Thursday, August 7, 2025
No menu items!
HomeNatureEBV induces CNS homing of B cells attracting inflammatory T cells

EBV induces CNS homing of B cells attracting inflammatory T cells

  • Bjornevik, K. et al. Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science 375, 296–301 (2022).

    ADS 
    CAS 

    Google Scholar
     

  • Filippi, M. et al. Multiple sclerosis. Nat. Rev. Dis. Primers 4, 43 (2018).


    Google Scholar
     

  • Oksenberg, J. R., Baranzini, S. E., Sawcer, S. & Hauser, S. L. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat. Rev. Genet. 9, 516–526 (2008).

    CAS 

    Google Scholar
     

  • Bray, P. F., Bloomer, L. C., Salmon, V. C., Bagley, M. H. & Larsen, P. D. Epstein–Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch. Neurol. 40, 406–408 (1983).

    CAS 

    Google Scholar
     

  • Leibowitz, U. et al. Epidemiological study of multiple sclerosis in Israel. II. Multiple sclerosis and level of sanitation. J. Neurol. Neurosurg. Psychiatry 29, 60–68 (1966).

    CAS 

    Google Scholar
     

  • Angelini, D. F. et al. Increased CD8+ T cell response to Epstein–Barr virus lytic antigens in the active phase of multiple sclerosis. PLoS Pathog. 9, e1003220 (2013).

    CAS 

    Google Scholar
     

  • Lünemann, J. D. et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129, 1493–1506 (2006).


    Google Scholar
     

  • Lanz, T. V. et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature 603, 321–327 (2022).

    ADS 
    CAS 

    Google Scholar
     

  • Bar-Or, A. et al. Rituximab in relapsing-remitting multiple sclerosis: a 72-week, open-label, phase I trial. Ann. Neurol. 63, 395–400 (2008).

    CAS 

    Google Scholar
     

  • Hauser, S. L. et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358, 676–688 (2008).

    CAS 

    Google Scholar
     

  • Hauser, S. L. et al. Ocrelizumab versus interferon β-1a in relapsing multiple sclerosis. N. Engl. J. Med. 376, 221–234 (2017).

    CAS 

    Google Scholar
     

  • Rubtsova, K. et al. B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J. Clin. Invest. 127, 1392–1404 (2017).


    Google Scholar
     

  • Punnanitinont, A. et al. TLR7 activation of age-associated B cells mediates disease in a mouse model of primary Sjogren’s disease. J. Leukoc. Biol. 115, 497–510 (2024).


    Google Scholar
     

  • Tsubaki, T. et al. Accumulation of plasma cells expressing CXCR3 in the synovial sublining regions of early rheumatoid arthritis in association with production of Mig/CXCL9 by synovial fibroblasts. Clin. Exp. Immunol. 141, 363–371 (2005).

    CAS 

    Google Scholar
     

  • Fox, R. I., Luppi, M., Kang, H. I. & Pisa, P. Reactivation of Epstein–Barr virus in Sjogren’s syndrome. Springer Semin. Immunopathol. 13, 217–231 (1991).

    CAS 

    Google Scholar
     

  • James, J. A. et al. Systemic lupus erythematosus in adults is associated with previous Epstein–Barr virus exposure. Arthritis Rheum. 44, 1122–1126 (2001).

    CAS 

    Google Scholar
     

  • Alspaugh, M. A., Jensen, F. C., Rabin, H. & Tan, E. M. Lymphocytes transformed by Epstein–Barr virus. Induction of nuclear antigen reactive with antibody in rheumatoid arthritis. J. Exp. Med. 147, 1018–1027 (1978).

    CAS 

    Google Scholar
     

  • SoRelle, E. D. et al. Time-resolved transcriptomes reveal diverse B cell fate trajectories in the early response to Epstein–Barr virus infection. Cell Rep. 40, 111286 (2022).

    CAS 

    Google Scholar
     

  • Mouat, I. C. et al. Gammaherpesvirus infection drives age-associated B cells toward pathogenicity in EAE and MS. Sci. Adv. 8, eade6844 (2022).

    ADS 
    CAS 

    Google Scholar
     

  • Miller, G. & Lipman, M. Comparison of the yield of infectious virus from clones of human and simian lymphoblastoid lines transformed by Epstein–Barr virus. J. Exp. Med. 138, 1398–1412 (1973).

    CAS 

    Google Scholar
     

  • Miller, G. & Lipman, M. Release of infectious Epstein–Barr virus by transformed marmoset leukocytes. Proc. Natl Acad. Sci. USA 70, 190–194 (1973).

    ADS 
    CAS 

    Google Scholar
     

  • Zdimerova, H. et al. Attenuated immune control of Epstein–Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur. J. Immunol. 51, 64–75 (2021).

    CAS 

    Google Scholar
     

  • van Langelaar, J. et al. Induction of brain-infiltrating T-bet-expressing B cells in multiple sclerosis. Ann. Neurol. 86, 264–278 (2019).


    Google Scholar
     

  • Jain, R. W. & Yong, V. W. B cells in central nervous system disease: diversity, locations and pathophysiology. Nat. Rev. Immunol. 22, 513–524 (2022).

    CAS 

    Google Scholar
     

  • SoRelle, E. D. et al. An EBV-associated atypical B cell signature in clinically isolated syndrome is implicated in progression of multiple sclerosis. Preprint at medRxiv https://doi.org/10.1101/2023.02.26.23286433 (2024).

  • Fournier, B. et al. Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors. J. Exp. Med. 219, e20211682 (2022).

    CAS 

    Google Scholar
     

  • Baranzini, S. E. et al. B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions. J. Immunol. 163, 5133–5144 (1999).

    CAS 

    Google Scholar
     

  • Yang, X. et al. Liquid–liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A. Int. J. Biol. Macromol. 310, 142986 (2025).

    CAS 

    Google Scholar
     

  • Evans, A. K. et al. Impact of noradrenergic inhibition on neuroinflammation and pathophysiology in mouse models of Alzheimer’s disease. J. Neuroinflammation 21, 322 (2024).

    CAS 

    Google Scholar
     

  • Reali, C. et al. B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis. Brain Pathol. 30, 779–793 (2020).

    CAS 

    Google Scholar
     

  • Choi, S. R. et al. Meningeal inflammation plays a role in the pathology of primary progressive multiple sclerosis. Brain 135, 2925–2937 (2012).


    Google Scholar
     

  • McHugh, D. et al. EBV renders B cells susceptible to HIV-1 in humanized mice. Life Sci. Alliance 3, e202000640 (2020).


    Google Scholar
     

  • White, R. E. et al. EBNA3B-deficient EBV promotes B cell lymphomagenesis in humanized mice and is found in human tumors. J. Clin. Invest. 122, 1487–1502 (2012).

    CAS 

    Google Scholar
     

  • Münz, C. Latency and lytic replication in the oncogenesis of the Epstein Barr virus. Nat. Rev. Microbiol. 17, 691–700 (2019).


    Google Scholar
     

  • Babcock, J. G., Hochberg, D. & Thorley-Lawson, A. D. The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506 (2000).

    CAS 

    Google Scholar
     

  • SoRelle, E. D., Reinoso-Vizcaino, N. M., Horn, G. Q. & Luftig, M. A. Epstein–Barr virus perpetuates B cell germinal center dynamics and generation of autoimmune-associated phenotypes in vitro. Front. Immunol. 13, 1001145 (2022).

    CAS 

    Google Scholar
     

  • Hochberg, D. et al. Demonstration of the Burkitt’s lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc. Natl Acad. Sci. USA 101, 239–244 (2004).

    ADS 
    CAS 

    Google Scholar
     

  • Nowag, H. et al. Macroautopphagy proteins assist Epstein Barr virus production and get incorporated into the virus particles. EBioMedicine 1, 116–125 (2014).

    ADS 

    Google Scholar
     

  • Lünemann, J. D. et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2. J. Exp. Med. 205, 1763–1773 (2008).


    Google Scholar
     

  • Serafini, B., Rosicarelli, B., Veroni, C., Mazzola, G. A. & Aloisi, F. Epstein–Barr virus-specific CD8 T cells selectively infiltrate the brain in multiple sclerosis and interact locally with virus-infected cells: clue for a virus-driven immunopathological mechanism. J. Virol. https://doi.org/10.1128/JVI.00980-19 (2019).

  • Gottlieb, A., Pham, H. P. T., Saltarrelli, J. G. & Lindsey, J. W. Expanded T lymphocytes in the cerebrospinal fluid of multiple sclerosis patients are specific for Epstein–Barr-virus-infected B cells. Proc. Natl Acad. Sci. USA 121, e2315857121 (2024).

    CAS 

    Google Scholar
     

  • Thomas, O. G. et al. Cross-reactive EBNA1 immunity targets α-crystallin B and is associated with multiple sclerosis. Sci. Adv. 9, eadg3032 (2023).

    CAS 

    Google Scholar
     

  • Tengvall, K. et al. Molecular mimicry between anoctamin 2 and Epstein–Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc. Natl Acad. Sci. USA 116, 16955–16960 (2019).

    ADS 
    CAS 

    Google Scholar
     

  • Sahir, F., Mateo, J. M., Steinhoff, M. & Siveen, K. S. Development of a 43 color panel for the characterization of conventional and unconventional T-cell subsets, B cells, NK cells, monocytes, dendritic cells, and innate lymphoid cells using spectral flow cytometry. Cytometry A https://doi.org/10.1002/cyto.a.24288 (2020).

  • Puccio, S. et al. CRUSTY: a versatile web platform for the rapid analysis and visualization of high-dimensional flow cytometry data. Nat. Commun. 14, 5102 (2023).

    ADS 
    CAS 

    Google Scholar
     

  • Adhikary, D. et al. Immunodominance of lytic cycle antigens in Epstein–Barr virus-specific CD4+ T cell preparations for therapy. PLoS ONE 2, e583 (2007).

    ADS 

    Google Scholar
     

  • Nuckel, J. et al. Association between IgG responses against the nucleocapsid proteins of alphacoronaviruses and COVID-19 severity. Front. Immunol. 13, 889836 (2022).


    Google Scholar
     

  • Soldan, S. S. et al. Epigenetic plasticity enables CNS-trafficking of EBV-infected B lymphocytes. PLoS Pathog. 17, e1009618 (2021).

    CAS 

    Google Scholar
     

  • Oner, A. & Kobold, S. Transwell migration assay to interrogate human CAR-T cell chemotaxis. STAR Protoc. 3, 101708 (2022).

    CAS 

    Google Scholar
     

  • Fennell, E. Single-cell RNA and B cell receptor sequencing processed data from EBV-infected and PBS humanised BRGS-A2DR2 mice. Zenodo https://doi.org/10.5281/zenodo.15602185 (2025).

  • Fennell, E. Multiplex immunofluorescence images of spleens from EBV-infected BRGS-A2DR2 mice. Zenodo https://doi.org/10.5281/zenodo.15599580 (2025).

  • RELATED ARTICLES

    Most Popular

    Recent Comments