Abstract
AB038. Thymomatous myasthenia gravis is associated with fluctuations in CD4-positive T-cell subsets through the activity of the PI3K-Akt-mTOR pathway
Shunta Ishihara1,2, Tsuyoshi Yaoi3, Masanori Shimomura1, Satoru Okada1, Tatsuo Furuya1, Sanzo Moriwaki4, Takashi Fujimura4, Sae Shibata4, Hiroshi Ogi4, Soh Tando3, Kyoko Itoh3, Masayoshi Inoue1
1Division of Thoracic Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan;
2Division of Thoracic Surgery, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan;
3Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan;
4SCREEN Holdings Co., Ltd., Kyoto, Japan
Correspondence to: Shunta Ishihara, MD, PhD. Division of Thoracic Surgery, Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan; Division of Thoracic Surgery, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan. Email: ishihara@koto.kpu-m.ac.jp.
Background: Molecular linkage between thymoma-associated lymphocytes and myasthenia gravis (MG) remain to be clarified. Therefore, we searched for MG-related gene candidates in the thymoma transcriptome.
Methods: Based on bulk thymoma RNA-seq data from The Cancer Genome Atlas (TCGA), we performed a weighted gene co-expression network analysis (WGCNA) focusing on genes associated with tumor-infiltrating immune cells and inflammation. For each identified co-expression variation gene group (module), correlation analysis with metadata (presence of MG) and gene set enrichment analysis (GSEA) were performed. Based on the candidate genes identified, immunohistochemical staining was performed on thymoma surgical specimens (N=9, 4 with MG, 5 without MG). The proportion of naïve T cells, regulatory T cells (T reg), Th17 cells and follicular T cells (Tfh) among CD4+ lymphocytes were analysed by multiple immunostaining (mIHC).
Results: The results of the WGCNA identified two modules that correlated significantly with the presence of MG. One module was positively correlated with MG, while the other was correlated in the opposite direction. Forty-five of the positively correlated one module and 63 of the negatively correlated another module were components of the PI3K-Akt signaling pathway. Immunohistochemical staining of the Akt, the hub molecule of the PI3K-Akt-mTOR pathway, was positive in 3 out of 4 (75%) MG-associated cases. CD4-positive lymphocyte subset analysis using mIHC showed more Th17 cells and fewer T reg cells in thymoma with MG compared to thymoma without MG.
Conclusions: The PI3K-Akt-mTOR pathway is activated in thymomas, leading to increased Th17 and decreased Treg, which could influence to MG association, an autoimmune condition.
Keywords: Thymoma; myasthenia-gravis; mTOR-pathway; multiplex-IHC
Acknowledgments
Funding: This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (grant number J22K16575, to S.I.).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-ab038/coif). S.I. reports support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (grant number J22K16575). 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 (as revised in 2013). The study was approved by the institutional review board at Kyoto Prefectural University of Medicine (approval No. ERB-C-931-8) and individual consent for this retrospective analysis was waived.
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-24-ab038
Cite this abstract as: Ishihara S, Yaoi T, Shimomura M, Okada S, Furuya T, Moriwaki S, Fujimura T, Shibata S, Ogi H, Tando S, Itoh K, Inoue M. AB038. Thymomatous myasthenia gravis is associated with fluctuations in CD4-positive T-cell subsets through the activity of the PI3K-Akt-mTOR pathway. Mediastinum 2024;8:AB038.
