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

Objective

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.

Methods

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.

Results

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).

Conclusions

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.

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