Abstract Acute anterior uveitis (AAU) is the most common extra‐articular manifestation of ankylosing spondylitis, leading to recurrent inflammation and irreversible visual impairment. Long‐term corticosteroid therapy is associated with substantial adverse effects, and effective strategies to prevent relapse are lacking. Single‐cell RNA sequencing (scRNA‐seq) was performed on peripheral blood mononuclear cells from seven patients with ankylosing spondylitis‐acute anterior uveitis (AS‐AAU) and six healthy controls, and aqueous humor samples were analyzed together with genome‐wide association study (GWAS) data. Bioinformatic pipelines were used to infer cell–cell communication, metabolic programs, extracellular vesicle (EV)‐related signals, and disease‐relevant cell types, followed by validation in clinically derived specimens. A monocyte subcluster with upregulated cytokine and chemokine transcripts and signatures of trained immunity, termed Mono‐TI, is identified. EVs potentially transport inflammatory mediators associated with Mono‐TI, thereby contributing to immune dysregulation. Pseudotime analysis indicates that Mono‐TI may differentiate into macrophages within the ocular microenvironment that share overlapping transcriptional features. Cell–cell interaction analysis positions Mono‐TI as a highly connected node, receiving IFN‐γ signals from CD8 + T cells and natural killer (NK) cells while actively regulating neutrophils. Integrated GWAS analysis further implicates Mono‐TI, together with CD8 + T cells and NK cells, as key contributors to disease pathogenesis. This study delineates the immune landscape of AS‐AAU and highlights a monocyte subset with trained immunity–like transcriptional signatures and related immune cell populations as central mediators of systemic and ocular inflammation and as promising therapeutic targets.
Sun et al. (Tue,) studied this question.