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


CONCLUSIONS
Dysregulated EBV infection in the pathological thymus appears common in MG and may contribute to the immunological alterations initiating and/or perpetuating the disease.
Department of Neurology IV, Neuromuscular Diseases and Neuroimmunology, Fondazione Istituto Neurologico Carlo Besta, Milan, Italy.
Paola
P
Cavalcante
Barbara
B
Serafini
Barbara
B
Rosicarelli
Lorenzo
L
Maggi
Massimo
M
Barberis
Carlo
C
Antozzi
Sonia
S
Berrih-Aknin
Pia
P
Bernasconi
Francesca
F
Aloisi
Renato
R
Mantegazza
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000473:pathology; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D006649:Histocompatibility Antigens / Q000378:metabolism; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000150:complications / Q000473:pathology / Q000821:virology; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D015703:Antigens, CD; D006649:Histocompatibility Antigens; D012367:RNA, Viral; D014764:Viral Proteins