Metabolism in inflamed immune microenvironments
- Project No: NCKIR10
- Intake: 2022 KIR Non Clinical
Supervisor: Prof. Alex Clarke
Co-supervisor: Prof. Claudia Monaco
Immune responses differ drastically depending on where they occur. Tissue microenvironments help control immunity by providing signalling cues, cellular interactions, and importantly, determining the supply of nutrients and metabolites. Metabolites may be supplied via systemic sources, from the microbiome, or produced locally. A crucial question is how metabolism in tissues alters the process of inflammation and its resolution. The germinal centre (GC) reaction is a tightly choreographed process occurring in secondary lymphoid tissue, as B cells refine their antigen specificity through interaction with T follicular helper cells. The GC reaction is essential for the production of high affinity antibodies, for example against SARS-CoV2. Importantly, events occurring in the GC reaction lead to the majority of non-Hodgkin’s lymphomas, and are dysfunctional in many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). How the metabolic microenvironment shapes the GC reaction in health and disease is unknown.
In this project, you will work out the metabolic landscape of germinal centres arising in lymphoid tissue from different tissue microenvironments and understand how it is altered in chronic inflammation. This is important, because metabolism can be manipulated therapeutically, and so identification of metabolic pathways upregulated in autoimmunity could lead to new treatments to modulate inflammation. To do so, you will use cutting edge technologies and methods which allow measurement of metabolism with high in vivo fidelity.
Metabolism, cancer, autoimmune disease, microenvironment.
This project provides a broad training in immunology, with comprehensive coverage of standard and advanced techniques including disease models, advanced flow cytometry, confocal imaging, and measurement of epigenetic modification. For study of metabolism, you will develop expertise in stable isotope resolved metabolomics, extracellular flux measurement using the Seahorse platform, and the bioinformatic analysis of these data. We collaborate with the National Physical Laboratory for mass spectrometry imaging (MSI), which you will have the opportunity of involvement with. You will combine MSI with high dimensional imaging to comprehensively map metabolism within tissues. You will also analyse human clinical samples obtained from patients with autoimmune disease. You will have the opportunity to attend the outstanding educational programme provided at the KIR, and to also regularly present their own data in group meetings, seminars, and at international conferences.
- Raza IG and Clarke AJ. (2021). B Cell Metabolism and Autophagy in Autoimmunity. Frontiers in Immunology, 2021, 12, 681105
- Müschen, M. (2019). Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation. Nat Rev Immunol, DOI: 10.1038/s41577-019-0154-3
- Boothby M and Rickert RC. (2017) Metabolic regulation of the immune humoral response. Immunity DOI: 10.1016/j.immuni.2017.04.009
- De Silva NS and Klein U. (2015) Dynamics of B cells in germinal centres. Nat Rev Immunol DOI: 10.1038/nri3804
Prof. Alex Clarke