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Myasthenia thymus reprograms class-switched B cells into BAFF-dependent survivors

Yuanqing Yan1, Diego Avella Patino2, Yimeng Zhao1

  • 1Department of Surgery, Division of Thoracic Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Science Advances
|August 12, 2026
PubMed

Myasthenia gravis (MG) presents a clinical challenge where autoantibody titers poorly predict disease severity, and thymectomy provides inconsistent benefits. We hypothesized that thymic B cells acquire survival mechanisms that bypass canonical tolerance checkpoints, enabling persistence independent of antigen-specific selection. Using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics to generate the largest MG atlas to date (237,661 cells), we identified a tolerance checkpoint swap in MG pathogenesis. Pathological class-switched B cells within thymic germinal centers exhibited reduced antigen presentation (CD74 and CD1C) and diminished CD40 costimulation while up-regulating TNFRSF17 to engage BAFF-driven survival. This shift allows polyclonal autoreactive B cells to evade stringent selection and seed peripheral sites. T follicular helper cells supported this reprogramming via increased TNFSF13B and CHGB expression, with the latter facilitating dopamine-mediated synaptic acceleration. These findings offer insight into clinical paradoxes in MG and point to the BAFF-BCMA axis as a potential therapeutic target and biomarkers for disease activity.

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