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Professor Ken Smith

Professor Ken Smith

Ken Smith is accepting applications for PhD students.

Ken Smith is available for consultancy.


Departments

Department of Medicine:
Head of Department of Medicine

Research Interests

Ken Smith established the Cambridge Immunology Strategic Research Network, which unifies both basic and translational immunological research across the broader Cambridge area.  He also runs the Immunity, Infection & Inflammation Theme of the NIHR Biomedical Research Centre, which has an annual budget of £850,000, and is designated as a Federation of Clinical Immunological Societies International Centre of Excellence.

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.

 

 Group Members

Dr Paul Lyons

Dr Richard Coulson (Bioinformatician)

Dr James Lee (Intermediate Fellow)

Dr Eoin McKinney (Intermediate Fellow)

Dr James Thaventhrian (Intermediate Fellow)

Dr Federico Alberici (Clinical Fellow)

Dr Dave Thomas (Clinical Fellow)

Dr Rachael Bashford-Rodgers (Postdoc Research Fellow)

Dr Alessandra De Riva (Postdoc Research Associate)

Dr Alice Denton (Postdoc Research Associate)

Dr Laura Bergamaschi (Postdoc Research Associate)

Dr Timothy Wilson (Postdoc Research Associate)

Dr Louise O’Brien (Laboratory Manager)

Mrs Ariana Betancourt (Research Assistant)

Ms Diana Pombal (Research Assistant)

Mrs Angela Reynolds (Data Curator)

Ms Mariana Fonseca (PhD Student)

Ms Annika Pecchia-Bekkum (PhD Student)

Dr James Peters (PhD Student)

Mr John Sowerby (PhD Student)

Keywords

GWAS ; autoimmunity ; B cells ; Fc receptors ; germinal center ; human studies ; prognosis ; animal models ; biomarkers ; clinical immunology ; randomised control trials

Topics

  • systemic lupus erythematosus
  • autoimmunity
  • renal disease
  • rheumatoid arthritis
  • arthritis
  • Prognosis
  • vasculitis
  • transplantation

Key Publications

 Professor Ken Smith Research Group Publication
 

McKinney EF, Lee, JC, Jayne DRW, Lyons PA and Smith KGC (2015). T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection. Nature, in press.

Linterman, MA, Denton, AE, Divekar, DP, Zvetkova, I, Kane, L, Ferreira, C, Veldhoen, M, Clare, S, Dougan G, Espéli, M, and Smith, KGC (2014). 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

Wallin , EF, Jolly, EC, Suchánek, O, Bradley, JA, Espéli, M, Jayne, DRW, Linterman, MA, and Smith, KGC (2014). Human T follicular helper and T follicular regulatory cell maintenance is independent of germinal centers. Blood, 124(17), 2666-74. doi:10.1182/blood-2014-07-585976

 Richard, AC, Lyons, PA, Peters, JE, Biasci, D, Flint, SM, Lee, JC, and Smith, KGC (2014). 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

Lee, JC, Espéli, M, Anderson, CA, Linterman, MA, Pocock, JM, Williams, NJ, et al, and Smith, KGC (2013). 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

Mok, Y, Schwierzeck, V, Thomas, DC, Vigorito, E, Rayner, TF, Jarvis, LB, et al, and Smith, KGC (2013). 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

Espéli, M, Clatworthy, MR, Bökers, S, Lawlor, KE, Cutler, AJ, Köntgen, F, et al, and Smith, KGC (2012). 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

Lyons, PA, Rayner, TF, Trivedi, S, Holle, JU, Watts, RA, Jayne, DR, et al, and Smith, KGC (2012). Genetically distinct subsets within ANCA-associated vasculitis.. N Engl J Med, 367(3), 214-223. doi:10.1056/NEJMoa1108735

Linterman, MA, Pierson, W, Lee, SK, Kallies, A, Kawamoto, S, Rayner, TF, et al, Smith, KGC and Vinuesa, CG (2011). Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med, 17(8), 975-982. doi:10.1038/nm.2425

Lee, JC, Lyons, PA, McKinney, EF, Sowerby, JM, Carr, EJ, Bredin, F, et al, and Smith, KGC (2011). Gene expression profiling of CD8 + T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. Journal of Clinical Investigation, 121(10), 4170-4179. doi:10.1172/JCI59255

McKinney, EF, Lyons, PA, Carr, EJ, Hollis, JL, Jayne, DR, Willcocks, LC, et al, and Smith, KGC (2010). A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med, 16(5), 586-591. doi:10.1038/nm.2130

Spleen from mice immunized with NP-KLH in alum for 11 days have been stained with an anti-IgD (blue), an anti-KI67 (red) and with TUNEL (green). The B cell follicle is stained with the anti-IgD whereas the germinal centre B cells are positive for the cell cycle marker KI67. B cell clones which are counter-selected in the germinal centre are dying by apoptosis and are positive for the TUNEL staining.