Single-cell multi-omics analysis identifies two distinct phenotypes of newly-onset microscopic polyangiitis

Abstract

Abstract Patients with autoimmune vasculitis present with diverse organ-threatening symptoms, but the underlying immunological basis of the clinical heterogeneity remains poorly understood. We conducted single-cell transcriptome and surface proteome analyses using CITE-seq on 109,350 peripheral blood mononuclear cells (PBMCs) and CyTOF on 737,794 PBMCs from newly-onset patients with microscopic polyangiitis (MPA) and age-matched healthy donors. Increased proportions of activated CD14+ monocytes, CD14+ monocytes expressing interferon signature genes (ISGs), cytotoxic CD8+ T cells, and killer immunoglobulin-like receptor (KIR)+ CD8+ T cells were distinctive features of MPA. Patient-specific analysis classified MPA into two groups characterized by CD14+ monocyte signature gene expression (MPA-MONO) and ISG expression (MPA-IFN). The MPA-MONO group was characterized by a high proportion of activated CD14+ monocytes, which persisted before and after immunosuppressive therapy. Patients in this group had a high rate of relapse and were clinically defined by increased monocyte ratio in the total PBMC count and high C-reactive protein titers. The MPA-IFN group was characterized by a high proportion of ISG+ CD14+ monocytes, which significantly decreased following treatment. Patients in this group showed good response to immunosuppressive therapy and were clinically defined by high serum interferon-alpha concentrations, renal symptoms, and high myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) titers. Our findings identify the immunological phenotypes of MPA and provide clinical recommendations for personalized treatment based on accurate prognostic prediction.