The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus

Front Immunol. 2023 Mar 27:14:1072598. doi: 10.3389/fimmu.2023.1072598. eCollection 2023.

Abstract

Introduction: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).

Methods: We performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.

Results: We report here that "Pan-vasculitis" signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.

Discussion: We conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy.

Keywords: autoimmune diseases; endotypes of disease; lupus (SLE); transcriptomics (RNA-seq); vasculitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis*
  • Antibodies, Antineutrophil Cytoplasmic
  • Genomics
  • Humans
  • Lupus Erythematosus, Systemic* / genetics
  • RNA, Messenger

Substances

  • Antibodies, Antineutrophil Cytoplasmic
  • RNA, Messenger

Grants and funding

This work was funded by the European Research Council under the European Union’s Horizon 2020 research and innovation program (agreement no. 742390), by the Greek Rheumatology Society and Professional Association of Rheumatologists (ERE-EPERE), by the Special Account for Research Grants (S.A.R.G.), National and Kapodistrian University of Athens, Athens, Greece (DV, Grants #12085, 12086) and by SYSCID consortium (European Union’s Horizon 2020 research and innovation programme under grant agreement No 733100). The research leading to these results has been co-funded by the European Commission under the H2020 Research Infrastructures contract no. 675121 (project VI-SEEM). Computational time was granted from the VI-SEEM project and the Greek national HPC facility—ARIS under project ID “RNA_LUPUS”.