Immune regulation, autoimmunity and disease outcome
The Smith laboratory is focused on understanding autoimmune disease and applying this knowledge to the clinical setting. We do this through the study of fundamental immunological mechanisms, particularly of B cell and germinal centre biology, enhanced by our exploitation of genetic and genomic data from well-characterised patient cohorts. These patient groups span a number of immune and inflammatory diseases, in particular systemic lupus erythematosus, vasculitis and inflammatory bowel disease. This combined approach, using human and animal data and state-of-the-art bioinformatic methodology, allows us to explore immunological mechanisms that are relevant to human disease, and to translate our results into applications of direct benefit to patients.
Immune regulation and autoimmunity
We have examined the role of the inhibitory receptor FcγRIIb in controlling B cell responses in mice and humans, and determined how natural genetic variation controls this receptor’s function, thereby providing insight into basic immune mechanisms as well as the development of autoimmunity and responses to infection. This has generated new concepts explaining tolerance and selection in the germinal centre (Espeli 2013), and defined how FcγRIIb influences transplant survival (Callaghan 2012, Clatworthy 2014) and mucosal tolerance (Sun 2013).
Other work has followed up on the first description of the follicular regulatory T cell (Linterman Nat. Med. 2011) to define the human equivalent of TFR (submitted), and demonstrate that persistent CD28 expression maintains immune responses (submitted). We have shown that a microRNA MiR-210 is a key B cell regulator preventing autoimmunity (Mok 2013) and a potent lymphoid oncogene (unpublished). We have also explored novel imaging modalities in inflammation (Clatworthy 2012), and created a mouse model of human hereditary haemolytic anaemia (Walker 2012). In ongoing collaborations with Singapore, we have helped to define the mechanisms of dengue neutralisation (Teoh 2012, Rivino 2013), and of novel anti-lipid autoantibodies in SLE (Jovanovic 2013).
Moving forward, we will focus more on understanding those mechanisms uncovered by our genomics programme.
Genetics of AAV
We established the European Vasculitis Genetics Consortium (which is also chaired by Ken Smith) to perform the first genome-wide association study in ANCA-Associated Vasculitis (AAV). We found it to be comprised of two genetically distinct diseases defined by autoantibody specificity (Lyons 2012), and subsequent studies are uncovering further genetic associations. Fine mapping has allowed us to identify two independent contributions to risk at both the PRTN3 and SERPIN1A loci, enabling follow-up functional studies using the Cambridge Bioresource. We have also imputed the classical HLA associations with disease, allowing an analysis of the important T cell epitopes driving disease and the beginning of a search for antigen-specific T cells in vivo. Analysis using the immuno-chip has defined three more genetic associations, each unique to AAV.
Ongoing work will define the functional effect of the variants already discovered, primarily in recruits from the Cambridge BioResource, and in patients. We will also integrate our genetic results with a more detailed immunological analysis of AAV, and to pursue this we are developing antigen-specific T and B cell assays to isolate MPO and PR3-specific cells, in collaboration with the Benaroya Institute in Seattle.
Transcriptomics and the biology of prognosis
Our genomics studies have led to the discovery of a CD8 T cell transcriptome-based biomarker now entering clinical trials (McKinney Nat. Med. 2010, Lee JCI 2011). Follow-up work to investigate the biology underlying the CD8 T cell transcriptional signature has shown that it associates with T cell exhaustion, and inversely with CD4 T cell co-stimulation. This has raised the prospect that this signature might be manipulated for therapeutic means, and has allowed the discovery of a further biomarker that provides a good outcome prediction for numerous autoimmune diseases and conversely a bad outcome prediction for a large number of responses to chronic infection.
This work, combined with novel genetic approaches, has led on to the identification of new outcome-associated pathways, such as one subtended by FOXO3A, which impact more than one disease and offer exciting new avenues to both therapy and biomarker development (Lee 2013). These findings demonstrate that the biology of disease outcome, or prognosis, is not the same as that of disease development, or diagnosis.
This area will become the major theme of the laboratory. We are seeking funding to continue to recruit our detailed patient cohorts in four major autoimmune disease areas. These have provided a unique resource, combining separated cell populations and detailed genomic analysis of patients at diagnosis, with prospective clinical follow-up data for what is now a median of 6 years. Continuing to refine the analysis of such patients (e.g. Zilbauer 2013), and to recruit more patients, is central to our on-going 'biomarker and mechanism' discovery programme.
Much additional interest will focus on the results of a prognosis GWAS. This exciting new 'biology of prognosis' will gradually become the major theme of the laboratory in future years.
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 KGC. Human SNP Links Differential Outcomes in Inflammatory and Infectious Disease to a FOXO3-Regulated Pathway. Cell 155, 57–69 (2013).
EspéliM, ClatworthyMR, Bökers S, LawlorKE, CutlerAJ, KöntgenF, LyonsPA, 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. J. Exp. Med. 209, 2307–2319 (2012).
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 Engl. J. Med. 367, 214–223 (2012).
Linterman MA, Pierson W, Lee SK, Kallies A, Kawamoto S, Rayner TF, Srivastava M, Divekar DP, Beaton L, Hogan JJ, Fagarasan S, Liston A, Smith KGC* and Vinuesa CG*(equal senior authors). Foxp3+ follicular regulatory T cells control the germinal center response. Nature Med. 17, 975–982 (2011).
Lee JC, Lyons PA, McKinney EF, Sowerby JM, Carr EJ, Bredin F, Rickman HM, Ratlamwala H, Hatton A, Rayner TF, Parkes M, Smith KGC. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn’s disease and ulcerative colitis. J. Clin. Invest. 121, 4170–4179 (2011).
McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DRW, Willcocks LC, Koukoulaki M, Hatton A, MacAry PA, Brazma A, Chaudhry AN and Smith KGC. A CD8 memory T cell transcription signature predicts prognosis in autoimmune diseases. Nature Med. 16, 586–589 (2010).
Willcocks LC, Carr EJ, Niederer HA, Rayner T, Williams T, Scott JAG, Urban B, Peshu N, Yang WL, Lau YL, Vyse T, Lyons PA, and Smith KGC. A defunctioning polymorphism in FcγR2B is associated with protection against malaria but susceptibility to Systemic Lupus Erythematosus. Proc. Natl Acad. Sci. USA 107, 7881–7885 (2010).
Willcocks LC, Lyons PA*, Clatworthy MR, Robinson JI, Y Wanling, Newland SA, Plagnol V, McGovern N, Condliffe A, Chilvers ER, Adu D, Jolly EC, Watts R, Lau YL, Morgan AW, Nash G and Smith KGC. Copy number of FcγRIIIb, which is associated with Systemic Lupus Erythematosus, correlates with protein expression and immune complex uptake. J. Exp. Med. 205, 1573–1582 (2008).
Brownlie RJ, Lawlor KE , Niederer H, Cutler AJ, Xiang Z, Clatworthy MR, Floto RA, Greaves DR, Lyons PA and Smith KGC. Distinct cell-specific control of autoimmunity and infection by FcγRIIb. J. Exp. Med. 205, 883–895 (2008).
Xiang Z, Cutler AJ, Brownlie RJ, Fairfax K, Lawlor KE, Severinson E, Walker EU, Manz RA, Tarlinton DM and Smith KGC. FcγRIIB controls bone marrow plasma cell persistence and apoptosis. Nature Immunol. 8, 419–429 (2007).