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Evolution of disease susceptibility - how ancient mosquitoes can ruin your life

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Perhaps 25% of people will end up with an autoimmune disease at some point in their life. These illnesses occur when the immune system turns on the body, no longer recognizing it as “self” and thus attacking it. Many of these diseases are common (type I diabetes, rheumatoid arthritis) or prominent (multiple sclerosis, lupus). We are all at risk of these illnesses, and our degree of risk is genetically determined. This genetic risk is inherited in a complex “polygenic” fashion, rather than in a simple mendelian one like haemophilia or cystic fibrosis. It results in huge variation in disease susceptibility between families, and often between races and ethnic groups.

I will examine the principles behind the inheritance of risk of autoimmunity, presenting evidence from studies in wild mice in Australia and Iran and in people from the UK, Hong Kong and Kenya. This suggests that the evolution of our predisposition to autoimmune disease is all about mosquitos, but that mosquitos might also be our saviours.

Ken Smith

MA B MedSc MBBS PhD FRACP FRCPA FRCP FHEA F MedSci

Genzyme Professor of Experimental Medicine, and Head of the Division of Renal Medicine, Department of Medicine, University of Cambridge

Khoo Oon Teik Professor of Nephrology, University of Singapore

Honorary Consultant Physician, Addenbrooke’s Hospital, Cambridge.

Fellow and Director of Studies in Clinical Medicine, Pembroke College, Cambridge

Programme Director, NIH - University of Cambridge Biomedical Research Graduate Programme.

Ken Smith trained in medicine at the University of Melbourne, and completed a BMedSc in the Nuffield Department of Surgery, University of Oxford, in T cell immunology. He trained in nephrology with an interest in autoimmune disease at the Royal Melbourne Hospital, and then completed pathology training specialising in clinical immunology. His PhD (with David Tarlinton and Prof Sir Gus Nossal: Walter and Eliza Hall Institute) examined aspects of B cell immunology, work subsequently built upon in two years working with Prof Douglas Fearon in Cambridge.

He now runs a laboratory in the Cambridge Institute for Medical Research which has two main components. The first studies basic immunological mechanisms, and how defects in regulatory control of the immune system can lead to autoimmunity and alter defence against infection. Recent work has focussed on how FcgRIIb, an inhibitory receptor for IgG, controls the immune system, and how polymorphic variants in it modulate immune responses and influence the development of autoimmunity and protection against bacterial infection and malaria. This has provided an insight into the evolution of predisposition to autoimmunity, and identified potential therapeutic strategies.

The second component is a translational programme which has recruited over 120 patients with autoimmune diseases (particularly SLE and vasculitis) and is studying them by correlating detailed prospective clinical data before and after novel therapies, with data generated from RNA microarrays and proteomic analysis. This work has led to the design of better informed clinical trials, and the identification of important genes involved in disease pathogenesis. It is now being extended to allow the study of Asian populations, in whom SLE is more common and severe, in collaboration with the National University of Singapore.

His clinical research focuses on trials of novel biological agents in autoimmunity and renal transplantation. In 2006 he was elected a Fellow of the Academy of Medical Sciences, and in 2007 was awarded the Lister Institute Research Prize.

This talk is part of the Ivory Tower Society, Pembroke College series.

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