Neutrophil single-cell analysis identifies a type II interferon-related subset for predicting relapse of autoimmune small vessel vasculitis
Masayuki Nishide, Kei Nishimura, Hiroaki Matsushita, S. Kawada, Hiroshi Shimagami, Shoichi Metsugi, Yasuhiro Kato, Takahiro Kawasaki, Kohei Tsujimoto, Ryuya Edahiro, Yuya Shirai, Eri Itotagawa, Maiko Naito, Yuji Yamamoto, Kazuki Matsukawa, Ryusuke Omiya, Yukinori Okada, Kunihiro Hattori, Masashi Narazaki, Atsushi Kumanogoh
Abstract
To identify the dynamics of neutrophil autoimmunity, here we focus on anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and perform single-cell transcriptome and surface proteome analyses on peripheral white blood cells from patients with new-onset microscopic polyangiitis (MPA). Compared with controls, two neutrophil populations, immature neutrophils and neutrophils with type II interferon signature genes (Neu_T2ISG), are increased in patients with MPA. Trajectory and cell–cell interaction analyses identify Neu_T2ISG as a subset that differentiates from mature neutrophils upon stimulation with IFN-γ and TNF, which synergize to induce myeloperoxidase and Fcγ receptors expression on the neutrophil cell surface and promote ANCA–induced neutrophil extracellular trap formation. Case-by-case analysis indicates that patients with a high proportion of the Neu_T2ISG subset are associated with persistent vasculitis symptoms. A larger cohort analysis shows that serum IFN-γ levels at disease onset correlate with susceptibility to disease relapse. Our findings thus identify neutrophil diversity at the single cell level and implicate a biomarker for predicting relapse in small vessel vasculitis. Neutrophils are early mediators for inflammation, but their functions in autoimmunity is still unclear. By using single cell analyses to compare patients with microscopic polyangiitis (MPA) and controls, here the authors find increased IFN-II-related neutrophils induced by IFN-γ and TNF signaling as a relapse risk marker for small vessel vasculitis.