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

Area of Science:

• Immunology
• Neuroimmunology
• Cellular Biology

Background:

• Myasthenia gravis (MG) autoantibody titers do not reliably predict disease severity, and thymectomy outcomes are inconsistent.
• A key challenge in MG is understanding how autoreactive B cells persist despite immune tolerance mechanisms.
• The thymus's role in B cell selection and tolerance is crucial but not fully elucidated in MG.

Purpose of the Study:

• To investigate the mechanisms by which thymic B cells in myasthenia gravis evade normal tolerance checkpoints.
• To identify cellular and molecular alterations in the thymus contributing to MG pathogenesis.
• To explore potential therapeutic targets and biomarkers for myasthenia gravis.

Main Methods:

• Generated the largest myasthenia gravis atlas to date using single-cell RNA sequencing, V(D)J repertoire analysis, and spatial transcriptomics (237,661 cells).
• Analyzed gene expression profiles of thymic B cells and T follicular helper cells within germinal centers.
• Investigated cell-cell interactions and signaling pathways involved in B cell survival and autoreactivity.

Main Results:

• Identified a 'tolerance checkpoint swap' in MG pathogenesis, where pathological B cells exhibit altered antigen presentation and costimulation.
• Pathological B cells upregulate TNFRSF17 to engage BAFF-driven survival, enabling polyclonal autoreactive cells to evade selection.
• T follicular helper cells support this B cell reprogramming through increased TNFSF13B and CHGB expression, potentially influencing synaptic function.

Conclusions:

• The findings reveal a novel mechanism of B cell tolerance evasion in the thymus contributing to myasthenia gravis.
• The BAFF-BCMA axis is implicated as a potential therapeutic target for myasthenia gravis.
• Altered thymic B cell populations and their interactions may serve as biomarkers for disease activity in MG.