Abstract
The thymus plays a key role in myasthenia gravis (MG), a B cell-mediated autoimmune disorder affecting neuromuscular junction. Most MG patients have thymic abnormalities, including hyperplasia and thymoma, a neoplasm of thymic epithelial cells. Epstein-Barr virus (EBV) is associated with autoimmune diseases and tumors. Recently, we showed EBV persistence and reactivation in hyperplastic MG thymuses, suggesting that EBV might contribute to intra-thymic B cell dysregulation in MG patients. Here, we investigated EBV involvement in thymoma-associated MG, by searching for EBV markers in MG (n=26) and non-MG (n=14) thymomas. EBV DNA and EBV-encoded small nuclear RNA (EBER) 1 transcript were detected in 14/26 (53.8%) and 22/26 (84.6%) MG thymomas, and only in 3 of 14 (21.4%) non-MG thymomas. Latent EBNA2 and late gp350/220 lytic transcripts were undetectable in all, but one, thymomas, and early lytic BZLF1 transcript was absent in all samples, suggesting that early infection events and EBV reactivation were very rare in thymomas. EBER1 and 2-positive cells were detected in MG, but not in non-MG, thymomas, as well as cells expressing EBV latency proteins (EBNA1, LMP1, LMP2A), that were mainly of B cell phenotype, indicating EBV association with MG rather than with thymoma. Toll-like receptor (TLR) 3 transcriptional levels were higher in MG than non-MG thymomas and positively correlated with EBER1 levels, suggesting a role for EBERs in TLR3 activation. Our findings show that EBV is commonly present in thymoma-infiltrating B cells of myasthenic patients, indicating a contribution of EBV to B cell-mediated autoreactivity in MG associated with thymic tumor.
Highlights
Myasthenia gravis (MG) is a prototypical antibodymediated autoimmune disease affecting the neuromuscular junction, mainly caused by anti-acetylcholine receptor (AChR) autoantibodies, leading to skeletal muscle weakness and fatigability [1]
An antiviral gene signature was identified in myasthenia gravis (MG) thymomas, characterized by increased expression of type I interferons (IFNs) and Toll-like receptor (TLR) 3, a TLR known to recognize viral double strand RNA molecules associated with replication of many viruses, suggesting that MG might develop after a pathogen infection in thymoma patients [18]
We confirmed increased transcriptional levels of TLR3 in MG thymomas compared with normal thymuses (Figure 5A) and, interestingly, we found that TLR3 was significantly overexpressed in MG-associated thymomas compared with thymomas from patients without MG (Figure 6A)
Summary
Myasthenia gravis (MG) is a prototypical antibodymediated autoimmune disease affecting the neuromuscular junction, mainly caused by anti-acetylcholine receptor (AChR) autoantibodies, leading to skeletal muscle weakness and fatigability [1]. Pathological abnormalities of the thymus characterize most AChRMG patients, and thymectomy may be associated with increased frequency of remission, suggesting thymus involvement in the onset and perpetuation of autoimmunity to the AChR [2,3,4,5]. Locally invasive neoplasms of thymic epithelial cells (TECs), associated with a variety of autoimmune diseases [7,8,9]; MG is present in approximately 30-45% of thymoma patients [9]. An antiviral gene signature was identified in MG thymomas, characterized by increased expression of type I interferons (IFNs) and Toll-like receptor (TLR) 3, a TLR known to recognize viral double strand (ds) RNA molecules associated with replication of many viruses, suggesting that MG might develop after a pathogen infection in thymoma patients [18]
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