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

[RSS-Bot]

Sci Adv. 2026 Aug 14;12(33):eaec3842. doi: 10.1126/sciadv.aec3842. Epub 2026 Aug 12.

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 (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.

PMID:42585334 | DOI:10.1126/sciadv.aec3842


Source: https://pubmed.ncbi.nlm.nih.gov/4258533 ... 8&v=2.20.1