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Abstract: PO1760

Differential Expression of Interferon-Stimulated Genes in ANCA-Associated Vasculitis

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Kotagiri, Prasanti, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
  • McKinney, Eoin F., University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
  • Lyons, Paul Anthony, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom
  • Smith, Kenneth GC, University of Cambridge, Cambridge, Cambridgeshire, United Kingdom

Group or Team Name

  • Smith Laboratory
Background

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a multi-systemic, necrotising vasculitis, causing severe morbidity and mortality. It is characterised by the presence of auto-reactive antibodies against neutrophil granule components, myeloperoxidase (MPO) and proteinase 3 (PR3). The disease course remains variable, and patients suffer substantial morbidity and mortality. Therapeutic advances are hampered by a lack of understanding of the mechanisms driving both initial disease susceptibility and long-term clinical outcome. To increase our understanding of disease mechanism and to uncover untargeted pathways for treatment, we studied the transcriptomes and serum proteomes of patients with active AAV.

Methods

The transcriptional profiles and protein expression of patients with AAV (31 PR3-AAV, 15 MPO-AAV, 1 dual ANCA positivity, 4 ANCA-negative) were studied at the time of diagnosis or during an active flare, whilst on minimal immunosuppression, along with healthy controls. AAV patients were profiled longitudinally at 3 and 12months. Separated leucocyte transcriptomes were profiled, using Affymetrix HuGene ST1.1 gene expression microarray. Transcriptional profiles were available on peripheral blood mononuclear cells (PBMCs), neutrophils, monocytes and CD4 and CD8 T cells. Protein expression was assessed on the SOMAscan platform. Analytical techniques included differential gene-expression, weighted gene co-expression network, gene set enrichment and multi-omics factor analyses.

Results

Here we identify, a module of interferon stimulated genes (ISG) that distinguishes the serological subtypes of AAV, MPO- and PR3-ANCA. This module of ISG was upregulated in MPO- compared with PR3-AAV during the time of active disease and at 3 months post treatment. The signature was present in the neutrophil, monocyte and PBMC transcriptome but was absent in T cells. Multi-omic factor analysis revealed a parallel upregulation of interferon like proteins in serum, coinciding with the increase in gene expression.

Conclusion

AAV causes severe morbidity and mortality. The differential expression of ISG in MPO compared with PR3-AAV highlights potential differences in pathogenesis. The presence of an interferon response in MPO-AAV opens new avenues for targeted treatment with agents such as Jak inhibitors and monoclonal anti-IFN-α antibodies.