Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma.
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ABSTRACT:
SUBMITTER: Yasumizu Y
PROVIDER: S-EPMC9305039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThymic epithelial tumors are rare malignant neoplasms that are frequently associated with paraneoplastic syndromes, especially myasthenia gravis. GTF2I is an oncogene mutated in a subgroup of thymomas that is reputed to drive their growth. However, for GTF2I wild-type tumors, the relevant mutations remain to be identified.MethodsWe performed a meta-analysis and identified 4,208 mutations in 339 patients. We defined a panel of 63 genes frequently mutated in thymic epithelial tumors, which we used to design a custom assay for next-generation sequencing. We sequenced tumor DNA from 67 thymomas of patients with myasthenia gravis who underwent resection in our institution.ResultsAmong the 67 thymomas, there were 238 mutations, 83 of which were in coding sequences. There were 14 GTF2I mutations in 6 A, 5 AB, 2 B2 thymomas, and one in a thymoma with unspecified histology. No other oncogenes showed recurrent mutations, while sixteen tumor suppressor genes were predicted to be inactivated. Even with a dedicated assay for the identification of specific somatic mutations in thymic epithelial tumors, only GTF2I mutations were found to be significantly recurrent.ConclusionOur evaluation provides insights into the mutational landscape of thymic epithelial tumors, identifies recurrent mutations in different histotypes, and describes the design and implementation of a custom panel for targeted resequencing. These findings contribute to a better understanding of the genetic basis of thymic epithelial tumors and may have implications for future research and treatment strategies.
| S-EPMC10475716 | biostudies-literature
Project description:ImportanceAcquired neuromyotonia is increasingly recognized as an autoimmune disorder, frequently associated with antibodies against voltage-gated potassium channel complex proteins.We present a case of acquired neuromyotonia as the heralding symptom of recurrent thymoma in a patient with myasthenia gravis.ObservationsA report of a single case of a 53-year-old man with myasthenia gravis and a prior thymectomy presenting with 2 months of diffuse, involuntary muscle twitching in the absence of myasthenic symptoms, electrophysiologically confirmed to be neuromyotonia. Further evaluation revealed the recurrence of malignant thymoma, accompanied by refractory arrhythmia. Serologic and cerebrospinal fluid testing confirmed the presence of antibodies directed against 2 voltage-gated potassium channel–associated proteins: LGI1 and Caspr2.Conclusions and relevanceThis case highlights the overlap of myasthenia, neuromyotonia, and thymoma, emphasizing the importance of appropriate tumor screening in the presence of either of the former 2 conditions.
| S-EPMC4096576 | biostudies-literature
Project description:ObjectivePathological alterations of the thymus are observed in the majority of patients with myasthenia gravis (MG). To explore the potential mechanisms of these alterations, we performed a transcriptome analysis and measured co-expression of aberrant long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs).MethodsRNA was extracted from eight patients with thymoma, five of whom had MG. Transcriptome profiles were acquired through mRNA and lncRNA microarray analysis. Quantitative reverse transcription polymerase chain reaction was used to verify the results of the microarray analysis. LncRNAs co-expressed with mRNA were analyzed with Pearson's coefficient. Next, cis-regulated and trans-regulated target genes were predicted. The functions of aberrant lncRNAs were explored on the basis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of target mRNAs.ResultsThe comparative microarray analysis identified 4360 lncRNAs and 2545 mRNAs with significant differential expression. The most significant GO enrichment terms were phosphoric ester hydrolase activity, phosphatase activity, and hydrolase activity, which were assigned as molecular functions. Regulation of endosome size was the most significant GO enrichment term assigned as a biological process, and Golgi apparatus was the most significant GO enrichment term assigned as cellular component. The reliability prediction terms of KEGG included calcium signaling pathway, glycosphingolipid biosynthesis, and caffeine metabolism.ConclusionMG-positive thymoma is associated with overactive biological processes and molecular functions, especially dephosphorylation and hydrolysis, which may affect thymocyte survival during selection in the thymus.
| S-EPMC8720629 | biostudies-literature
Project description:The thymus is involved in autoimmune Myasthenia gravis (MG) associated with anti-acetylcholine (AChR) antibodies. In MG, thymic regulatory T cells (Treg) are not efficiently suppressive, and conventional T cells (Tconv) are resistant to suppression. To better understand the specific role of the thymus in MG, we compared the phenotype and function of peripheral and thymic Treg and Tconv from controls and MG patients. Suppression assays with thymic or peripheral CD4 + T cells showed that the functional impairment in MG was more pronounced in the thymus than in the periphery. Phenotypic analysis of Treg showed a significant reduction of resting and effector Treg in the thymus but not in the periphery of MG patients. CD31, a marker lost with excessive immunoreactivity, was significantly reduced in thymic but not blood resting Treg. These results suggest that an altered thymic environment may explain Treg differences between MG patients and controls. Since thymic epithelial cells (TECs) play a major role in the generation of Treg, we co-cultured healthy thymic CD4 + T cells with control or MG TECs and tested their suppressive function. Co-culture with MG TECs consistently hampers regulatory activity, as compared with control TECs, suggesting that MG TECs contribute to the immune regulation defects of MG CD4 + T cells. MG TECs produced significantly higher thymic stromal lymphopoietin (TSLP) than control TECs, and a neutralizing anti-TSLP antibody partially restored the suppressive capacity of Treg derived from co-cultures with MG TECs, suggesting that TSLP contributed to the defect of thymic Treg in MG patients. Finally, a co-culture of MG CD4 + T cells with control TECs restored numbers and function of MG Treg, demonstrating that a favorable environment could correct the immune regulation defects of T cells in MG. Altogether, our data suggest that the severe defect of thymic Treg is at least partially due to MG TECs that overproduce TSLP. The Treg defects could be corrected by replacing dysfunctional TECs by healthy TECs. These findings highlight the role of the tissue environment on the immune regulation.
| S-EPMC7218102 | biostudies-literature
Project description:Background: Approximately 50% of thymoma patients also show myasthenia gravis (MG), which is an autoimmune disease; however, the pathogenesis of MG-associated thymoma remains elusive. Our aim was to investigate immune-related lncRNA profiles of a set of candidate genes for better understanding of the molecular mechanism underlying the pathogenesis of thymoma with or without MG. Methods: Molecular profiles of thymoma with or without MG were downloaded from The Cancer Genome Atlas, and Pearson's correlation analysis was performed to identify immune-related lncRNAs. T test was used to examine the differential expression and differential methylation between thymoma patients with or without MG. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the function of target genes of immune-related lncRNAs. Results: Analyses of the 87 thymoma samples with complete MG information revealed that 205 mRNAs and 56 lncRNAs showed up-regulated expression in thymoma with MG patients, while 458 mRNAs and 84 lncRNAs showed down-regulated expression. The methylation level of three immune-related lncRNAs (AP000787.1, AC004943.1, WT1-AS, FOXG1-AS1) was significantly decreased in thymoma tissues, and the methylation level of these immune-related lncRNAs (WT1-AS: Cor = 0.368, p < 0.001; FOXG1-AS1: Cor = 0.288, p < 0.01; AC004943.1: Cor = -0.236, p < 0.05) correlated with their expression. GO and KEGG pathway analysis revealed that targets of the immune-related lncRNA FOXG1-AS1 were enriched in small GTPase binding and herpes simplex virus 1 infection. Transcription coregulator activity and cell cycle were the most enriched pathways for targets of lncRNA AC004943.1. LncRNA WT1-AS targets were most enriched in actin binding and axon guidance. Conclusion: Our results revealed the immune-related molecular profiling of thymoma with MG and without MG and identified key pathways involved in the underlying molecular mechanism of thymoma-related MG. These findings provide insights for further research of potential markers for thymoma-related MG.
| S-EPMC8580862 | biostudies-literature
Project description:BackgroundThymic epithelial tumors (TETs) are rare malignancies with unique association to the autoimmune disease myasthenia gravis (MG). Heat shock proteins (HSPs) harbor great potential as cancer biomarkers and HSP inhibitors approach clinical cancer therapy.MethodsTo explore HSP pathophysiology, we assessed sera (immunoassays) and tissues (immunohistochemistry) of TETs (and thymic tissues) for HSP27, phosphorylated (p)HSP27, HSP70 and HSP90α expression in 114 TETs and 26 non-thymomatous MG patients undergoing extended thymectomy.ResultsSerum concentrations of HSP90α were significantly increased in patients with thymic carcinomas, thymomas, thymic neuroendocrine tumors and non-thymomatous MG compared to patients who underwent thymectomy revealing regular thymic morphology or controls. In thymoma patients, high serum HSP90α represented a significantly worse prognostic factor for free-from-recurrence, and complete tumor resection led to decreased levels. The expression of HSP90 in nuclei and cytoplasm of tumor cells and non-neoplastic lymphocytes varied with WHO histological subtype. HSP90 was expressed in centroblasts of thymic germinal centers in MG patients. Higher pHSP27 serum concentrations were observed in seropositive MG and those not treated with steroids.ConclusionsHSP data suggest high potential for HSPs as TET cancer biomarkers or as candidates for targeted therapy. Caution is warranted in TET patients with associated MG overexpressing HSPs.
| S-EPMC7458630 | biostudies-literature
Project description:B-cell subsets in peripheral blood (PB) and tumor microenvironment (TME) were evaluated to determine myasthenia gravis (MG) severity in patients with thymoma-associated MG (TMG) and the distribution of B cells in type B TMG. The distribution of mature B cells, including Bm1-Bm5, CD19+ and CD20+ B cells and non-switched (NSMBCs) and switched (SMBCs) memory B cells, were determined in 79 patients with thymoma or TMG. Quantitative relationships between the T and TMG groups and the TMG-low and TMG-high subgroups were determined. NSMBCs and SMBCs were compared in TME and PB. Type B thymoma was more likely to develop into MG, with types B2 and B3 being especially associated with MG worsening. The percentage of CD19+ B cells in PB gradually increased, whereas the percentage of CD20+ B cells and the CD19/CD20 ratio were not altered. The (Bm2 + Bm2')/(eBm5 + Bm5) index was significantly higher in the TMG-high than in thymoma group. The difference between SMBC/CD19+ and NSMBC/CD19+ B cell ratios was significantly lower in the thymoma than TMG group. NSMBCs assembled around tertiary lymphoid tissue in thymomas of patients with TMG. Few NSMBCs were observed in patients with thymoma alone, with these cells being diffusely distributed. MG severity in patients with TMG can be determined by measuring CD19+ B cells and Bm1-Bm5 in PB. The CD19/CD20 ratio is a marker of disease severity in TMG patients. Differences between NSMBCs and SMBCs in PB and TME of thymomas can synergistically determine MG severity in patients with TMG.
| S-EPMC10834956 | biostudies-literature
Project description:OBJECTIVE: The capacity of thymomas to generate mature CD4+ effector T cells from immature precursors inside the tumor and export them to the blood is associated with thymoma-associated myasthenia gravis (TAMG). Why TAMG(+) thymomas generate and export more mature CD4+ T cells than MG(-) thymomas is unknown. METHODS: Unfixed thymoma tissue, thymocytes derived thereof, peripheral blood mononuclear cells (PBMCs), T-cell subsets and B cells were analysed using qRT-PCR and western blotting. Survival of PBMCs was measured by MTT assay. FAS-mediated apoptosis in PBMCs was quantified by flow cytometry. NF-?B in PBMCs was inhibited by the NF-?B-Inhibitor, EF24 prior to FAS-Ligand (FASLG) treatment for apoptosis induction. RESULTS: Expression levels of the apoptosis inhibitor cellular FLICE-like inhibitory protein (c-FLIP) in blood T cells and intratumorous thymocytes were higher in TAMG(+) than in MG(-) thymomas and non-neoplastic thymic remnants. Thymocytes and PBMCs of TAMG patients showed nuclear NF-?B accumulation and apoptosis resistance to FASLG stimulation that was sensitive to NF-?B blockade. Thymoma removal reduced cFLIP expression in PBMCs. INTERPRETATION: We conclude that thymomas induce cFLIP overexpression in thymocytes and their progeny, blood T cells. We suggest that the stronger cFLIP overexpression in TAMG(+) compared to MG(-) thymomas allows for the more efficient generation of mature CD4+ T cells in TAMG(+) thymomas. cFLIP overexpression in thymocytes and exported CD4+ T cells of patients with TAMG might contribute to the pathogenesis of TAMG by impairing central and peripheral T-cell tolerance.
| S-EPMC4574807 | biostudies-literature
Project description: Not available
| S-EPMC9196941 | biostudies-literature
Project description:A unique feature of thymomas is their unrivaled frequency of associated myasthenia gravis (MG). Previous studies reported that MG+ thymomas contain a larger number of mature "pre-emigrant" CD4+ T cells than MG- thymomas and that most thymomas do not contain AIRE expressing cells irrespective of MG status. These findings suggest that CD4+ T cells that mature inside the abnormal microenvironment of thymomas and egress to the blood are critical to the development of thymoma-associated MG (TAMG) irrespective of thymoma histotype. However, underlying mechanisms have remained enigmatic. To get hints to mechanisms underlying TAMG, we pursue three hypotheses: (i) Functional pathways with metabolic and immunological relevance might be differentially expressed in TAMG(+) compared to TAMG(-) thymomas; (ii) differentially enriched pathways might be more evident in immature lymphocyte-poor (i.e., tumor cell/stroma-rich) thymoma subgroups; and (iii) mechanisms leading to TAMG might be different among thymoma histological subtypes. To test these hypotheses, we compared the expression of functional pathways with potential immunological relevance (N = 380) in relation to MG status separately in type AB and B2 thymomas and immature lymphocyte-rich and lymphocyte-poor subgroups of these thymoma types using the TCGA data set. We found that <10% of the investigated pathways were differentially upregulated or downregulated in MG+ compared to MG- thymomas with significant differences between AB and B2 thymomas. The differences were particularly evident, when epithelial cell/stroma-rich subsets of type AB and B2 thymomas were analyzed. Unexpectedly, some MG-associated pathways that were significantly upregulated in AB thymomas were significantly downregulated in B2 thymomas, as exemplified by the oxidative phosphorylation pathway. Conversely, the MG-associated pathway related to macrophage polarization was downregulated in MG+ AB thymoma and upregulated in MG+ B2 thymoma. We conclude that functional pathways are significantly associated with TAMG, and that some mechanisms leading to TAMG might be different among thymoma histological subtypes. Functions related to metabolisms, vascular and macrophage biology are promising new candidate mechanisms potentially involved in the pathogenesis of TAMG. More generally, the results imply that future studies addressing pathomechanisms of TAMG should take the histotype and abundance of tumor cells and non-neoplastic stromal components of thymomas into account.
| S-EPMC7176899 | biostudies-literature