Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus

Paola Cavalcante, Barbara Serafini, Barbara Rosicarelli, Lorenzo Maggi, Massimo Barberis, Carlo Antozzi, Sonia Berrih-Aknin, Pia Bernasconi, Francesca Aloisi, Renato Mantegazza

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Objective: 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. Methods: 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. Results: 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. Interpretation: Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.

Original languageEnglish
Pages (from-to)726-738
Number of pages13
JournalAnnals of Neurology
Volume67
Issue number6
DOIs
Publication statusPublished - Jun 2010

Fingerprint

Myasthenia Gravis
Human Herpesvirus 4
Thymus Gland
Epstein-Barr Virus Infections
Germinal Center
Autoimmune Diseases
B-Lymphocytes
RNA
Virus Latency
Cercopithecine Herpesvirus 1
Proteins
DNA
Natural Killer Cells
Dendritic Cells
In Situ Hybridization
Immune System
Immunohistochemistry
T-Lymphocytes
Polymerase Chain Reaction
Messenger RNA

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. / Cavalcante, Paola; Serafini, Barbara; Rosicarelli, Barbara; Maggi, Lorenzo; Barberis, Massimo; Antozzi, Carlo; Berrih-Aknin, Sonia; Bernasconi, Pia; Aloisi, Francesca; Mantegazza, Renato.

In: Annals of Neurology, Vol. 67, No. 6, 06.2010, p. 726-738.

Research output: Contribution to journalArticle

Cavalcante, Paola ; Serafini, Barbara ; Rosicarelli, Barbara ; Maggi, Lorenzo ; Barberis, Massimo ; Antozzi, Carlo ; Berrih-Aknin, Sonia ; Bernasconi, Pia ; Aloisi, Francesca ; Mantegazza, Renato. / Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. In: Annals of Neurology. 2010 ; Vol. 67, No. 6. pp. 726-738.
@article{8d31fda0bd7342048e271d6f9fe3a8cd,
title = "Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus",
abstract = "Objective: 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. Methods: 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. Results: 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. Interpretation: Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.",
author = "Paola Cavalcante and Barbara Serafini and Barbara Rosicarelli and Lorenzo Maggi and Massimo Barberis and Carlo Antozzi and Sonia Berrih-Aknin and Pia Bernasconi and Francesca Aloisi and Renato Mantegazza",
year = "2010",
month = "6",
doi = "10.1002/ana.21902",
language = "English",
volume = "67",
pages = "726--738",
journal = "Annals of Neurology",
issn = "0364-5134",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus

AU - Cavalcante, Paola

AU - Serafini, Barbara

AU - Rosicarelli, Barbara

AU - Maggi, Lorenzo

AU - Barberis, Massimo

AU - Antozzi, Carlo

AU - Berrih-Aknin, Sonia

AU - Bernasconi, Pia

AU - Aloisi, Francesca

AU - Mantegazza, Renato

PY - 2010/6

Y1 - 2010/6

N2 - Objective: 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. Methods: 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. Results: 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. Interpretation: Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.

AB - Objective: 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. Methods: 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. Results: 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. Interpretation: Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.

UR - http://www.scopus.com/inward/record.url?scp=77952920585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77952920585&partnerID=8YFLogxK

U2 - 10.1002/ana.21902

DO - 10.1002/ana.21902

M3 - Article

VL - 67

SP - 726

EP - 738

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

IS - 6

ER -