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Ken Smith

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.

Smith lab

Key papers

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).

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).

Professor Ken Smith

Professor of Medicine

Department: Medicine

Contact:

01233 762645

01223 336849 (PA)

 

Plain English

White blood cells of the immune system recognise and target foreign antigens, including viruses and cancer cells. Autoimmune disease arises when immune cells instead start to recognize and destroy normal healthy tissue. Our research aim is to characterize the different types of autoimmune disease and their underlying basis. Through our detailed studies of DNA changes in groups of patients, we have identified distinct subtypes of autoimmune disease and developed new biomarkers for diagnosis. We are also focusing on how particular factors can influence the progression and outcome of a disease. This may have important implications for determining the treatment plan for individual patients.

Group members

Christophe Bourges · Rachael Bashford-Rogers · Laura Bergamaschi · Ariana Betancourt · Chris Connor · Richard Coulson · Alice Denton · James Lee · Paul Lyons · Eoin McKinney · Annika Pecchia-Bekkum · Diana Pombal · Angela Reynolds · John Sowerby · James Thaventhiran · David Thomas · Tim Wilson · Limy Wong

Funding

Wellcome Trust

British Heart Foundation

Arthritis Research UK

Lupus Research Institute

Medical Research Council

European Union

NIHR Cambridge Biomedical Research Centre

National Association for Colitis and Crohn's Disease

GSK

MedImmune