Noncanonical Differentiation of Memory B Cells Drives Latent Tuberculosis Infection Reactivation Upon Tumor Necrosis Factor-Alpha Inhibitor Therapy: An Integrative Transcriptomic Study

Abstract

Aim

Tumor necrosis factor inhibitors (TNFi) are widely used for the treatment of autoimmune diseases, with latent tuberculosis infection (LTBI) reactivation being a significant unresolved issue. The pathogenic mechanisms are not fully understood. Integrated transcriptomic analysis could provide insights into monitoring tuberculosis progression after TNFi therapy and help reduce LTBI reactivation.

Methods

We selected six transcriptomic datasets from studies related to TNFi treatment and tuberculosis. Pathway enrichment, pseudotime, and transcription factor analyses were performed to explore the underlying mechanisms.

Results

Our analysis revealed distinct transcriptional changes in memory B cells during tuberculosis progression and TNFi therapy. In active tuberculosis (ATB), ROR1⁺ memory B cells were identified in a noncanonical differentiation trajectory, characterized by downregulation of B cell-related genes (e.g., CD22, EBF1, MS4A1), reduced translational capacity, and suppression of immune response pathways, accompanied by upregulation of oxidative phosphorylation, which highlighted metabolic alterations during tuberculosis progression. A similar subtype also emerged in TNFi-treated patients, suggesting that metabolic reprogramming of memory B cells may disrupt immune balance, thereby contributing to LTBI reactivation and ATB development following TNFi therapy.

Conclusions

The study integrates bioinformatics and single-cell RNA sequencing to reveal the role of memory B cells in ATB progression and TNFi treatment, offering insights into TNFi-associated TB susceptibility and potential therapeutic targets.