Dr Prasanti Kotagiri1, Prof Eoin McKinney1, Dr Paul Lyons1, Prof Ken Smith1
1Cambridge University, Cambridge, United Kingdom
Background
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel, multi-systemic, necrotising vasculitis, causing severe morbidity and mortality. It is accompanied by the presence of auto-reactive antibodies against neutrophil granules. The two main target antigens are myeloperoxidase (MPO) and proteinase 3 (PR3). Treatment remains non-specific and un-targeted.
Aim:
We studied the gene (transcriptome) and protein (proteome) expression of patients with active AAV, to better understand disease process and uncover untargeted pathways for treatment.
Methods
The transcriptional profiles and protein expression of patients with AAV and Systemic Lupus Erythematosis (SLE) were studied at the time of diagnosis or during an active flare. AAV patients were profiled longitudinally. Separated leucocyte transcriptome profiling, using Affymetrix HuGene ST1.1 gene expression microarray, was conducted. Protein expression was assessed on the SOMAscan platform. Analytical techniques included differential gene-expression, weighted gene co-expression network and multi-omics factor analyses.
Results
We uncovered a modular expression of interferon stimulated genes in MPO-AAV which was absent in PR3-AAV. The interferon signature was confirmed by its presence in SLE, a disease well known for its heightened expression. This signature was present during the time of active disease and at 3 months post treatment. The interferon signature was not able to differentiate the two antibodies subtypes at 12 months. The signature was present in the Neutrophil, Monocyte and PBMC transcriptome but absent in T cells. Multi-omic factor analysis revealed upregulated interferon like proteins, coinciding with the increase in gene expression.
Conclusion
AAV causes severe morbidity and mortality. The differential expression of interferon in MPO compared with PR3-AAV highlights differences in pathogenesis. The presence of an interferon response in MPO-AAV opens new avenues for targeted treatment.
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.