Figure 1 Single cell sequencing of B cells from NMDA receptor antibody encephalitis
MRC New Investigator
- Honorary Senior Clinical Research Fellow
- Consultant Neurologist
I head the Oxford Autoimmune Neurology Group and lead a team of researchers investigating the role of different parts of the immune system in autoimmune conditions affecting the central nervous system (CNS).
My current research aims to understand clinical features and the molecular immunopathogenesis of neuroinflammatory conditions, with a particular focus on autoimmune encephalitis. I have identified clinical features characterizing several types of neurological conditions mediated by autoantibodies. I have generated high-throughput single-cell sequencing libraries from multiple tissues, including peripheral blood and cerebrospinal fluid, in patients with autoantibody-mediated CNS diseases (Fig. 1).
I have a particular interest in the role of T cells in autoimmune encephalitis. Although B cells have been extensively studied in autoimmune encephalitis, T cells have been relatively neglected. However, there are several strands of emerging evidence that T cells have a key role in this condition:
- One of the largest magnitude MHC associations in any autoimmune disease is found in LGI1 antibody encephalitis
- patient derived autoantibodies are frequently immunoglobulin class switched and hypermutated, two characteristics which mandate T cell help and strongly implicate T cells as necessary for pathogenic autoantibody production
- There are marked T cell infiltrates within the brain parenchyma of patients with multiple types of autoimmune encephalitis
Therefore, T cells offer a novel immunotherapeutic target with translational potential that may address unmet clinical need in autoimmune encephalitis.
For autoreactive T cells to enter the peripheral immune repertoire, they must have escaped thymic negative selection, in which developing T cells are screened against multiple autoantigens by thymic epithelial cells and other stromal cell populations. To this end, my research also explores different aspects of thymic biology in both normal development and with genetic disruption of thymic epithelial cell function (Fig. 2). I used functional genomics methods to investigate the mechanisms underlying thymic function and other aspects of adaptive immunity.
Thus, through a combination of single cell sequencing and multiplexed spatial proteomics, I aim to understand how T cells with autoreactivity against CNS antigens can escape thymic negative selection.
I regularly teach undergraduate medical students at the University of Oxford and doctors on autoimmune encephalitis and functional neurological disorders.
I run the Oxford Autoimmune Neurology Clinic at the John Radcliffe Hospital with Oxford University Hospitals NHS Foundation Trust. In this capacity, I assess and treat patients with multiple different types of autoimmune encephalitis and other neuroinflammatory conditions. I am happy to be referred patients with autoimmune encephalitis from medical professionals throughout the UK.
Theorell J. et al, (2024), Proceedings of the National Academy of Sciences, 121
Handel AE. et al, (2024), JAMA Neurol