Original Research
AB014. Autoreactome analysis reveals novel autoantibodies in thymoma-associated myasthenia gravis
Linda L. Kusner1, Taylor Bauman1, Henry J. Kaminski1, Jiaxin Chen1,2
1Laboratory for Myasthenia Gravis Research, George Washington University, Washington, DC, USA;
2Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Correspondence to: Linda L. Kusner, PhD. Laboratory for Myasthenia Gravis Research, George Washington University, 2300 Eye Street, Washington, DC 20037, USA. Email: lkusner@gwu.edu.
Background: Thymomas are unique among neoplasms for their strong association with a number of autoantibody-mediated diseases with upwards of half of patients having acetylcholine receptor antibody-positive myasthenia gravis (thymoma-associated MG, TAMG). The majority of thymomas have a deficiency in the autoimmune regulator (AIRE) protein, a key factor in maintaining central immune tolerance, which suggests a general propensity to autoantibody formation. The propensity to produce autoantibodies against striated muscle proteins, ryanodine receptor, and potassium channels has been documented, however, the scope of the autoantibodies has not been fully assessed. The objective of the study was to determine an autoantibody profile in TAMG patients. We utilized a broad-based approach to interrogate this question.
Methods: Eighteen control and 43 sera from patients with TAMG from George Washington and Indiana Universities were used to assess the autoreactome using molecular indexing by self-assembly to assess over 16,000 full-length proteins and nearly 400,000 peptide sequences for autoreactive antibodies.
Results: Controls and TAMG subjects demonstrated a wide variation in autoreactivity from 62 to 623 protein directed autoantibodies with no clear differences among individuals. No uniformity was observed across individuals for a protein target. However, a subpopulation of TAMG subjects had high levels of antibodies directed against a range of interferons. Within this group of patients, all had antibodies towards TRIM46 and P2X4 receptor. TRIM46 is a known paraneoplastic antigen in neurological disease, but not previously identified in thymoma. TRIM46 and P2RX4 receptor are linked to T cell signaling or differentiation. There was no association with thymoma World Health Organization (WHO) classification or other patient characteristics.
Conclusions: The presence of these autoantibodies would indicate disrupted immune tolerance mechanisms in TAMG patients, particularly those affecting antigen processing and regulatory T-cell function driven by autoantibody formation. P2X4 receptor is a purinergic and ligand-gated ion channel, which, when activated, leads to interferon secretion. If the P2X4 receptor antibodies activate lead to high, localized levels of interferons, then an interferonopathy supportive for autoreactivity would be expected.
Keywords: Thymoma; myasthenia gravis (MG); autoimmunity; interferons; P2X4 receptor
Acknowledgments
We extend our appreciation to all research coordinators and patients who supported this work.
Funding: This study was supported by the MGNet the Rare Disease Clinical Research Network grant NIH US54 NS115054.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form. (available at https://med.amegroups.com/article/view/10.21037/med-25-ab014/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 review board of George Washington University (No. 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-ab014
Cite this abstract as: Kusner LL, Bauman T, Kaminski HJ, Chen J. AB014. Autoreactome analysis reveals novel autoantibodies in thymoma-associated myasthenia gravis. Mediastinum 2025;9:AB014.
