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

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.

Cardiovascular risk in ANCA-associated vasculitis: monocyte phenotyping reveals distinctive signatures between serological subsets

“…There are mixed findings on monocyte composition in AAV (4), similar to the field of CVD (32). Whereas in most CVD studies an increased percentage of IM and NCM was found (32), in AAV, upregulation of CM appears intricately linked to the underlying pathophysiology of the disease, as shown by a recent single-cell RNA sequencing study, highlighting a link between the expansion of activated and interferon signature expressing classical monocyte subsets and resistance to therapy and kidney infiltration (33, 34). As expected, the CM subset expressed high CCR2 levels, and it was found that CCR2 was associated with arterial wall inflammation (35).…”

Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of systemic sclerosis

“…To analyze in-depth pro les of each cell population using single-cell transcriptomes, we further subdivided each cell population using previously reported marker genes [13][14][15][16] . UMAP plots of monocyte subsets and pro les of highly expressed genes are provided in Extended Data Fig.…”

“…CITE-seq was performed using the same antibodies as in our previous report 15 . Thawed PBMCs were treated with DNA-barcoded antibodies, and single-cell suspensions were processed using the 10x Genomics Chromium Controller (10x Genomics).…”

Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis

“…Moreover, recent ow cytometric, single cell RNA sequencing (scRNA-seq) and immunohistochemical analyses of kidney biopsy samples have provided deeper insights into pathomechanisms of immune cells in ANCA-GN [12][13][14][15] . However, the relevant speci c spatial localization of immune cells, and their cellular interactions are largely unknown.…”