Identification of pathways involved in immune regulation and B cell selection

Lead Research Organisation: University of Oxford

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
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Publications


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Cornall RJ (2008) HO-1 extends to stem cells. in Blood

 
Description Fellow Academy of Medical Sciences
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Support for careers and funding
 
Description Kidney Research UK Grants Committee
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Oxford Biomedical Research Centre Immunity Theme
Amount £200,000 (GBP)
Organisation Oxford University Hospitals NHS Trust 
Department NIHR Oxford Biomedical Research Centre
Sector Public
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 04/2012 
End 05/2017
 
Description Wellcome Trust Clinical Studentship
Amount £260,577 (GBP)
Organisation The Wellcome Trust Ltd 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 09/2010 
End 09/2013
 
Title DOCK8 deficient mice 
Description DOCK8 deficient mice due to an ENU mutation 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2012 
Provided To Others? Yes  
Impact Research into the causes of the human DOCK8 immunodeficiency syndrome 
 
Title Humanised PD1 knockin mice 
Description Mice containing the human PD1 receptor 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2011 
Provided To Others? Yes  
Impact Economic. Funds from selling the mice have been added to our research grant. 
 
Title Themis deficient mice 
Description Mice deficient in the protein Themis (aka Anarchin) 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact None yet 
 
Description Australian National University 
Organisation Australian National University (ANU)
Department John Curtin School of Medical Research (JCSMR)
Country Australia, Commonwealth of 
Sector Academic/University 
PI Contribution Joint characterisation of immune phenotypes
Collaborator Contribution Generation and joint characterisation of immune deficiencies
Impact Publications. Studying genetics and immunology
 
Description King's College London 
Organisation King's College London (KCL)
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution We contributed sequencing of patient with early onset lupus and the analysis of these data.
Collaborator Contribution Supply of patient samples
Impact No
Start Year 2011
 
Description National Institute of Health 
Organisation National Institutes of Health (NIH)
Country United States of America 
Sector Public 
PI Contribution The supply of DOCK8 deficient mice, which are a model for human DOCK8 immunodeficiency. Information about possible mechanisms, supplied as a pre-publication data. We also supplied expertise in the use of transgenic models and B cell immunology.
Collaborator Contribution Supply of pre-publication information about human DOCK9 immunodeficiency. Experiments to test the relevance of findings in animal models in human patient samples. Collaboration on the development of hypotheses.
Impact DOCK8 is critical for the survival and function of NKT cells. Crawford G, Enders A, Gileadi U, Stankovic S, Zhang Q, Lambe T, Crockford TL, Lockstone HE, Freeman A, Arkwright PD, Smart JM, Ma CS, Tangye SG, Goodnow CC, Cerundolo V, Godfrey DI, Su HC, Randall KL, Cornall RJ. Blood. 2013 Sep 19;122(12):2052-61. doi: 10.1182/blood-2013-02-482331. Epub 2013 Aug 8. Lambe T, Crawford G, Johnson AL, Crockford TL, Bouriez-Jones T, Smyth AM, Pham THM, Zhang Q, Freeman AF, Cyster JG, Su H and Cornall RJ. DOCK8 is essential for T cell survival and limits the maintenance of CDT cell memory. Eur J Immunol 2011, 41: 3423-3520
Start Year 2009
 
Description Oxford University 
Organisation Medical Research Council (MRC)
Department MRC Human Immunology Unit
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Public 
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 University of Bristol 
Organisation University of Bristol
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution DNA sequencing of samples from patients with hereditary nephrotic syndrome.
Collaborator Contribution Supply of DNA samples and technical expertise in the area of steroid-resistant nephrotic syndrome.
Impact No
Start Year 2011
 
Description University of Calafornia San Fransisco 
Organisation University of California
Department University of California, San Francisco
Country United States of America 
Sector Academic/University 
PI Contribution The supply of DOCK8 deficient and other mutant mouse samples for study in vivo.
Collaborator Contribution Expertise in the in vivo analysis and imaging of lymphocytes and their migration.
Impact No
 
Description University of Newcastle 
Organisation Newcastle University
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution The generation of animal models containing mutations in novel genes associated with immunodeficiency
Collaborator Contribution Confidential pre-publication information about Mendelian mutations causing human immunodeficiency, which they have identified in patients from the north of England.
Impact No
Start Year 2012
 
Title Animal Models of Human Inhibitory Receptors 
Description Development of animal strains expressing human inhibitory receptors with Prof Simon Davis, Oxford University 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed No
Impact Development of anti-cancer drugs by Pharmaceutical companies has involved use of these strains
 
Description Admissions meeting with students 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact Talked to High school students.

Notably, some of these students did apply for admission to the university.
Year(s) Of Engagement Activity 2011,2012
 
Description Admissions talk to school teachers 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach National
Primary Audience Schools
Results and Impact Talking about admissions to Oxford to teachers.

Questions asked about the admissions process.
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Podcast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A podcast about my research for a general audience

None discernable - apart from rude comments from my sons.
Year(s) Of Engagement Activity 2012
 
Description Student work-experience 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 5 local private and state school students have been on summer placements in the lab.

Prelude to university applications in science and engineering. 3 have applied to Oxford
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Website 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Design of website presenting work.

None
Year(s) Of Engagement Activity 2009,2010,2011,2012