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.
Transcriptomics and the biology of prognosis
The clinical course of autoimmune disease varies greatly even between individuals with the same condition. Thus AAV in one patient might respond to therapy never to relapse, while another with identical clinical features on presentation might suffer relapses, renal failure and death. Thus to a patient with immune-mediated disease, long-term disease course is a far more important determinant of their future than the specific diagnosis they are given. An understanding of the molecular basis underlying outcome, rather than diagnosis, in immune mediated disease promises to allow the development of predictive biomarkers and thus personalized therapy. More importantly, the pathways that drive differential outcome are likely to present new therapeutic targets that may be effective across different diseases.
Our genomics studies have led to the discovery 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). Other work identified a CD8 T cell transcription signature which predicted long-term outcome in important immune-mediated diseases including AAV, systemic lupus erythematosus (SLE), CD and ulcerative colitis (McKinney et al. Nat. Med. 2010, Lee et al. JCI 2011). This signature is associated with CD8 T-cell exhaustion (McKinney et al., Nature, In press), a process by which CD8 T-cells lose the capacity for cytolysis, proliferation and effector cytokine production. Exhaustion of antigen-specific T-cells is driven by a combination of chronic antigen exposure/TCR stimulation and loss of accessory signals provided from other lineages such as CD4 T-cells. CD8 T-cell exhaustion was associated with poor outcome in infection (dengue, hepatitis C, yellow fever, malaria, influenza) and good outcome in autoimmunity (e.g. type 1 diabetes [T1D], AAV, SLE… (McKinney et al., Nature, In press)). 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 exciting new 'biology of prognosis' will gradually become the major theme of the laboratory in future years. 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. Continuing to refine the analysis of such patients, and to recruit more patients, is central to our on-going 'biomarker and mechanism' discovery programme.
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 et al. J Exp Med 2012), 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 et al. Nat. Med. 2011) to define the human equivalent of TFR, and demonstrate that persistent CD28 expression maintains immune responses and is required for protective immunity to infection (Linterman et al. eLife 2014). We have shown that a microRNA MiR-210 is a key B cell regulator preventing autoimmunity (Mok 2013) and a potent lymphoid oncogene. 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 (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 is defining 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. This work is continuing with funding from the British Heart Foundation and ARUK.
McKinney EF, Lee, JC, Jayne DRW, Lyons PA and Smith KGC. T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection. Nature in press (2015).
Linterman, MA, Denton, AE, Divekar, DP, Zvetkova, I, Kane, L, Ferreira, C, Veldhoen, M, Clare, S, Dougan G, Espéli, M, and Smith, KGC. 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 (2014).
Wallin , EF, Jolly, EC, Suchánek, O, Bradley, JA, Espéli, M, Jayne, DRW, Linterman, MA, and Smith, KGC. Human T follicular helper and T follicular regulatory cell maintenance is independent of germinal centers. Blood 124, 2666-74. doi:10.1182/blood-2014-07-585976 (2014).
Richard, AC, Lyons, PA, Peters, JE, Biasci, D, Flint, SM, Lee, JC, and Smith, KGC. 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 (2014).
Lee, JC, Espéli, M, Anderson, CA, Linterman, MA, Pocock, JM, Williams, NJ, et al, and Smith, KGC. 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 (2013).
Mok, Y, Schwierzeck, V, Thomas, DC, Vigorito, E, Rayner, TF, Jarvis, LB, et al, and Smith, KGC. 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 (2013).
Espéli, M, Clatworthy, MR, Bökers, S, Lawlor, KE, Cutler, AJ, Köntgen, F, et al, and Smith, KGC. 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 (2012).
Lyons, PA, Rayner, TF, Trivedi, S, Holle, JU, Watts, RA, Jayne, DR, et al, and Smith, KGC. Genetically distinct subsets within ANCA-associated vasculitis. N. Engl. J. Med. 367(3), 214-223. doi:10.1056/NEJMoa1108735 (2012).
Linterman, MA, Pierson, W, Lee, SK, Kallies, A, Kawamoto, S, Rayner, TF, et al, Smith, KGC and Vinuesa, CG. Foxp3+ follicular regulatory T cells control the germinal center response. Nature Med. 17(8), 975-982. doi:10.1038/nm.2425 (2011).
Lee, JC, Lyons, PA, McKinney, EF, Sowerby, JM, Carr, EJ, Bredin, F, et al, and Smith, KGC. Gene expression profiling of CD8 + T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J. Clin. Invest. 121(10), 4170-4179. doi:10.1172/JCI59255 (2011).
McKinney, EF, Lyons, PA, Carr, EJ, Hollis, JL, Jayne, DR, Willcocks, LC, et al, and Smith, KGC. A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nature Med. 16(5), 586-591. doi:10.1038/nm.2130 (2010).