Disease susceptibility Pathways in Multiple Sclerosis
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
My group is studying the genes involved in the pathogenesis of multiple sclerosis so that effective therapies may be developed. Several genes have been shown to contribute to MS susceptibility – for example the KIR receptors that are expressed on immune cells called NK cells, tumour necrosis factor-receptor 1, the interleukin-7 receptor alpha chain, and the (e) the T-box transcription factor eomesodermin (EOMES) gene region. These genes are very close to each other on the chromosomes, and so it has been difficult to work out their relative importance. We have developed methods that will allow us to study each of these genes in isolation, and determine how each contributes to the pathogenecity of MS. Data from our studies will be used in the development of new and more effective therapies for this debilitating disease.
Technical Summary
Goals To provide a functional understanding of how MHC class I and class II genes confer risk to multiple sclerosis (MS). Our research has focussed predominantly on exploring the pathogenesis of a HLA-associated disease of the central nervous system – multiple sclerosis (MS). We have translated MS-associated genotypes to phenotypes and in doing so have shed light on disease mechanisms and provided therapeutic opportunities. We have shown that the DRB1*1501 allele is the primary risk gene in MS and that its disease-mediating effect can be modified by the linked DRB5*0101 (1). We have demonstrated functional interactions between MS associated genes and shown how protective genes can regulate risk genes, leading to less severe disease (1-4). Further, we have determined the functional and structural bases for interactions between MS-risk genes and environmental factors. Our studies in autoimmune encephalomyelitis (EAE) an animal model of MS, have shown that the acid sensitive ion channel ASIC1 is important in pathogenesis. Tissue acidosis in the spinal cord of EAE mice causes the ASIC1 channels to open, and as these are permeable to Na+ and Ca2+ ions (2) the clinical deficit and axonal degeneration caused by excessive accumulation of these two ions is reduced. Thus we have identified this acid sensing ion channel as a potential therapeutic target in MS. Future research plans Future work will focus on the study of several immune genes showing MS associated variations by using humanized and transgenic mouse models: (a) the KIR receptors that are expressed on NK cells, and their interaction with difference HLA-C alleles; (b) tumour necrosis factor-receptor 1; (c) the interleukin-7 receptor alpha chain; and the (e) the T-box transcription factor eomesodermin (EOMES) gene region. We will also carry out multiple MS family whole genome sequencing. References: (1) Gregersen et al 2006 Nature 443:574 (2) Friese et al 2007 Nature Med 12:1483 (3) Friese et al 2008 Nature Med 14: 1227 (4) Harkiolaki et al 2009 Immuity 30: 348 (5) Fugger et al 2009 Nature Rev Immunol 9: 408.
People |
ORCID iD |
Lars Fugger (Principal Investigator) |
Publications
Attfield KE
(2022)
The immunology of multiple sclerosis.
in Nature reviews. Immunology
Cortes A
(2020)
Identifying cross-disease components of genetic risk across hospital data in the UK Biobank.
in Nature genetics
Cortes A
(2017)
Bayesian analysis of genetic association across tree-structured routine healthcare data in the UK Biobank.
in Nature genetics
Dendrou CA
(2017)
Immunomodulation in multiple sclerosis: promises and pitfalls.
in Current opinion in immunology
Dendrou CA
(2018)
HLA variation and disease.
in Nature reviews. Immunology
Faergeman S
(2020)
A novel neurodegenerative spectrum disorder in patients with MLKL deficiency
in Cell Death & Disease
Fugger L
(2020)
Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases.
in Cell
Kaufmann M
(2022)
Identification of early neurodegenerative pathways in progressive multiple sclerosis.
in Nature neuroscience
Kaufmann M
(2021)
Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.
in Med (New York, N.Y.)
Kaur G
(2017)
Structural and regulatory diversity shape HLA-C protein expression levels.
in Nature communications
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 | Novel therapeutic drug to treat MS patients |
Organisation | Bristol-Myers Squibb |
Country | United States |
Sector | Private |
PI Contribution | Pre-clinical testing the efficacy of a new therapeutic target using in vitro and in vivo models. |
Collaborator Contribution | Pre-clinical testing the efficacy of a new therapeutic target using in vitro and in vivo models. |
Impact | None, yet |
Start Year | 2020 |
Description | Single cell RNA sequencing |
Organisation | Broad Institute |
Country | United States |
Sector | Charity/Non Profit |
PI Contribution | Isolation and processing of samples, experimental design, and hands on help from one of my postdocs, who is a visiting researcher to the Broad. |
Collaborator Contribution | Assistance with sequencing, data analysis and data interpretation. |
Impact | A manuscript for peer-review publication is still in process. This work is multi-disciplinary and requires biologists, bioinformaticians and statisticians. |
Start Year | 2017 |
Description | Structural biology |
Organisation | Monash University |
Country | Australia |
Sector | Academic/University |
PI Contribution | We are leading a project where specific technologies, performed by our collaborators at Monach University, will perform some of the experiments for us. We provide the source materials for this. |
Collaborator Contribution | Application of specific technologies and methods in which to test specific questions related to our project. |
Impact | None, yet |
Start Year | 2020 |
Description | MS Life patient day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Talk given to MS patients at an organised MS Life event in London to discuss the outcomes of research into amiloride that originated from our research. The talk was entitled, 'when things go sour'. |
Year(s) Of Engagement Activity | 2016 |
Description | Meeting with MS patients and their families |
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 | Public/other audiences |
Results and Impact | better understanding of MS and how it is being treated now and in the future Positive feedback |
Year(s) Of Engagement Activity | 2011,2012,2013,2014 |
Description | Multiple sclerosis patient information day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | 150 MS patients and their carers attended an information day on Saturday 4th March 2023, where nurses, clinicians and research scientists gave talks about current research efforts, how we manage patient recruitment to new clinical trials and how patients and their families and friends can be involved in Oxford research. Specifically, our talk was about how patients can donate blood samples for research purposes and how there are many different ways we can use these samples (DNA, RNA, proteins, serum) to use in lots of projects. We also discussed why longitudinal sampling was so integral to our and other research studies, emphasising how we strive to understand and follow the journey of everyone's disease, when also combining these findings with clinical data. There were many questions following the talk and many more during the lunch break. In particular, patients asked whether additional samples can be taken when they are not routinely coming to the hospital for appointments. At present, this possibility is being put in place so that research nurses can go to patient's homes, so that anyone who is willing and able contribute to research studies, can do so whenever possible. This includes at later disease stages when treatments are no longer being used. This was a very well received day and offered great reassurances to patients that they can continue to contribute to research as much as possible at all stages of their disease. |
Year(s) Of Engagement Activity | 2023 |
Description | Public Engagement profile on the research group's website |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | As part of our research group's website (https://www.ocni.co.uk/public), we invite members of the public to contact us about questions they have related to our research on neuroinflammatory diseases. |
Year(s) Of Engagement Activity | 2018 |
Description | Talk for the University of the Third Age (U3A) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Third sector organisations |
Results and Impact | Talk given by one of the senior postdoctoral researchers to a group of members of the University of the Third Age about MS research and the lab's focus on understanding how genetic susceptibility is characterised and studied. |
Year(s) Of Engagement Activity | 2018 |