Welcome 1 of 3
Welcome 2 of 3
Welcome 3 of 3
Research
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 studies immunological mechanisms underlying immune-mediated disease and immunodeficiency in humans, most recently through involvement in the NIHR BioResource Rare Diseases Primary immunodeficiency programme. The lab also runs a translational program in autoimmune disease (particularly SLE, vasculitis and IBD) that has led to the discovery of a prognosis-predicting biomarker entering clinical trials, and to the identification of new pathways driving disease outcomes in autoimmunity and infection. By integrating human and animal studies and using advanced bioinformatic methodology, the laboratory tries to explore fundamental immunological mechanisms that are relevant to human disease, and to translate these results into applications of direct benefit to patients.
1. McKinney E.F., Cuthbertson I, Harris K.M., Smiklek, D.E., Connor, C., Manferri, G., Carr, E.J., Zamvil, S.S., and Smith K.G.C. “A subset of regulatory CD8+ Natural Killer cells predict favourable clinical outcome in relapsing multiple sclerosis”. Nature Communications. 2021;12(1):635. doi:10.1038/s41467-020-20594-2.
2. Thaventhiran, J.E.D., Lango Allen, H., Burren O.S., Henry, J., Farmery, R., Staples, E., Zhang, Z., Rae, W., Greene, D., Simeoni, I., Penkett, C., Stephens, J., Thomas, M., Sargur, R., Gordins, P., Baxendale, H., Tuijnenburg, P., Worth, A., Hanson, S., Buckland,M.S., Gilmour, K., Maimaris, J., Lyons, P., Sansom, D.M., Lynch, A.G., Ellinghaus, E., Ellinghaus, D., Hemming Karlsen, T., Cutler, A.J., Kumararatne, D.S., NIHR Bioresource, Savic, S., Burns, S.O., Kuijpers, T.W., Ouwehand, W.H., Thrasher, A.J., and Smith, K.G.C. “Genetics of primary immunodeficiency revealed by genome sequencing a sporadic cohort.” Nature, 2020;583:90- 95. doi:10.1038/s41586-020-2265-1.
3. Lyons, P.A., Peters, J.E., Alberici, .F., Liley, J., Coulson, R.M.R., Astle, W., Baldini, C., Bonatti, F., Cid, M.C., Elding, H., Emmi, G., Epplen, J., Guillevin, L., Jayne, D.R.W., Jiang, T., Gunnarsson, I., Lamprecht, P., Leslie, S., Little, M.A., Martorana, D., Moosig, F., Neumann, T., Ohlsson, S., Quickert, S., Ramirez, G.A., Rewerska, B., Schett, G., Sinico, R.A., Szczeklik, W., Tesar, V., Vukcevic, D., European Vasculitis Genetics Consortium., Terrier, B., Watts, R.A. Vaglio, A., Holle, J.U., Wallace, C., and Smith, K.G.C. "Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status." Nature Communications, 2019;10:5120. doi:10.1038/s41467-019-12515-9.
4. Bashford-Rogers, R.J.M., Bergamaschi, L., McKinney, E.F., Pombal, D.C., Mescia, F., Lee, J.C., Thomas, D.C., Flint, S.M., Kellam, P., Jayne, D.R.W., Lyons, P.A., and Smith, K.G.C. "Analysis of the B cell receptor repertoire in six immune-mediated diseases" Nature, 2019;574:122-126. doi:10.1038/s41586-019-1595-3.
5. Lee, J.C., Biasci, D., Roberts, R., Gearry, R.B., Mansfield, J.C., Ahmad, T., Prescott, N.J., Satsangi, J., Wilson, D.C., Jostins, L., Anderson, C.A., Consortium, U.I.G., Traherne, J.A., Lyons, P.A., Parkes, M. and Smith, K.G.C. "Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease." Nature Genetics, 2017; 49:262-268; PMC5730041
6. Thomas, D.C., Clare, S., Sowerby, J.M., Pardo, M., Juss, J.K., Goulding, D.A., van der Weyden, L., Storisteanu, D., Prakash, A., Espeli, M., Flint, S., Lee, J.C., Hoenderdos, K., Kane, L., Harcourt, K., Mukhopadhyay, S., Umrania, Y., Antrobus, R., Nathan, J.A., Adams, D.J., Bateman. A., Choudhary, J.S., Lyons, P.A., Condliffe, A.M., Chilvers, E.R., Dougan, G. and Smith, K.G.C. "Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity." Journal of Experimental Medicine, 2017;214:1111-1128. doi:10.1084/jem.20161382.
7. 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., Smith, K.G.C., "Nbeal2 is required for neutrophil and NK cell function, and pathogen defence." Journal of Clinical Investigation, 2017; 127:3521- 3526; PMC5669559
8. McKinney, E.F., Lee, J.C., Jayne, D.R., Lyons, P.A. and Smith, K.G.C. "T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection." Nature, 2015;523:612-616. doi:10.1038/nature14468. Paper describing a mechanism underlying the CD8 T-cell prognostic biomarker to show that T-cell exhaustion may play a central role in determining outcome in many autoimmune, inflammatory and infectious diseases (see Nat. Rev. Immunol. 2015;15:468).
9. Lee, J.C., Espeli, M., Anderson, C.A., et al., and Smith, K.G.C. "Human SNP links differential outcomes in inflammatory and infectious disease to a FOXO3-regulated pathway." Cell, 2013;155:57-69. doi:10.1016/j.cell.2013.08.034.
10. Espeli, M., Clatworthy, M.R., Bokers, S., Lawlor, K.E., Cutler, A.J., Kontgen, F., Lyons, P.A. and Smith, K.G.C. "Analysis of a wild mouse promoter variant reveals a novel role for FcgammaRIIb in the control of the germinal center and autoimmunity." Journal of Experimental Medicine, 2012;209:2307-2319. doi:10.1084/jem.20121752.
11. Lyons, P.A., Rayner, T.F., Trivedi, S., Holle, J.U., Watts, R.A., Jayne, D.R., Baslund, B., Brenchley, P., Bruchfeld, A., Chaudhry, A.N., Cohen Tervaert, J.W., Deloukas, P., Feighery, C., Gross, W.L., Guillevin, L., Gunnarsson, I., Harper, L., Hruskova, Z., Little, M.A., Martorana, D., Neumann, T., Ohlsson, S., Padmanabhan, S., Pusey, C.D., Salama, A.D., Sanders, J.S., Savage, C.O., Segelmark, M., Stegeman, C.A., Tesar, V., Vaglio, A., Wieczorek, S., Wilde, B., Zwerina, J., Rees, A.J., Clayton, D.G. and Smith, K.G.C. "Genetically distinct subsets within ANCA-associated vasculitis." New England Journal of Medicine, 2012;367:214-223. doi:10.1056/NEJMoa1108735.
12. Lee, J.C., Lyons, P.A., McKinney, E.F., Sowerby, J.M., Carr, E.J., Bredin, F., Rickman, H.M., Ratlamwala, H., Hatton, A., Rayner, T.F., Parkes, M. and Smith, K.G.C. "Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis." Journal of Clinical Investigation, 2011;121:4170-4179. doi:10.1172/JCI59255.
13. Linterman, M.A., Pierson, W., Lee, S.K., Kallies, A., Kawamoto, S., Rayner, T.F., Srivastava, M., Divekar, D.P., Beaton, L., Hogan, J.J., Fagarasan, S., Liston, A., Smith, K.G.C.* and Vinuesa, C.G.* (equal senior authors). "Foxp3+ follicular regulatory T cells control the germinal center response." Nature Medicine, 2011;17:975-982. doi:10.1038/nm.2425.
14. Willcocks, L.C., Carr, E.J., Niederer, H.A., Rayner, T.F., Williams, T.N., Yang, W., Scott, J.A., Urban, B.C., Peshu, N., Vyse, T.J., Lau, Y.L., Lyons, P.A. and Smith, K.G.C. "A defunctioning polymorphism in FCGR2B is associated with protection against malaria but susceptibility to systemic lupus erythematosus." Proceedings of the National Academy of Sciences of the United States of America, 2010;107:7881-7885. doi:10.1073/pnas.0915133107.
15. McKinney, E.F., Lyons, P.A., Carr, E.J., Hollis, J.L., Jayne, D.R., Willcocks, L.C., Koukoulaki, M., Brazma, A., Jovanovic, V., Kemeny, D.M., Pollard, A.J., Macary, P.A., Chaudhry, A.N. and Smith, K.G.C. "A CD8+ T cell transcription signature predicts prognosis in autoimmune disease." Nature Medicine, 2010;16:586-591. doi:10.1038/nm.2130.
16. Willcocks, L.C., Lyons, P.A., Clatworthy, M.R., Robinson, J.I., Yang, W., Newland, S.A., Plagnol, V., McGovern, N.N., Condliffe, A.M., Chilvers, E.R., Adu, D., Jolly, E.C., Watts, R., Lau, Y.L., Morgan, A.W., Nash, G. and Smith, K.G.C. "Copy number of FCGR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake." Journal of Experimental Medicine, 2008;205:1573-1582. doi:10.1084/jem.20072413.
17. Xiang, Z., Cutler, A.J., Brownlie, R.J., Fairfax, K., Lawlor, K.E., Severinson, E., Walker, E.U., Manz, R.A., Tarlinton, D.M. and Smith, K.G.C. "FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis." Nature Immunology, 2007;8:419-429. doi:10.1038/ni1440.
18. Smith, K.G.C., Jones, R.B., Burns, S.M. and Jayne, D.R. "Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment." Arthritis & Rheumatology, 2006;54:2970-2982. doi:10.1002/art.22046.
19. Floto, R.A., Clatworthy, M.R., Heilbronn, K.R., Rosner, D.R., MacAry, P.A., Rankin, A., Lehner, P.J., Ouwehand, W.H., Allen, J.M., Watkins, N.A. and Smith, K.G.C. "Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts." Nature Medicine, 2005;11:1056-1058. doi:10.1038/nm1288.
20. Smith, K.G.C., Light, A., O'Reilly, L.A., Ang, S.M., Strasser, A. and Tarlinton, D. "bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells." Journal of Experimental Medicine, 2000;191:475-484; doi:10.1084/jem.191.3.475.