AB016. Towards understanding mechanisms of thymectomy benefit for myasthenia gravis
Original Research

AB016. Towards understanding mechanisms of thymectomy benefit for myasthenia gravis

Henry J. Kaminski1, Linda L. Kusner1, Ali Taheriyoun2, Keith Crandall2, Ali Rahnavard2

1Laboratory for Myasthenia Gravis Research, George Washington University, Washington, DC, USA; 2Biostatistics and Bioinformatics, George Washington University, Washington, DC, USA

Correspondence to: Henry J. Kaminski, MD. Laboratory for Myasthenia Gravis Research, George Washington University, 2150 Pennsylvania Ave., NW, 9TH Floor, Washington, DC, 20037, USA. Email: hkaminski@mfa.gwu.edu.

Background: The MGTX trial demonstrated therapeutic benefit of thymectomy for myasthenia gravis (MG), however, the biological mechanisms contributing to this benefit remain unclear with the standard explanation being limited to removal of a site of autoantibody production. To evaluate the systemic change in the peripheral circulation, we assessed whole blood transcriptional profile for mechanisms underlying the effect of extended transsternal thymectomy (ETTX) in MG.

Methods: We utilized whole blood RNA samples collected during the MGTX trial and applied generalized linear mixed models and differential gene expression. Our goal was to identify gene expression patterns and biochemical pathways associated with ETTX. We correlated transcriptional profile to quantitative MG (QMG) and area under the QMG over time analysis (AUQMG).

Results: Filtering the genes based on the prevalence and variation, 3,175 genes were included in the analysis. At the false discovery rate (FDR) of 0.05, 222 genes were identified as differentially expressed in ETTX subjects compared to those receiving prednisone only. Sorted by gene ratio, top pathways were focal adhesion, cell-substrate junction, ribosome structure, secretory granule membrane, regulation of cell-cell adhesion and specifically immune response-regulating cell surface receptor signaling pathways. We detected 151 genes upregulated in association with higher QMG scores. The greatest increases involved DEFA3, CYP4F3, LTF, HLA.C_3, AHSP, and KRT. These genes enrich for immune response-activating signaling, mononuclear cell differentiation, GTPase regulator activity, immune response-regulating cell surface receptor signaling, lymphocyte differentiation, and leukocyte cell-cell adhesion. For area under the quantitative myasthenia gravis time curve (AUQMG), 307 genes were differentially expressed with 109 genes upregulated in association with higher AUQMG. Among these, CD69, SNORD17, RPS7, NIBAN3, and RPS27 showed the highest expression levels. These genes enrich for regulation of protein catabolic process, immune response-activating signaling, viral process, ubiquitin-like protein ligase binding, and macroautophagy pathways.

Conclusions: Our initial findings—set to expand in the coming months—reveal that ETTX modulates distinct transcriptional programs and biochemical pathways involved in immune signaling, ribosomal function, and cellular metabolism. These insights shed light on the broader molecular mechanisms driving the therapeutic effects of ETTX, extending beyond the traditional view of thymectomy as merely the removal of an antibody-producing site.

Keywords: Thymectomy; treatment-response; myasthenia gravis (MG); RNASeq

Acknowledgments

None.

Footnote

Funding: The study was supported by the MGNet a member of the Rare Disease Clinical Research Network Consortium (RDCRN)NIH U54 NS115054 and NIH/NINDS U01 NS042685 (MGTX).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-ab016/coif). H.J.K. serves as an unpaid editorial board member of Mediastinum from August 2025 to July 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the institutional ethics board of MGTX participating site and the George Washington University for use of de-identified samples (091222) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

doi: 10.21037/med-25-ab016
Cite this abstract as: Kaminski HJ, Kusner LL, Taheriyoun A, Crandall K, Rahnavard A. AB016. Towards understanding mechanisms of thymectomy benefit for myasthenia gravis. Mediastinum 2025;9:AB016.

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