#1154 Type I interferon pathway is upregulated in microscopic polyangiitis (vs granulomatosis with polyangiitis)

Abstract

Abstract Background and Aims The two main types of ANCA-associated vasculitis (AAV), microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), share common characteristics but also differ on many aspects (epidemiological, genetic, clinical, outcomes). These differences did not justify, to date, different patient management. To identify more specific targetable pathways, we characterized the kidney transcriptome of MPA vs. GPA patients with AAV-glomerulonephritis (AAV-GN). Method This retrospective study included adult patients with AAV-GN from the French Maine-Anjou Registry. Immune gene transcript analysis was performed on RNA extracted from 97 kidney biopsies using NanoString technology. Significant transcripts were examined to identify immune pathways of interest. We then used a publicly available dataset to explore these identified pathways (qPCR / ELISA). Results We compared kidney biopsies from GPA (n = 33) and MPA (n = 64) patients. There was no difference in eGFR between both groups at diagnosis. Of the 750 evaluated immune transcripts, 8 genes were found differentially expressed between MPA and GPA patients, all being upregulated in MPA (log2FC > 1, q-value < 0.05) (Fig. 1A). Seven (out of 8) genes belonged to the type I interferon (IFN-I) signaling pathway. A personal analysis of unpublished, publicly available, data1 identified a significantly more pronounced IFN-I signature in the peripheral blood mononuclear cells of patients with MPO-AAV when compared to those with PR3-AAV (Fig. 1B). Serum levels or CXCL10, a cytokine that mediates immune responses through the recruitment and activation of numerous immune cells under the regulation of IFN-I, were found higher in MPO-AAV patients (Fig. 1C). Conclusion We identified a type I interferon signature, both in kidneys and in blood, in patients with MPA (or MPO-AAV) in comparison to GPA (or PR3-AAV). This is in line with previous lines of evidence brough by Kessenbrock et al. and Kessler et al. suggesting a role for IFN-I in AAV and especially in MPO-AAV. This signature may help gain a deeper understanding of the AAV-GN pathogenesis and provide insights for developing new therapeutic options.