Cambridge Institute for Medical Research

Professor Ken Smith

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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
• The British Heart Foundation
• The 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