Dr Prasanti Kotagiri1, Dr Laura Bergamaschi1, Ms Diana Pombal1, Ms Sofie Tolmeijer1, Ms Sarah Zanky1, Ms Federica Mescia1, Prof Eoin Mckinney1, Dr Paul Lyons1, Prof Ken Smith1
1Cambridge University, Cambridge, UK
Background
Systemic Lupus Erythematousos (SLE) is a multi-systemic disease characterised by the presence of pathogenic autoantibodies directed against nucleic acids and their binding proteins. Despite recent increases in the number of treatments available, disease course remains variable. Further therapeutic advances are hampered by a lack of understanding of the mechanisms driving both initial disease susceptibility and long-term clinical outcome.
Aim
We studied the transcriptomes of patients with active SLE to better understand the disease process and uncover novel pathways for treatment.
Methods
Patients were recruited at the time of diagnosis or during an active flare. Blood samples were flow-sorted into B, T and dendritic cell subsets, NK cells, monocytes and neutrophils. Bulk RNA-Seq libraries were generated and paired end sequenced using Illumina HiSeq4000. Analytical techniques included differential gene-expression, weighted gene co-expression network and multi-omics factor analyses.
Results
Here we identify, the upregulation of the AP-1 signalling pathway (FOS, JUN, DUSP, NFKBIA, PER1, TNFAIP3) in SLE compared with both disease and healthy controls. The AP-1 signalling pathway was more notable upregulated in lymphoid lineage cell subsets (both naïve and memory) compared with myeloid. Expression of the AP-1 pathway in B cells positively correlated with the average number of base pair mutations per unique B cell receptor IGHM isotype. Validation of high expression of the AP-1 pathway was confirmed on analysis of independent SLE micro-array datasets.
Conclusion
The widespread increased expression of the AP-1 signalling pathway in adaptive immune cells of SLE likely plays a key role in regulating cell differentiation, proliferation and survival. Further understanding the upstream pathways leading to activation may uncover novel therapeutic targets and help explain the suboptimal treatment outcomes of interferon-blockade.
Biography:
Dr Prasanti Kotagiri is a Nephrologist and early career researcher with a strong interest in B cell immunology. On completion of her training, she was a recipient of the Jacquot Research Entry Fellowship enabling her to undertake a PhD at Cambridge University in the Smith laboratory. Her work involved studying the immune cell transcriptome and B cell receptor repertoire in auto-immunity, infection and vaccination. She has first author papers in Nature, Immunity and Cell reports. Since relocating to Melbourne she has continued collaborating with Cambridge and is a Senior Lecturer in the Department of Medicine, University of Melbourne.