About the Project
Our aims are to understand B cell development and diseases associated with abnormal antibody production. Inadequate or excessive immune responses lead to immunodeficiency or autoimmune and inflammatory diseases, which place a major economic and social burden on world health and the quality of human life. So, we are interested in the normal processes of immune function and how individuals vary due to inherited or acquired differences.
Investigating human immunodeficiency and other forms of inherited disease is a good way to discover new immune functions and a great way to train in the field. One project involves a new form of inherited B cell specific immunodeficiency caused by deficiency in a novel cation transporter, caused by a variety of different mutations in individuals in the Europe and the USA. Other projects involve the study of other forms of inherited disease and building transgenic and CRISPR targeted models.
The threshold for activation of B cell receptor is important because it determines the selection of B cells into different subsets, the response to foreign antigens and immune tolerance to self. We are beginning to appreciate that the threshold varies through the development of B cells and probably through the lifetime of an individual; but we know little about its molecular basis or how it might be manipulated therapeutically. These are some of the most fundamental questions in immunology with broad implications.
Our third area of interest is in developing new strategies to inhibit the immune response using antibody therapeutics. These projects are a collaboration with Professor Simon Davis’ group and are described by him.
Our student projects cover all of these areas. We will use molecular biology, genetics, cellular immunology, gene targeting, and immunoglobulin and TCR transgenic models to study these basic questions in immunology.
Our programme is suitable for someone with a background in biochemistry, immunology, medicine or a similar degree who is interested in using cellular, genetic and biochemical approaches to studying human disease. It may be appropriate for a student in chemistry who wants to learn immunology and apply basic principles to the study of cells with imaging etc. A wide variety of lab techniques will be used and our students become expert in cell biology and immunology. Experience of immunology is not a requirement, since teaching is available in the University and lab.
As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework.
References
53BP1 cooperation with the REV7-shieldin complex underpins DNA structure-specific NHEJ. Ghezraoui H, Oliveira C, Becker JR, Bilham K, Moralli D, Anzilotti C, Fischer R, Deobagkar-Lele M, Sanchiz-Calvo M, Fueyo-Marcos E, Bonham S, Kessler BM, Rottenberg S, Cornall RJ, Green CM, Chapman JR. Nature. 2018 Aug;560(7716):122-127.
Capturing resting T cells: the perils of PLL. Santos AM, Ponjavic A, Fritzsche M, Fernandes RA, de la Serna JB, Wilcock MJ, Schneider F, Urbančič I, McColl J, Anzilotti C, Ganzinger KA, Aßmann M, Depoil D, Cornall RJ, Dustin ML, Klenerman D, Davis SJ, Eggeling C, Lee SF. Nat Immunol. 2018 Mar;19(3):203-205.
B cells require autophagy for metabolic homeostasis and self-renewal. Clarke AJ, Riffelmacher T, Braas D, Cornall RJ, Simon AK. JEM. 2018 Feb 5;215(2):399-413.
Themis2 lowers the threshold for B cell activation during positive selection. Cheng D, Deobagkar-Lele M, Zvezdova E, Choi S, Uehara S, Baup D, Bennett SC, Bull KR, Crockford TL, Ferry H, Warzecha C, Marcellin M, de Peredo AG, Lesourne R, Anzilotti C, Love PE, Cornall RJ. Nat Immunol. 2017 Feb;18(2):205-213B1a.
Mutation in Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity. Siggs OM, Stockenhuber A, Deobagkar-Lele M, Bull KR, Crockford TL, Kingston BL, Crawford G, Anzilotti C, Steeples V, Ghaffari S, Czibik G, Bellahcene M, Watkins H, Ashrafian H, Davies B, Woods A, Carling D, Yavari A, Beutler B, Cornall RJ. PNAS U S A. 2016 113: E3706-15.
Mutation of the ER retention receptor KDELR1 leads to cell-intrinsic lymphopenia and a failure to control chronic viral infection. Siggs OM, Popkin DL, Krebs P, Li X, Tang M, Zhan X, Zeng M, Lin P, Xia Y, Oldstone MB, Cornall RJ, Beutler B. PNAS U S A. 112(42):E5706-14 2015
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