Epstein-Barr virus latent infection and BAFF expression in B cells in the multiple sclerosis brain: implications for viral persistence and intrathecal B-cell activation.
A cardinal feature of multiple sclerosis (MS) is the persistent intrathecal synthesis of antibodies. Our previous finding that a large fraction of B cells infiltrating the MS brain are infected with Epstein-Barr virus (EBV) raises the possibility that this virus, because of its ability to establish a latent infection in B cells and interfere with their differentiation, contributes to B-cell dysregulation in MS. The aim of this study was to gain further insight into EBV latency programs and their relationship to B-cell activation in the MS brain. Immunohistochemical analysis of postmortem MS brain samples harboring large EBV deposits revealed that most B cells in white matter lesions, meninges, and ectopic B-cell follicles are CD27+ antigen-experienced cells and coexpress latent membrane protein 1 and latent membrane protein 2A, 2 EBV-encoded proteins that provide survival and maturation signals to B cells. By combining laser-capture microdissection with preamplification reverse transcription-polymerase chain reaction techniques, EBV latency transcripts (latent membrane protein 2A, EBV nuclear antigen 1) were detected in all MS brain samples analyzed. We also found that B cell-activating factor of the tumor necrosis factor family is expressed in EBV-infected B cells in acute MS lesions and ectopic B-cell follicles. These findings support a role for EBV infection in B-cell activation in the MS brain and suggest that B cell-activating factor of the tumor necrosis factor family produced by EBV-infected B cells may contribute to this process resulting in viral persistence and, possibly, disruption of B-cell tolerance.
Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
Barbara
B
Serafini
Martina
M
Severa
Sandra
S
Columba-Cabezas
Barbara
B
Rosicarelli
Caterina
C
Veroni
Giuseppe
G
Chiappetta
Roberta
R
Magliozzi
Richard
R
Reynolds
Eliana Marina
EM
Coccia
Francesca
F
Aloisi
D015703:Antigens, CD / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D001921:Brain / Q000166:cytology*; D002461:Cell Line, Transformed; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000473:pathology; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006801:Humans; D042282:Microdissection / Q000379:methods; D018613:Microscopy, Confocal; D009103:Multiple Sclerosis / Q000150:complications / Q000473:pathology* / Q000821:virology*; D011180:Postmortem Changes; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D053264:B-Cell Activating Factor; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; C505719:TNFSF13B protein, human; D014763:Viral Matrix Proteins; C417029:EBV-encoded nuclear antigen 1