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

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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AIRE Recruits P-TEFb for Transcriptional Elongation of Target Genes in Medullary Thymic Epithelial Cells

Molecular and Cellular Biology ◽

10.1128/mcb.01085-07 ◽

2007 ◽

Vol 27 (24) ◽

pp. 8815-8823 ◽

Cited By ~ 95

Author(s):

Irena Oven ◽

Naděžda Brdičková ◽

Jiri Kohoutek ◽

Tomaž Vaupotič ◽

Mojca Narat ◽

...

Keyword(s):

Epithelial Cells ◽

Rna Polymerase ◽

Rna Polymerase Ii ◽

Target Genes ◽

Ectopic Expression ◽

Lymphocytic Infiltration ◽

Salivary Protein ◽

Thymic Epithelial Cells ◽

Transcriptional Elongation ◽

Medullary Thymic Epithelial Cells

ABSTRACT AIRE is a transcriptional activator that directs the ectopic expression of many tissue-specific genes in medullary thymic epithelial cells, which plays an important role in the negative selection of autoreactive T cells. However, its mechanism of action remains poorly understood. In this study, we found that AIRE regulates the step of elongation rather than initiation of RNA polymerase II. For these effects, AIRE bound and recruited P-TEFb to target promoters in medullary thymic epithelial cells. In these cells, AIRE activated the ectopic transcription of insulin and salivary protein 1 genes. Indeed, by chromatin immunoprecipitation, we found that RNA polymerase II was already engaged on these promoters but was unable to elongate in the absence of AIRE. Moreover, the genetic inactivation of cyclin T1 from P-TEFb abolished the transcription of AIRE-responsive genes and led to lymphocytic infiltration of lacrimal and salivary glands in the CycT1−/− mouse. Our findings reveal critical steps by which AIRE regulates the transcription of genes that control central tolerance in the thymus.

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miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells

10.1101/2021.07.01.450769 ◽

2021 ◽

Author(s):

Pedro P Tanaka ◽

Ernna H Oliveira ◽

Mayara C Machado ◽

Max J Duarte ◽

Amanda F Assis ◽

...

Keyword(s):

Epithelial Cells ◽

Large Scale ◽

Interaction Analysis ◽

Luciferase Reporter ◽

Thymic Epithelial Cells ◽

Posttranscriptional Control ◽

Autoimmune Regulator ◽

Aire Gene ◽

Medullary Thymic Epithelial Cells

Background: The autoimmune regulator (Aire) gene is critical for the appropriate establishment of central immune tolerance. As one of the main controllers of promiscuous gene expression in the thymus, Aire promotes the expression of thousands of downstream tissue-restricted antigen (TRA) genes, cell adhesion genes and transcription factor genes in medullary thymic epithelial cells (mTECs). Despite the increasing knowledge about the role of Aire as an upstream transcriptional controller, little is known about the mechanisms by which this gene could be regulated. Results: Here, we assessed the posttranscriptional control of Aire by miRNAs. The in silico miRNA-mRNA interaction analysis predicted thermodynamically stable hybridization between the 3UTR of Aire mRNA and miR-155, which was confirmed to occur within the cellular milieu through a luciferase reporter assay. This finding enabled us to hypothesize that miR-155 might play a role as an intracellular posttranscriptional regulator of Aire mRNA. To test this hypothesis, we transfected a murine mTEC cell line with a miR-155 mimic in vitro, which reduced the mRNA and protein levels of Aire. Moreover, large-scale transcriptome analysis showed the modulation of 311 downstream mRNAs, which included 58 TRA mRNAs. Moreover, miR-155 mimic-transfected cells exhibited a decrease in their chemotaxis property compared with control thymocytes. Conclusion: Overall, the results indicate that miR-155 may posttranscriptionally control Aire mRNA as well as a crucial process by which mTECs allow migration of thymocytes through chemotaxis.

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Faculty Opinions recommendation of Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1072067.525050 ◽

2007 ◽

Author(s):

Bruno Kyewski

Keyword(s):

T Cells ◽

Epithelial Cells ◽

Regulatory T Cells ◽

Thymic Epithelial Cells ◽

Medullary Thymic Epithelial Cells ◽

Self Antigen ◽

Selection Of

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Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

The Journal of Immunology ◽

10.4049/jimmunol.1402694 ◽

2014 ◽

Vol 194 (3) ◽

pp. 921-928 ◽

Cited By ~ 16

Author(s):

Kristin Rattay ◽

Janine Claude ◽

Esmail Rezavandy ◽

Sonja Matt ◽

Thomas G. Hofmann ◽

...

Keyword(s):

Gene Expression ◽

Protein Kinase ◽

Epithelial Cells ◽

Interaction Partner ◽

Thymic Epithelial Cells ◽

Interacting Protein ◽

Autoimmune Regulator ◽

Medullary Thymic Epithelial Cells ◽

Promiscuous Gene Expression

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Lymphotoxin β Receptor Regulates the Development of CCL21-Expressing Subset of Postnatal Medullary Thymic Epithelial Cells

The Journal of Immunology ◽

10.4049/jimmunol.1203203 ◽

2013 ◽

Vol 190 (10) ◽

pp. 5110-5117 ◽

Cited By ~ 65

Author(s):

Enkhsaikhan Lkhagvasuren ◽

Mie Sakata ◽

Izumi Ohigashi ◽

Yousuke Takahama

Keyword(s):

Epithelial Cells ◽

Thymic Epithelial Cells ◽

Medullary Thymic Epithelial Cells ◽

Β Receptor

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A Striational Muscle Antigen and Myasthenia Gravis-Associated Thymomas Share an Acetylcholine-Receptor Epitope

Developmental Immunology ◽

10.1155/1992/86853 ◽

1992 ◽

Vol 2 (2) ◽

pp. 77-84 ◽

Cited By ~ 27

Author(s):

Alexander Marx ◽

Mary Osborn ◽

Socrates Tzartos ◽

Kerstin I. Geuder ◽

Berthold Schalke ◽

...

Keyword(s):

Epithelial Cells ◽

Myasthenia Gravis ◽

Acetylcholine Receptor ◽

Tumor Antigens ◽

Molecular Mimicry ◽

Thymic Epithelial Cells ◽

Characteristic Finding ◽

The Common ◽

Secondary Phenomenon ◽

Type Ii Fibers

The coincidence of autoantibodies against the acetylcholine receptor (AChR) and muscle striational antigens (SA) is a characteristic finding in thymoma-associated myasthenia gravis (MG), but their origins are still unresolved. Some common muscle antigens that were shown to be targets of anti-SA autoantibodies in thymoma-associated MG have also been detected in normal or neoplastic thymic epithelial cells, suggesting that the release of (eventually altered) antigens from the thymic tumors could elicit SA autoimmunity. In contrast to this model, we report here that titin, which is a recently reported target of SA autoimmunity, is not expressed in thymomas. In addition, we show that skeletal muscle type-II fibers exhibit a striational immunoreactivity with monoclonal antibody mAb155, which was previously identified to label a very immunogenic cytoplasmic epitope of the AChR and neoplastic epithelial cells of MGassociated thymomas. We conclude from these findings that titin autoimmunity in thymoma-associated MG is either due to a molecular mimicry mechanism involving tumor antigens (other than titin) or is a secondary phenomenon following release of titin from muscle. Based on the common immunoreactivity of the AChR, a striational antigen and thymoma, we suggest as the pathogenetic mechanism of thymoma-associated MGa "circulus vitiosus" in which SA autoimmunity could help maintain the AChR autoimmunity that is primarily elicited by the thymomas.

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