Pathways Involved in Immune Regulation and B Cell Selection
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
Our aim is to understand the genetics of immune disease in humans, and to develop new therapeutic strategies that can interrupt the development of autoimmunity. To understand how abnormal regulation of the immune system leads to autoimmune disease we are studying the cells involved in ‘immunological memory’ which is the basis for all vaccination strategies and leads to the development of long-term immunity to infectious disease. We have developed new methods of tracking cells and characterizing the events involved in generation of immunity and we are using these to study self tolerance to antigens inside cells – for example those involved in the autoimmune disease systemic lupus erythematosus (SLE). We have used a model to look for defects in the immune response to self and foreign antigens, and are linking genes with their biological outcomes. We have identified a protein called Roquin, as a potentially important protein in the development of rheumatoid arthritis and SLE and we are now working on molecules that could be used as a therapy to reduce the self-directed immune response in these two debilitating diseases.
Technical Summary
Goals To understand how the immune system regulates the response to antigens - in particular how B cells are selected and how dysregulation leads to autoimmune disease. Our focus is on how cells involved in long-term immunity are generated and sustained as part of immunological memory. We have developed functional approaches to track cells and characterize pathways involved both in the immune response and in self tolerance. Using these methods we have investigated self-tolerance to intracellular antigens such as those targeted in the autoimmune disease systemic lupus erythematosus (SLE). We have shown that when mHEL, highly tolerogenic on the cell surface, is tethered in the ER by an ER retention moiety it becomes immunogeneic and positively selects self-renewing B1 B cells and high titres of high affinity IgM autoantibody (1). We have used genetic strategies to identify new pathways regulating the immune response to antigens. Genome-wide ENU mutagenesis has been used to screen for defects in the immune response to self and foreign antigens, and we have refined strategies for dissecting immunological defects and for linking biochemical pathways between genes and phenotypes. By using ENU we identified the autoimmune regulator Roquin and determined its role in the negative regulation of follicular helper T (TFH) cells from a screen for autoimmune mice (2). Roquin mediates the destruction of mRNA encoding the T cell costimulatory molecule ICOS, important as TFH cells and ICOS dependent signals are required for germinal centre formation and high affinity antibodies. As TFH cells are activated in rheumatoid arthritis and increased in frequency in SLR, we have developed a potential therapeutic blocking antibody against the human ICOS ligand, as well as PD-1 superagonists, to target TFH cells. With our collaborators at the MRC Genome Stability Unit (University of Sussex) we have contributed to the field of stem cell biology by showing how DNA repair of double strand breaks by DNA ligase IV is essential for the maintenance of stem cells during aging (3). The identification and characterization of Themis, a novel protein required for survival and positive selection of T cells (4) illustrates how rare variants can open up new lines of research. Our recent development of a screening method for defects in immunization led us to identify two ENU mutant strains of mice, both deficient in the guanine nucleotide exchange factor (GEF) DOCK8. Both of these strains failed to sustain an antibody response to T-dependent antigen. Future research plans Our future work will focus on: (a) study of the role of DOCK family proteins in immune function, B cell selection and memory; (b) creation of a consortium to study the genetics of immune disease in humans; (c) development of new therapeutic strategies targeting autoimmiune pathways in humans. References: (1) Ferry et al 2003 J Exp Med 198: 1415 (2) Vinuesa et al 2005 Nature 435:452 (3) Nijnik et al 2007 Nature 447: 686 (4) Johnson et al. 2009 Nature Immunology 10: 831 (5) Randall et al. 2009 Nature Immunology 10:1283 546/3444
People |
ORCID iD |
Richard Cornall (Principal Investigator) |
Publications
Abeler-Dörner L
(2020)
High-throughput phenotyping reveals expansive genetic and structural underpinnings of immune variation.
in Nature immunology
Adams ER
(2020)
Antibody testing for COVID-19: A report from the National COVID Scientific Advisory Panel.
in Wellcome open research
Anzilotti C
(2019)
An essential role for the Zn2+ transporter ZIP7 in B cell development.
in Nature immunology
Burrows N
(2020)
Dynamic regulation of hypoxia-inducible factor-1a activity is essential for normal B cell development.
in Nature immunology
Cheng D
(2017)
Themis2 lowers the threshold for B cell activation during positive selection.
in Nature immunology
Choi S
(2017)
THEMIS: Two Models, Different Thresholds.
in Trends in immunology
Clarke AJ
(2018)
B1a B cells require autophagy for metabolic homeostasis and self-renewal.
in The Journal of experimental medicine
COvid-19 Multi-Omics Blood ATlas (COMBAT) Consortium. Electronic Address: Julian.knight@well.ox.ac.uk
(2022)
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.
in Cell
Deobagkar-Lele M
(2017)
Themis2: setting the threshold for B-cell selection.
in Cellular & molecular immunology
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00008/1 | 01/04/2017 | 31/03/2023 | £2,738,000 | ||
MC_UU_00008/2 | Transfer | MC_UU_00008/1 | 01/04/2017 | 31/03/2023 | £1,821,000 |
MC_UU_00008/3 | Transfer | MC_UU_00008/2 | 01/04/2017 | 31/03/2023 | £2,257,000 |
MC_UU_00008/4 | Transfer | MC_UU_00008/3 | 01/04/2017 | 31/03/2023 | £1,459,000 |
MC_UU_00008/5 | Transfer | MC_UU_00008/4 | 01/04/2017 | 31/03/2023 | £1,346,000 |
MC_UU_00008/6 | Transfer | MC_UU_00008/5 | 01/04/2017 | 31/03/2023 | £1,660,000 |
MC_UU_00008/7 | Transfer | MC_UU_00008/6 | 01/04/2017 | 31/03/2023 | £401,000 |
MC_UU_00008/8 | Transfer | MC_UU_00008/7 | 01/04/2017 | 31/03/2024 | £2,876,000 |
MC_UU_00008/9 | Transfer | MC_UU_00008/8 | 01/04/2017 | 31/03/2023 | £2,568,000 |
MC_UU_00008/10 | Transfer | MC_UU_00008/9 | 01/04/2017 | 31/03/2023 | £2,060,000 |
MC_UU_00008/11 | Transfer | MC_UU_00008/10 | 01/04/2017 | 31/03/2023 | £1,477,000 |
Description | Leadership of the Nuffield Department of Medicine's response to the COVID19 pandemic |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Multiple impacts supported by NDM; Oxford vaccine and transfer to AZ, RECOVERY, Mobile APPs, National Serosurveys for ONS, ISARIC protocols, Clinical Pathology, Spike protein and antibody variation, Support for global initiatives. I have led these activities as HOD, and been involved in supporting day to day research activity in my secondary role as an MRC Investigator. |
Description | Oxford University |
Organisation | Medical Research Council (MRC) |
Department | MRC Human Immunology Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We supplied tissues and collaborated in analysis of mutant mcie |
Collaborator Contribution | Collaboration to look at NKT cell function |
Impact | None yet |
Start Year | 2009 |
Description | Patrick Maxwell |
Organisation | University of Cambridge |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Support of the study of VHL and HIF signaling in B cell development and function |
Collaborator Contribution | Development and analysis of animal models |
Impact | Insight into basic immunology |
Start Year | 2016 |
Company Name | MIROBIO LTD |
Description | A company developing antibody based treatments for inflammatory and to induce tolerance in autoimmune disease and transplantation. |
Year Established | 2018 |
Impact | Employment of 10-20 staff currently. Raised £27m in capital from UK and US funders. |
Description | Interviews with Journalists |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interviews on COVID19 and the University's response with national and international newspapers |
Year(s) Of Engagement Activity | 2020 |
Description | Journal of a Pandemic Year |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | To describe the University's and Department's response to the COVID19 pandemic |
Year(s) Of Engagement Activity | 2021 |
URL | https://www.youtube.com/watch?v=MDVGKkHIiko |
Description | Our Immune System - the battle within |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | "Our Immune System - the battle within" is a video animation created by Mukta Deobagkar (Cornall Lab) and Mafalda Da Cunha Santos (Davis Lab), released on oxfordsparks.ox.ac.uk on 7th March 2019 |
Year(s) Of Engagement Activity | 2019 |