Research
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 (Principal Research Associate)
Dr Prasanti Kotagiri (Clinical Research Associate - PhD student)
Dr Federica Mescia (Clinical Fellow)
Dr Fiona Price-Kuehne (Academic Clinical Fellow)
Dr Laura Bergamaschi (Postdoc Research Associate – Lab Manager (part-time))
Ms Diana Pombal (Research Assistant)
Mr Kelvin Hunter (Bioinformatician:Web & Database Developer)
Dr Will Rae (WT Clinical PhD Student)
Mr Zinan Zhang (NIH OxCam PhD student)
Mrs Cecilia Matara (Research Nurse)
Ms Maddie Eppining (NIH OxCam PhD student)
Dr Aimee Hanson (Postdoc Research Associate)
Dr Victoria Pelly (Postdoc Research Associate)
Dr Katrin Thorarinsdottir (Postdoc Fellow)
Johanna Jung (PhD student)
Ms Maja Nackenhorst (visiting PhD student)
Publications
Professor Ken Smith Research Group Publications
Bergamaschi L, Mescia F, Turner L, Hanson AL, Kotagiri P, Dunmore BJ, Ruffieux H, De Sa A, Huhn O, Morgan MD, Gerber PP. Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease. Immunity. 2021 May 16.
McKinney EF, Cuthbertson I, Harris KM, Smilek DE, Connor C, Manferrari G, Carr EJ, Zamvil SS, Smith KG. A CD8+ NK cell transcriptomic signature associated with clinical outcome in relapsing remitting multiple sclerosis. Nature Communications. 2021 Jan 27;12(1):1-9.
Bergamaschi, Laura, Federica Mescia, Lorinda Turner, Aimee Hanson, Prasanti Kotagiri, Benjamin J. Dunmore, Helene Ruffieux et al. "Early Immune Pathology and Persistent Dysregulation Characterise Severe COVID-19." (2020). Pre-print.
Thaventhiran JE, Allen HL, Burren OS, Rae W, Greene D, Staples E, Zhang Z, Farmery JH, Simeoni I, Rivers E, Maimaris J. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 2020 May 6:1-6.
Wilson TJ, Clare S, Mikulin J, Johnson CM, Harcourt K, Lyons PA, Dougan G, Smith KG. Signalling lymphocyte activation molecule family member 9 is found on select subsets of antigen‐presenting cells and promotes resistance to Salmonella infection. Immunology. 2020 Apr;159(4):393-403.
Lyons PA, Peters JE, Alberici F, Liley J, Coulson RM, Astle W, Baldini C, Bonatti F, Cid MC, Elding H, Emmi G. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nature communications. 2019 Nov 12;10(1):1-3.
Bashford-Rogers RJ, Bergamaschi L, McKinney EF, Pombal DC, Mescia F, Lee JC, Thomas DC, Flint SM, Kellam P, Jayne DR, Lyons PA. Analysis of the B cell receptor repertoire in six immune-mediated diseases. Nature. 2019 Sep 25:1-5.
Spencer S, Köstel Bal S, Egner W, Lango Allen H, Raza SI, Ma CA, Gürel M, Zhang Y, Sun G, Sabroe RA, Greene D. Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. Journal of Experimental Medicine. 2019 Sep 2;216(9):1986-98.
Espéli, M., Bashford-Rogers, R., Sowerby, J.M., Alouche, N., Wong, L., Denton, A.E., Linterman, M.A. and Smith, K.G.C. "FcgRIIb differentially regulates pre-immune and germinal center B cell tolerance in mouse and human." Nat Commun., 2019; 10:1970; PMC6488660.
Biasci, D., Lee, J.C., Noor, N.M., Pombal, D.R., Hou, M., Lewis, N., Ahmad, T., Hart, A., Parkes, M., McKinney, E.F., Lyons, P.A., and Smith, K.G.C. “A blood-based prognostic biomarker in inflammatory bowel disease.” Gut, 2019; 10.1136/gutjnl-2019-318343.
Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MA, Black GC, Brennan P. Germline selection shapes human mitochondrial DNA diversity. Science. 2019 May 24;364(6442).
Tuijnenburg, P., Lango Allen, H., Burns, S.O., Greene, D., Jansen, M.H., Staples, E., Stephens, J., Carss, K.J., Biasci, D., Baxendale, H., Thomas, M., Chandra, A., Kiani-Alikhan, S., Longhurst, H.J., Seneviratne, S.L., Oksenhendler, E., Simeoni, I., de Bree, G.J., Tool, A.T.J., van Leeuwen, E.M.M., Ebberink, E.H.T.M., Meijer, A.B., Tuna, S., Whitehorn, D., Brown, M., Turro, E., Thrasher, A.J., Smith, K.G.C., Thaventhiran, J.E., Kuijpers, T.W. and NIHR BioResource–Rare Diseases Consortium. "Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans." J Allergy Clin Immunol., 2018; 142.4:1285-1296
Thomas, D.C., Charbonnier, L.M., Schejtman, A., Aldhekri, H., Coomber, E.L., Dufficy, E.R., Beenken, A.E., Lee, J.C., Clare, S., Speak, A.O., Thrasher, A.J., Santilli, G., Al-Mousa, H., Alkuraya, F.S., Chatila, T.A. and Smith, K.G.C. "EROS/CYBC1 mutations: Decreased NADPH oxidase function and chronic granulomatous disease." J Allergy Clin Immunol., 2018; S0091-6749.18:31423-4
Ito, Y., Carss, K.J., Duarte, S.T., Hartley, T., Keren, B., Kurian, M.A., Marey, I., Charles, P., Mendonça, C., Nava, C., Pfundt, R., Sanchis-Juan, A., van Bokhoven, H., van Essen, A., van Ravenswaaij-Arts, C., NIHR BioResourse., Care4Rare Canada Consortium., Boycott, K.M., Kernohan, K.D., Dyack, S. and Raymond, F.L. "De Novo Truncating Mutations in WASF1 Cause Intellectual Disability with Seizures." Am J Hum Genet., 2018; 103.1;144-153
Stubbs, S., Lyons, P.A., Lester, J., Wong, L., Jolly, E.C., Frost, S.D.W., Smith, K.G.C. and Henney, J.L. " Stubbs, Sam and Lyons, Paul A. and Lester, James and Wong, Limy and Jolly, Elaine C. and Frost, Simon D. W. and Smith, Kenneth G.C. and Heeney, Jonathan L., "The Plasma Virome Post-Kidney Transplantation Predicts Clinical Outcome." The Lancet, 2018; https://ssrn.com/abstract=3234792
Whitworth, J., Smith, P.S., Martin, J.E., West, H., Luchetti, A., Rodger, F., Clark, G., Carss, K., Stephens, J., Stirrups, K., Penkett, C., Mapeta, R., Ashford, S., Megy, K., Shakeel, H., Ahmed, M., Adlard, J., Barwell, J, Brewer, C., Casey, R.T., Armstrong, R., Cole, T., Evans, D.G., Fostira, F., Greenhalgh, L., Hanson, H., Henderson, A., Hoffman, J., Izatt, L., Kumar, A., Kwong, A., Lalloo, F., Ong, K.R., Paterson, J., Park, S.M., Chen-Shtoyerman, R., Searle, C., Side, L., Skytte, A.B., Snape, K., Woodward, E.R. NIHR BioResource - Rare Diseases Consortium., Tischkowitz. M.D. and Maher, E.R. “Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes." Am J Hum Genet., 2018; 103.1:3-18
Farmery, J.H.R., Smith, M.L., NIHR BioResource - Rare Diseases. and Lynch, A.G. "Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data." Sci Rep., 2018; 8.1:1300
Richard, A.C., Peters, J.E., Savinykh, N., Lee, J.C., Hawley, E.T., Meylan, F., Siegel, R.M., Lyons, P.A. and Smith, K.G.C. "Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease". PLoS Gen., 2018; 14.9:e1007458
Lawless, D., Geier, C.B., Farmer, J.R., Lango Allen, H., Thwaites, D., Atschekzei, F., Brown, M., Buchbinder, D., Burns, S.O., Butte, M.J., Csomos, K., Deevi, S.V.V., Egner, W., Ehl, S., Eibl, M.M., Fadugba, O., Foldvari, Z., Green, D.M., Hendrickson,, S.E., Holland, S.M., John, T., Klemann, C., Kuijpers, T.W., Moreira, F., Piller, A., Rayner-Matthews, P., Romberg, N.D., Sargur, R., Schmidt, R.E., Schroder,, C., Schuetz, C., Sharapova, S.O. and Smith, K.G.C. "Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency". J Allergy Clin Immunol., 2018; 141.6:2303-2306
Sowerby, J.M., Thomas, D.C., Clare, S., Espéli, M., Guerrero, J.A., Hoenderdos, K., Harcourt, K., Marsden, M., Abdul-Karim, J., Clement, M., Antrobus, R., Umrania, Y., Barton, P., Flint, S.M., Juss, J.K., Condliffe, A.M., Lyons, P.A., Humphreys, I.R., Chilvers, E.R., Ouwehand, W.H., Dougan, G. and Smith, K.G.C. "Nbeal2 is required for neutrophil and NK cell function, and pathogen defence." J Clin Invest., 2017; 127:3521-3526.
Horton, S., Giotopoulos, G., Yun, H., Vohra, S., Sheppard, O., Bashford-Rogers, R., Rashid, M., Clipson, A., Chan, W., Sasca, D., Osaki, L.Y.H., Basheer, F., Gallipoli, P., Burrows, N., Erdem, A., Sybirna, A., Förster, S., Zhao, W., Sustic, T., Harrison, A.P., Laurenti, E., Okosun, J., Hodson, D., Wright, P., Smith, K.G.C., Maxwell, P., Fitzgibbon, J., Du, M., Adams, D., and Huntly, B.J.P. "Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors" Nat Cell Biol., 2017; 19:1093-1104.
Sarah Spencer, Sevgi Kostel Bal, William Egner, Hana Lango Allen, Irfan Raza Syed, Chi Ma, Meltem Gurel, Yuan Zhang, Guangping Sun, Ruth Sabroe, Daniel Greene, William Rae, Tala Shahin, Katarzyna Kania, Rico Chandra Ardy, Marini Thian, Emily Staples, Annika Pecchia-Bekkum, William Worrall, Jonathan Stephens, Matthew Brown, Salih Tuna, Melanie York, Fiona Shackley, Diarmuid Kerrin, Ravishankar Sargur, Alison Condliffe, Hamid Nawaz Tipu, Hye Sun Kuehn, Sergio Rosenzweig, Ernest Turro, Simon Tavare, Adrian Thrasher, Duncan Jodrell, Kenneth Smith, Kaan Boztug, Joshua Milner, and James Thaventhiran, " Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses" JEM 2019 - accepted June 2019
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 (2017). 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
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 (2017). 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
Peters JE, Lyons PA, Lee JC, Richard AC, Fortune MD, Newcombe PJ, Richardson S and Smith KGC (2016). 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
McKinney EF, Lee, JC, Jayne DRW, Lyons PA and Smith KGC (2015). T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection. Nature (2015):Nature, 523 (7562):612-6. 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 (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
Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Tuong ZK, Bach K, Sungnak W, Worlock KB, Yoshida M, Kumasaka N, Kania K, Engelbert J, Olabi B, Spegarova JS, Wilson NK, Mende N, Jardine L, Gardner LCS, Goh I, Horsfall D, McGrath J, Webb S, Mather MW, Lindeboom RGH, Dann E, Huang N, Polanski K, Prigmore E, Gothe F, Scott J, Payne RP, Baker KF, Hanrath AT, Schim van der Loeff ICD, Barr AS, Sanchez-Gonzalez A, Bergamaschi L, Mescia F, Barnes JL, Kilich E, de Wilton A, Saigal A, Saleh A, Janes SM, Smith CM, Gopee N, Wilson C, Coupland P, Coxhead JM, Kiselev VY, van Dongen S, Bacardit J, King HW; Cambridge Institute of Therapeutic Immunology and Infectious Disease-National Institute of Health Research (CITIID-NIHR) COVID-19 BioResource Collaboration, Rostron AJ, Simpson AJ, Hambleton S, Laurenti E, Lyons PA, Meyer KB, Nikolić MZ, Duncan CJA, Smith KGC, Teichmann SA, Clatworthy MR, Marioni JC, Göttgens B, Haniffa M. Single-cell multi-omics analysis of the immune response in COVID-19. Nat Med. 2021 Apr 20. doi: 10.1038/s41591-021-01329-2. Epub ahead of print. PMID: 33879890.
Collier DA, De Marco A, Ferreira IATM, Meng B, Datir RP, Walls AC, Kemp SA, Bassi J, Pinto D, Silacci-Fregni C, Bianchi S, Tortorici MA, Bowen J, Culap K, Jaconi S, Cameroni E, Snell G, Pizzuto MS, Pellanda AF, Garzoni C, Riva A; CITIID-NIHR BioResource COVID-19 Collaboration, Elmer A, Kingston N, Graves B, McCoy LE, Smith KGC, Bradley JR, Temperton N, Ceron-Gutierrez L, Barcenas-Morales G; COVID-19 Genomics UK (COG-UK) Consortium, Harvey W, Virgin HW, Lanzavecchia A, Piccoli L, Doffinger R, Wills M, Veesler D, Corti D, Gupta RK. Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies. Nature. 2021 Mar 11. doi: 10.1038/s41586-021-03412-7. Epub ahead of print. PMID: 33706364.
Kemp SA, Collier DA, Datir RP, Ferreira IATM, Gayed S, Jahun A, Hosmillo M, Rees-Spear C, Mlcochova P, Lumb IU, Roberts DJ, Chandra A, Temperton N; CITIID-NIHR BioResource COVID-19 Collaboration; COVID-19 Genomics UK (COG-UK) Consortium, Sharrocks K, Blane E, Modis Y, Leigh KE, Briggs JAG, van Gils MJ, Smith KGC, Bradley JR, Smith C, Doffinger R, Ceron-Gutierrez L, Barcenas-Morales G, Pollock DD, Goldstein RA, Smielewska A, Skittrall JP, Gouliouris T, Goodfellow IG, Gkrania-Klotsas E, Illingworth CJR, McCoy LE, Gupta RK. SARS-CoV-2 evolution during treatment of chronic infection. Nature. 2021 Apr;592(7853):277-282. doi: 10.1038/s41586-021-03291-y. Epub 2021 Feb 5. PMID: 33545711; PMCID: PMC7610568.
