection. ELIFE 3. doi:10.7554/eLife.03180 (2014).
Wallin , EF, Jolly, EC, Suchánek, O, Bradley, JA, Espéli, M, Jayne, DRW, Linterman, MA, and Smith, KGC. Human T follicular helper and T follicular regulatory cell maintenance is independent of germinal centers. Blood 124, 2666-74. doi:10.1182/blood-2014-07-585976 (2014).
Richard, AC, Lyons, PA, Peters, JE, Biasci, D, Flint, SM, Lee, JC, and Smith, KGC. Comparison of gene expression microarray data with count-based RNA measurements informs microarray interpretation. BMC Genomics 15, 649. doi:10.1186/1471-2164-15-649 (2014).
Lee, JC, Espéli, M, Anderson, CA, Linterman, MA, Pocock, JM, Williams, NJ, et al, and Smith, KGC. Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway. Cell 155(1), 57-69. doi:10.1016/j.cell.2013.08.034 (2013).
Mok, Y, Schwierzeck, V, Thomas, DC, Vigorito, E, Rayner, TF, Jarvis, LB, et al, and Smith, KGC. MiR-210 is induced by Oct-2, regulates B cells, and inhibits autoantibody production. J. Immunol. 191(6), 3037-3048. doi:10.4049/jimmunol.1301289 (2013).
Espéli, M, Clatworthy, MR, Bökers, S, Lawlor, KE, Cutler, AJ, Köntgen, F, et al, and Smith, KGC. Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity. J. Exp. Med. 209(12), 2307-2319. doi:10.1084/jem.20121752 (2012).
Lyons, PA, Rayner, TF, Trivedi, S, Holle, JU, Watts, RA, Jayne, DR, et al, and Smith, KGC. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367(3), 214-223. doi:10.1056/NEJMoa1108735 (2012).
Linterman, MA, Pierson, W, Lee, SK, Kallies, A, Kawamoto, S, Rayner, TF, et al, Smith, KGC and Vinuesa, CG. Foxp3+ follicular regulatory T cells control the germinal center response. Nature Med. 17(8), 975-982. doi:10.1038/nm.2425 (2011).
Lee, JC, Lyons, PA, McKinney, EF, Sowerby, JM, Carr, EJ, Bredin, F, et al, and Smith, KGC. Gene expression profiling of CD8 + T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J. Clin. Invest. 121(10), 4170-4179. doi:10.1172/JCI59255 (2011).
McKinney, EF, Lyons, PA, Carr, EJ, Hollis, JL, Jayne, DR, Willcocks, LC, et al, and Smith, KGC. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nature Med. 16(5), 586-591. doi:10.1038/nm.2130 (2010).
