Epstein-Barr virus in tumor-infiltrating B cells of myasthenia gravis thymoma: an innocent bystander or an autoimmunity mediator?

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.

B cells latently infected with murine gammaherpesvirus 68 (MHV‐68) are present in the mouse thymus–A step toward immune evasion?

“…Taken together, our data clearly indicate that latently infected B cells are present in the thymus. This principal finding is in accordance with recent reports suggesting that EBV can reside in thymic B cells and express an unusual combination of viral genes ( and references cited therein), which is, however, a controversial finding . What remains to be shown is whether infected B cells in the thymus express viral genes that can result in a functional T‐cell tolerance against certain viral epitopes.…”

Identifying the culprits in neurological autoimmune diseases

“…In contrast to healthy individuals, MG patients have hyperplastic and involuted thymuses infiltrated with EBV B- and plasma cells. This suggests that the virus could be implicated in the autoimmune process within intra-thymic MG, possibly by the activation and perpetuation of autoreactive B cells and the stimulation of pathogenic TLR7 and TLR9 signaling [ 124 ]. In a study done in Japan, researchers found that antibodies against EBV early antigen IgG (anti-EA) was significantly elevated in the serum of NMO patients in comparison to MS patients and controls.…”

Toll‐like receptors 7 and 9 in myasthenia gravis thymus: amplifiers of autoimmunity?

“…31,35 We found that transcriptional levels of both TLR7 and TLR9 were significantly higher in each MG thymus subgroup than in the control thymus group (relative expression values: 5.2 ± 0.8 versus 0.62 ± 0.08 for TLR7, P < 0.01; 1.05 ± 0.2 versus 0.21 ± 0.11 for TLR9, P < 0.05), without any effect of prethymectomy treatment with corticosteroids on thymic TLR7 and TLR9 expression. 23 By contrast, expression of the two receptors was not significantly altered in thymomas from MG patients compared with thymomas from patients without MG and normal thymuses, 59,60 suggesting that intrathymic TLR7 and TLR9 overexpression is a prominent feature of nonthymomatous MG. Intriguingly, we observed a strong overexpression of TLR7 and TLR9 in B cells and plasma cells of hyperplastic and involuted MG thymuses in comparison with B cells and plasma cells of control thymuses (Fig. 1).…”