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

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bioRxiv [Preprint]. 2025 Sep 21:2025.09.19.677075. doi: 10.1101/2025.09.19.677075.

ABSTRACT

Myasthenia gravis (MG) presents a clinical challenge where autoantibody titers against the neuromuscular junction fail to predict disease severity or treatment response, and thymectomy provides inconsistent benefit despite removing the source of autoreactive B cells. We hypothesized that thymic B cells acquire survival mechanisms that bypass normal tolerance checkpoints, enabling persistence independent of antigen-specific selection. Using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics from human thymic samples, representing the largest MG atlas to date (237,661 cells), we discovered a previously unrecognized tolerance checkpoint swap in MG pathogenesis. Pathological class-switched B cells within thymic germinal centers exhibited reduced antigen presentation capacity (decreased CD74, CD1C expression) and diminished CD40 co-stimulation while upregulating TNFRSF17 to engage BAFF survival signals. This shift from T cell-dependent activation to BAFF-driven survival allowed polyclonal autoreactive B cells to persist without stringent selection and seed peripheral sites. T follicular helper cells supported this reprogramming through increased TNFSF13B and CHGB expression, the latter enabling dopamine-mediated acceleration of B cell synapses. These findings resolve longstanding clinical paradoxes in MG and identify the BAFF-BCMA axis as an actionable therapeutic target. Measuring serum BAFF and soluble BCMA could provide superior biomarkers to antibody titers, while BAFF inhibition or CD40 agonism could restore normal tolerance checkpoints, offering new therapeutic strategies for MG and potentially other autoimmune diseases.

PMID:41000735 | PMC:PMC12458123 | DOI:10.1101/2025.09.19.677075


Source: https://pubmed.ncbi.nlm.nih.gov/4100073 ... t9+e462414