Article

Epstein-Barr Virus Persistence and Reactivation in Myasthenia Gravis Thymus

Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
Annals of Neurology (Impact Factor: 9.98). 06/2010; 67(6):726-38. DOI: 10.1002/ana.21902
Source: PubMed

ABSTRACT

Increasing evidence supports a link between Epstein-Barr virus (EBV), a ubiquitous B-lymphotropic human herpesvirus, and common B-cell-related autoimmune diseases. We sought evidence of EBV infection in thymuses from patients with myasthenia gravis (MG), an autoimmune disease characterized by intrathymic B-cell activation.
Seventeen MG thymuses (6 follicular hyperplastic, 6 diffuse hyperplastic, 5 involuted) and 6 control thymuses were analyzed using in situ hybridization for EBV-encoded small RNAs (EBERs), immunohistochemistry for EBV latent and lytic proteins, and polymerase chain reaction for EBV DNA and mRNA.
All 17 MG thymuses showed evidence of active EBV infection, whereas none of the control thymuses were infected. Cells expressing EBERs (12 of 17) and EBV latency proteins (EBNA2, LMP1, and LMP2A) (16 of 17) were detected in medullary infiltrates and in germinal centers. Cells expressing early (BFRF1, BMRF1) and late (p160, gp350/220) lytic phase EBV proteins were present in 16 MG thymuses. Latency (EBNA1, LMP2A) or lytic (BZLF1) transcripts (often both) were present in all MG thymuses, and EBV DNA (LMP1 gene) was detected in 13 MG thymuses. We also found CD8+ T cells, CD56 + CD3-natural killer cells, and BDCA-2+ plasmacytoid dendritic cells in immune infiltrates of MG thymuses, but not germinal centers, suggesting an attempt of the immune system to counteract EBV infection.
Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.

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    • "The effects of Poly(I:C) seemed to synergize with the already high expression of CXCL13 in Tg mice and drive B cells into the thymus. Pathogen infections are suspected to induce MG in susceptible patients[39]. Inflammation subsequent to pathogen infection appears to be a key event to optimize the recruitment of mature lymphocytes to peripheral organs[40]and even in the thymus[41]. Poly(I:C) a synthetic molecule mimicking dsRNA from viral infections is capable of triggering thymic events related to MG through the intra-thymic overexpression of IFN-β[24]. "
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    • "The role of viral infections in MG, however, is controversial. One study had described Epstein-Barr virus (EBV) infected B cells in MG thymus[69], but later reports did not reproduce the data[70] [71]. MG patients have high titers of antibodies against the EBV protein EBNA1, but this could be an epiphenomenon unrelated to MG pathogenesis[72]. "
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