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: 11.91). 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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Available from: Barbara Serafini, Aug 11, 2015
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    • "Recently, the same group has also proposed a role of EBVinfections in the pathology of MG. Viral DNA and cells expressing EBV-specific RNAs and membrane proteins were found in the thymus of MG patients, but not in control adults (Cavalcante et al., 2010b). However, the suggested etiological role of EBV in MG was lately challenged by two groups, which had not found evidence for an EBV infection in the MG thymus neither on DNA nor on protein level (Meyer et al., 2011; Kakalacheva et al., 2011). "
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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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    • "Although EBER signals were generally localized in the nuclei, a cytoplasmic localization was also observed in a variable proportion of EBER + cells (up to 25%), predominantly in cells with a plasma cell morphology (Serafini and Aloisi, personal communication ). We have excluded that our in situ hybridization protocol yields non-specific EBER signals by analysing non-pathological (lymph node, spleen and thymus) and pathological (tonsil, lymphoblastic leukaemia, Epstein–Barr virus-negative lymphomas) lymphoid tissues (Serafini et al., 2007, 2010 and unpublished data; Cavalcante et al., 2010) and highly infiltrated brain samples from cases with acute inflammatory neurological diseases, mostly of infectious origin (Serafini et al., 2007, 2010). Among the latter, rare nuclear EBER signals were detected in only 2 samples out of 12 analysed (1 luetic meningitis and 1 tuberculous meningoencephalitis ), indicating that abundant Epstein–Barr virus infection in the CNS might be specific to multiple sclerosis. "
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