Single-cell analyses highlight the proinflammatory contribution of C1q-high monocytes to Behçet’s disease

Significance

Behçet’s disease (BD) is a systemic vasculitis, and its pathogenesis is elusive. Limited understanding of the immune disturbances in BD hindered the identification of therapeutic targets. Here, we performed single-cell and bulk RNA sequencing to reveal the comprehensive landscape of cellular and molecular changes in BD blood. We observed the mobilization of monocytes, especially a monocyte subset (C1q-high monocytes) in BD. Further assays revealed the proinflammatory features and clinical relevance of this subset. Activated interferon-γ (IFN-γ) signaling in BD patients induced C1q-high monocyte expansion, which was recovered by tofacitinib treatment. Our findings provide comprehensive understanding of BD immunopathogenesis, highlighting the proinflammatory contribution and therapeutic potential of C1q-high monocytes.

Abstract

Behçet’s disease (BD) is a chronic vasculitis characterized by systemic immune aberrations. However, a comprehensive understanding of immune disturbances in BD and how they contribute to BD pathogenesis is lacking. Here, we performed single-cell and bulk RNA sequencing to profile peripheral blood mononuclear cells (PBMCs) and isolated monocytes from BD patients and healthy donors. We observed prominent expansion and transcriptional changes in monocytes in PBMCs from BD patients. Deciphering the monocyte heterogeneity revealed the accumulation of C1q-high (C1q ^hi) monocytes in BD. Pseudotime inference indicated that BD monocytes markedly shifted their differentiation toward inflammation-accompanied and C1q ^hi monocyte–ended trajectory. Further experiments showed that C1q ^hi monocytes enhanced phagocytosis and proinflammatory cytokine secretion, and multiplatform analyses revealed the significant clinical relevance of this subtype. Mechanistically, C1q ^hi monocytes were induced by activated interferon-γ (IFN-γ) signaling in BD patients and were decreased by tofacitinib treatment. Our study illustrates the BD immune landscape and the unrecognized contribution of C1q ^hi monocytes to BD hyperinflammation, showing their potential as therapeutic targets and clinical assessment indexes.