Age-associated B cells contribute to inflammation via antibody-independent mechanisms in Takayasu's arteritis.

Abstract

Although Takayasu's arteritis (TAK) is not a prototypical autoantibody-mediated disease, accumulating evidence suggests that B cells are involved. This study aimed to investigate the pathway of B-cell activation and its contributions to TAK pathogenesis. Histological analysis of paravascular lymph nodes and affected arteries was conducted to investigate B-cell activation pathways in TAK. Bulk RNA-seq, single-cell RNA-seq (scRNA-seq), flow cytometry, and in vitro experiments were performed to characterize the composition, transcriptomic features and functional profiles of B cells. The numeric and phenotypic alterations induced by TNF and JAK inhibition were assessed both in vitro and in 4 patients with TAK. Histological (n=5), flow cytometric (n=125) and bulk RNA-seq (n=12) analyses indicated the presence of extrafollicular response and upregulated age-associated B cell (ABC) production in TAK, along with cross-dataset transcriptomic differences between B cells from patients with TAK and systemic lupus erythematosus (SLE). Cross-dataset scRNA-seq analysis and in vitro experiments (n=5) demonstrated that ABC differentiation in TAK was largely uncoupled from antibody-secreting cell (ASC) generation, unlike that in SLE. Functional experiments showed that ABCs exhibited proinflammatory properties, including proinflammatory cytokine production, and that CD11c⁺ B cells, which contain the ABC compartment, promoted Th17 cell differentiation (n=6). In vitro, tofacitinib was more effective than adalimumab at reducing ABC proportions and attenuating their proinflammatory phenotype (n=15), consistent with trends in the exploratory clinical follow-up (n=4). ABCs promote inflammation through proinflammatory functions independent of ASC differentiation in TAK. JAK inhibition exerts distinct suppressive effects on ABCs compared with anti-TNF therapy.