Honorary Consultant Rheumatologist & Arthritis Research UK Clinician Scientist Fellow
Myles Lewis studied preclinical medicine at Cambridge University, and clinical medicine at Oxford University. During his Rheumatology clinical training at multiple London teaching hospitals, he has worked extensively on Systemic Lupus Erythematosus (SLE) and other connective tissue diseases. He was awarded a Clinical Research Fellowship from the Wellcome Trust in 2005, for his PhD at the Hammersmith Hospital/Imperial College London, focused on understanding the causes of accelerated heart disease in SLE. In 2011 for his current research on the role of ubiquitination in SLE and autoimmune disease, he was awarded a Clinician Scientist Fellowship by Arthritis Research UK.
Summary of Research
My research involves understanding the effects of ubiquitination pathways on the immune system, and their impact on autoimmune rheumatic diseases especially SLE, rheumatoid arthritis and other connective tissue disorders. Ubiquitination is a critical post-translocational modification in which target proteins are labelled with the small protein ubiquitin. Further ubiquitin moieties can be sequentially added, leading to chains of polyubiquitin on the target protein. Different ubiquitin chain types have radically different consequences on the function of individual proteins: lysine-48 linked ubiquitin chains signal for the target protein to be degraded by the proteasome, whereas lysine-63 or linear ubiquitin chains are critical for activation of proteins in pathways involved in inflammation. Thus different ubiquitin chain types are a very important control system which can either switch off or switch on individual proteins. Numerous genes recently identified in genome-wide association studies in autoimmune diseases are key ubiquitination or deubiquitination regulators, such as TNFAIP3 (A20), TNIP1 (ABIN-1) and UBE2L3. The importance of these genes is demonstrated by their association with multiple autoimmune diseases including SLE, rheumatoid arthritis, juvenile idiopathic arthritis, coeliac disease, Crohn’s disease, ulcerative colitis and psoriasis. Furthermore numerous lupus susceptibility genes, including Fc receptors, IRF5, IRAK1 and IKZF1, are targeted by ubiquitination as an important part of their functional regulation. My research focuses on trying to understand how genetic variation in ubiquitination genes influences B cell differentiation and autoantibody production through regulation of the master inflammation transcription factor NF-kB, and thus increases susceptibility to lupus and autoimmune disease.
Our work has important translational medical implications, since we aim to determine whether certain ubiquitination genes represent novel targets for new therapies to treat lupus and other autoimmune diseases. We are also studying whether variants of these genes could be used clinically as biomarkers to predict disease severity or response to treatment, as a stratified approach to medical therapy for lupus and other rheumatic diseases.
Members of the Group
Research Staff: Dr Daniele Mauro, Dr Xiujuan Hou
Former Staff: Mr Simon Vyse, Dr Adrian Shields
Lewis MJ, Vyse S, Shields AM, Boeltz S, Gordon PA, Spector TD, Lehner PJ, Walczak H, Vyse TJ. UBE2L3 polymorphism amplifies NF-κB activation and promotes plasma cell development linking linear ubiquitination to multiple autoimmune diseases. Am J Hum Genet 2015; 96(2): 221-34. PMID: 25640675
Lewis MJ, Vyse TV. “Connective Tissue Disease” in Chapter “Genetics and the Environment” in Oxford Textbook of Rheumatology, 2013, 4th edition, Ed. Watts RA et al.
Lewis MJ, Malik TH, Fossati-Jimeck L, Carassiti D, Cook HT, Haskard DO, Botto M. Combining lupus and hyperlipidaemia in mice reveals distinct roles for complement in glomerulonephritis and atherosclerosis. Arthritis Rheum 2012; 64(8): 2707-18. PMID: 22392450
Lewis MJ, Malik TH, Ehrenstein MR, Boyle JJ, Botto M, Haskard DO. Immunoglobulin M is required for protection against atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 2009; 120(5): 417-26. PMID: 19620499
Lewis MJ, Botto M. Complement deficiencies in humans and animals: Links to autoimmunity. Autoimmunity 2006; 39(5): 367-78. PMID: 16923536
Lewis MJ, D’Cruz D. Adhesion molecules, mycophenolate mofetil and systemic lupus erythematosus. Lupus 2005; 14: s17-s26. PMID: 15803927