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

Abstract

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 (<i>CD74</i> and <i>CD1C</i>) and diminished <i>CD40</i> costimulation while up-regulating <i>TNFRSF17</i> 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 <i>TNFSF13B</i> and <i>CHGB</i> 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.