Position(s): Head of Department ; Professor of Medicine

Division: Renal Medicine

Email: kgcs2@cam.ac.uk

Tel.: 01223 762645

Secretary: TBA

Immune Regulation, Autoimmune Disease and Infection

The immune system has evolved to defend us from infection, but defects in the regulation of immunity can give rise to autoimmune disease. We have two inter-related research programmes aimed at understanding how defective immune regulation impacts on human disease

The first aims to increase our understanding of the regulation of immune reactivity, and the role that defects in this play in predisposition to autoimmunity, infection and transplant rejection. We have examined in detail an inhibitory immune receptor, FcγRIIb, which acts as a “brake” on the immune system. We have shown that when naturally occurring polymorphisms render this “brake” ineffective, mice are predisposed to autoimmune diseases such as systemic lupus erythematosus (SLE). These SLE-associated polymorphisms are common in wild mice, suggesting they may provide an evolutionary advantage by protecting from infection. This led to the discovery that FcγRIIb controls the balance between defence from infection and susceptibility to septic shock. More recently we have shown that a single transmembrane domain mutation in FcγRIIb in humans abolishes its inhibitory effect by excluding it from lipid rafts, a novel mechanism for altering receptor function. This mutation is not only associated with SLE, but it may protect from certain infectious diseases, helping explain the evolution of human predisposition to autoimmune disease. We are studying a number of other aspects of inhibitory receptor function, and mechanisms by which these receptors can be manipulated for therapeutic ends.

To pursue our second programme, the Cambridge Hinxton Centre for Translational Research in Autoimmune Disease (CHiC TRIAD) was established. This is a collaboration between clinicians from Addenbrooke’s Hospital, immunologists and clinician scientists from the CIMR (led by Paul Lyons), and bioinformaticians from the European Bioinformatics Institute. The project is integrating clinical and laboratory data to examine how gene expression signatures determined by microarray can be used to study autoimmune diseases such as SLE and vasculitis, as well as transplant rejection. The aim is to predict therapeutic responses, allow tailoring of treatment in individual patients, and deepen our understanding of the aetiology and pathogenesis of these important medical problems. Over the last three years a collaborative research programme with the National University of Singapore has been established, to attempt to determine why SLE in Asian populations is more common and more severe than in Caucasian populations. This is Singapore based, and is funded by the Singapore NMRC and the Duke-NUS Graduate Medical School

Funding

• The Wellcome Trust
• Medical Research Council
• Kidney Research UK
• Genzyme Renal Innovations Programme
• Arthritis Research Campaign
• British Heart Foundation
• Evelyn Trust
• The National Association for Colitis and Crohn’s Disease

Collaborations

• Paul Lehner (CIMR)
• Rudi Manz (Deutsches Rheumaforschungszentrum Berlin)
• David Tarlinton (WEHI, Melbourne)
• Frank Koentgen (Ozgene, Perth)
• Jean Langhorne (NIMR, Mill Hill)
• Gavin Pettigrew and Andrew Bradley (Dept of Surgery)
• David Jayne (Addenbrooke’s Hospital)
• Britta Urban (Oxford)
• Tom Williams and Kevin Marsh (Kilifi, Kenya)

Group Members

• Susanne Bokers
• Edward Carr
• Menna Clatworthy
• Marion Espeli
• Alex Hatton
• Lorna Jarvis
• Elaine Jolly
• James Lee
• Michelle Linterman
• Paul Lyons
• Rebeccah Mathews
• Eoin McKinney
• Huzefa Ratlamwala
• Tim Rayner
• Denise Schofield
• Vera Schwierzeck
• David Thomas
• Sapna Trivedi

Publications

• 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 (2010) A CD8 memory T cell transcription signature predicts prognosis in autoimmune diseases Nature Medicine in press
• Clatworthy MR, Watson CJE, Plotnek G, Bardsley V, Chaudhry AN, Bradley JA and Smith KGC (2009) B cell depleting induction therapy and acute cellular rejection New England Journal of Medicine 360; 2683-2685
• Rebecca J Brownlie, Kate E Lawlor, Heather A Niederer, Antony J Cutler, Zou Xiang, Menna R Clatworthy, R Andres Floto, David R Greaves, Paul A Lyons, and Kenneth GC Smith (2008) Distinct cell-specific control of autoimmunity and infection by FcγRIIb Journal of Experimental Medicine Vol 205 (4) 883-895
• Lisa C Willcocks, Paul A Lyons, Menna R Clatworthy, James I Robinson, Wanling Yang, Stephen A Newland, Vincent Plagnol, Naomi N McGovern, Alison M Condliffe, Edwin R Chilvers, Dwomoa Adu, Elaine C Jolly, Richard Watts, Yu Lung Lau, Ann W Morgan, Gerard Nash, and Kenneth GC Smith (2008) Copy number of FCγR3B, which is associated with systemic lupus erythematosus, correlates with protein expression and immune complex uptake Journal of Experimental Medicine Vol 205 (7) 1573-1582
• Zou Xiang, Antony J Cutler, Rebecca J Brownlie, Kirsten Fairfax, Kate E Lawlor, Eva Severinson, Elizabeth U Walker, Rudolf A Manz, David M Tarlinton & Kenneth GC Smith (2007) FcγRIIb controls bone marrow plasma cell persistence and apoptosis Nature Immunology 8, 419-429
• Clatworthy MR, Willcocks L, Urban B, Langhorne J, Williams T, Peshu N, Watkins NA, Floto RA, and Smith KGC(2007) SLE-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria Proceedings of the National Academy of Sciences USA (Track II)104: 7169-7174
• Smith KGC , Jones R, Burns S and Jayne DRW (2006) Long term comparison of rituximab treatment for refractory SLE and vasculitis; remission, relapse and re-treatment Arthritis and Rheumatism 54:2970-2982
• Floto, RA, Clatworthy, MR.*, Heilbronn, KR, Rosner, DR, Macary, PA, Rankin, A, Lehner, PJ, Ouwehand, WH, Allen, JM, Watkins, NA & Smith, KGC (2005) Loss of function of a lupus-associated FcγRIIb polymorphism through exclusion from lipid rafts Nature Medicine 11, 1056-1058
• Clatworthy MR and Smith KGC (2004) FcγRIIb balances efficient pathogen clearance and the cytokine-mediated consequences of sepsis Journal of Experimental Medicine 199, 717-723
• Lanoue A*, Clatworthy MR*, Smith P, Green S, Townsend MJ, Jolin HE, Smith KGC, Fallon PG and McKenzie ANJ (2004) SIGN-R1 contributes to protection against lethal pneumococcal infection in mice Journal of Experimental Medicine 200, 1383-1393
• Rudge EU *, Cutler AJ *, Pritchard NR* & Smith KGC (2002) Interleukin 4 reduces expression of inhibitory receptors on B cells and abolishes CD22 and FcγRIIb-mediated B cell suppression Journal of Experimental Medicine 195, 1079-1085
• Pritchard, NR, Cutler, AJ, Uribe, S, Chadban, SJ, Morley, BJ & Smith KGC (2000) Autoimmune-prone mice share an Fcgr2 promoter haplotype associated with reduced expression and function of the negative regulatory Fc receptor FcgRII Current Biology 10, 227-230
• Smith KGC , Light, A, O’Reilly, LA, Ang, SM, Strasser, A & Tarlinton, DM (2000) 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 191, 475-484
• Tarlinton, D.M. & Smith KGC (2000) Dissecting affinity maturation – a model explaining selection of antibody forming cells and memory B cells in the germinal centre Immunology Today 21, 436-441
• Smith KGC, Tarlinton, DM, Doody, GM, Hibbs, ML & Fearon, DT (1998). Inhibition of the B cell by CD22: a requirement for Lyn Journal of Experimental Medicine 187, 807-811