Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

Yasumizu, Y.; Ohkura, N.; Murata, H.; Kinoshita, M.; Funaki, S.; Nojima, S.; Kido, K.; Kohara, M.; Motooka, D.; Okuzaki, D.; Suganami, S.; Takeuchi, E.; Nakamura, Y.; Takeshima, Y.; Arai, M.; Tada, S.; Okumura, M.; Morii, E.; Shintani, Y.; Sakaguchi, S.; Okuno, T.; Mochizuki, H.

doi:10.1101/2021.12.19.473411

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bioRxiv · 10.1101/2021.12.19.473411

Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma

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Abstract

Myasthenia gravis (MG) is a neurological disease caused by autoantibodies against neuromuscular-associated proteins. While MG is frequently developed in thymoma patients, the etiologic factors for MG are not well understood. Here, by constructing a comprehensive atlas of thymoma using bulk and single-cell RNA-seq, we identified ectopic expression of neuromuscular molecules in MG-associated thymoma (MG-thymoma). These molecules were originated from a distinct subpopulation of medullary thymic epithelial cells (mTECs), which we named neuromuscular mTECs (nmTECs). MG-thymoma also exhibited microenvironments dedicated to autoantibody production, including ectopic germinal center formation, T follicular helper cell accumulation, and type 2 conventional dendritic cell migration. Cell-cell interaction analysis also predicted the interaction between nmTECs and T/B cells via CXCL12-CXCR4. The enrichment of nmTECs presenting neuromuscular molecules within MG-thymoma was further confirmed by immunohistochemically and by cellular composition estimation from MG-thymoma transcriptome. Altogether, this study suggests that nmTECs play a significant role in MG pathogenesis via ectopic expression of neuromuscular molecules.

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Yasumizu, Y., Ohkura, N., Murata, H., Kinoshita, M., Funaki, S., Nojima, S., Kido, K., Kohara, M., Motooka, D., Okuzaki, D., Suganami, S., Takeuchi, E., Nakamura, Y., Takeshima, Y., Arai, M., Tada, S., Okumura, M., Morii, E., Shintani, Y., Sakaguchi, S., Okuno, T., Mochizuki, H.. 2021-12-21. Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma. https://doi.org/10.1101/2021.12.19.473411

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