Age-Associated B Cells Contribute to Inflammation Via Antibody-Independent Mechanisms in Takayasu Arteritis

Although Takayasu 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.

Histologic 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 tumor necrosis factor (TNF) and JAK inhibition were assessed both in vitro and in four patients with TAK.

Histologic (n = 5), flow cytometric (n = 125), and bulk RNA-seq (n = 12) analyses indicated the presence of extrafollicular response and up-regulated age-associated B cell (ABC) production in TAK, along with cross-data set transcriptomic differences between B cells from patients with TAK and systemic lupus erythematosus (SLE). Cross-data set 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.