Investigating the molecular basis of human immunodeficiency syndromes

During my DPhil, I have been studying mouse models of human disease variants in order to study the molecular mechanisms of immune tolerance. Initially, in particular, I studied the role of NDRG1 in B cell anergy, using molecular tools alongside a CRISPR-edited Ndrg1-/- mouse model. NDRG1 was found to be the most highly differentially expressed gene in anergic B cells compared to naive follicular B cells by RNAseq analysis, and qPCR data shows that NDRG1 shares a pattern of transcriptional regulation with that seen in T lymphocytes as published in 2015 by Oh et al (Nat Comms). My project focused on further understanding the role of NDRG1 in B cells, especially in the context of the signal 1 and 2 hypothesis of lymphocyte activation and during the induction and maintenance of B cell anergy.
More recently, I have been focused on understanding the role of prolidase in immune tolerance. Prolidase deficiency is a rare, multisystem disorder, with 10-15% of patients also presenting with SLE. Pepd-/- mice appear to have anti-nuclear antibodies and an activated T cell phenotype, with increased CD4+ effectors in the thymus and periphery and increased numbers of Tregs in the periphery. Further analysis of the mouse model and use of tools such as mass cytometry will help to understand in particular which cell types are affected and how the function is altered by loss of prolidase activity, in order to link how the metabolic defect leads to loss of tolerance.