Background
The B-lymphocytes in Autoimmunity and Malignancies Laboratory investigates the immunobiology of B-lymphocytes, particularly the B cell survival factors BAFF and APRIL, and their receptors BAFF-R, TACI and BCMA. Professor Mackay has shown that excess BAFF leads to autoimmunity in mice and is associated with human autoimmunity, in particular systemic lupus erythematosus (SLE).
The BAFF receptor TACI is highly expressed on memory B cells in SLE patients, and BAFF-TACI interactions lead to elevated autoantibody production which drives disease pathology. The genetic deletion of TACI has been shown to protect against SLE, but the underlying mechanism remains largely unknown.
Aim
- Investigate the cellular mechanism by which TACI signalling leads to exaggerated autoantibody production in SLE.
- Investigate how altered gut microbiota (through the regulation of immunoglobulin A production by TACI) and metabolites are associated with SLE disease severity.
- Use a new mouse model of lupus overexpressing human BAFF to be combined to a model expressing human TACI.
- Compare targeting TACI versus belimumab treatment (a lupus treatment blocking BAFF).
This project will use a range of immunological techniques (mouse models of disease, flow cytometry, confocal microscopy, ELISA), metagenomic sequencing, microbiome analysis and metabolomics to characterise the immunological mechanisms of action. We will validate the research findings using clinical samples.
Project Potential
Current therapies for human lupus are strongly immune-suppressive and/or toxic. The limitations of these treatments were especially evident during the COVID-19 pandemic, which has seen a disproportionate number of patients with SLE developing a severe/fatal COVID-19 infection. There is a need for new therapies able to stop autoimmunity without compromising vital immune defences.