Immune Regulation, Autoimmune Disease and Infection

We aim to discover how genetically determined variation in immune regulation balances the risks of autoimmune disease and infection. Regulation of the B cell immune response is a major interest. We have investigated the function of inhibitory receptors such as FcyRIIb, which act as “brakes” on the immune system. We have shown that even subtle changes in expression of FcyRIIb on B cells can prevent or induce SLE in mice. Natural polymorphisms in FcyRIIb are associated with immune dysregulation (see Figure) and autoimmune diseases such as systemic lupus erythematosus (SLE) in both mouse and man. Some reduce function and are common in Asia and Africa, where malaria is endemic. [Read More…]

Lee JC, Espéli M, Anderson CA, Linterman MA, Pocock JM, Williams NJ, Roberts R, Viatte S, Fu B, Peshu N, Hien TT, Phu NH, Wesley E, Edwards C, Ahmad T, Mansfield JC, Gearry R, Dunstan S, Williams TN, Barton A, Vinuesa CG; UK IBD Genetics Consortium, Parkes M, Lyons PA, Smith KG. “Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway.” Cell. 2013; 155(1):57-69.
Espéli M, Clatworthy MR, Bökers S, Lawlor KE, Cutler AJ, Köntgen F, Lyons PA, Smith KGC.  “Analysis of a wild mouse Fcgr2b 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.

Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DRW, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P, Feighery C, Gross WL, Guillevin L,Gunnarsson I, Harper L, Hrušková Z, Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD, Salama AD, Sanders J-S F, Savage CO, Segelmark M, Stegeman CA, Tesař V, Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG and Smith KGC. “Genetically Distinct Subsets within ANCA-Associated Vasculitis.” New England Journal of Medicine, 2012;367:214-223.

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. et al. (2010). A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 16, 586-591.

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., Smith, K. G. C. (2011). Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 121, 4170-4179.

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. et al. (2011). Foxp3(+) follicular regulatory T cells control the germinal center response. Nat Med 17, 975-982.