Giovanni Ristori, Rome, Italy; Silvia Romano, Rome, Italy; Giulia Coarelli, Rome, Italy; Maria Chiara Buscarinu, Rome, Italy; Marco Salvetti, Rome, Italy
Published February 19, 2014
We thank Dr. Brenner for his comments. Prevention of autoimmunity by adjuvant immunotherapy partially depends on inducible nitric oxide synthase [1] and the relationship between NOTCH-signaling and Epstein Barr Virus (EBV). It would be interesting to determine the mechanisms underlying the converging sero-epidemologic evidence that link EBV to MS. [2] This relationship is based on the molecular interaction between Epstein Barr Nuclear Antigen 2 (EBNA2) and Recombination Binding Protein for immunoglobulin kappa J region (RBP-Jk): EBNA2 functions as a transcriptional activator by interacting with DNA-binding RBP-Jk, and relieving the transcriptional repression that is mediated by a large multiprotein complex. [3] The EBNA2 gene is the most polymorphic of all EBV genes [4] and is densely targeted by host and virus micro-RNAs. [5] This interaction may be vital and MS studies on EBNA2 variants are ongoing. The possibility that adjuvant immunotherapy may counteract the pathogenic loop due to EBV or its genomic variants deserves further research. Moreover, future trials with BCG vaccine in demyelinating diseases might include analysis of EBV status (serology, viral load, genotyping) and NOTCH-signaling components.
1. Kahn DA, Archer DC, Gold DP, Kelly CJ. Adjuvant immunotherapy is dependent on inducible nitric oxide synthase. J Exp Med 2001;193:1261- 1268.
2. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288-299.
3. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 2004;4:757-768.
4. Tierney RJ, Edwards RH, Sitki-Green D, et al. Multiple Epstein-Barr virus strains in patients with infectious mononucleosis: comparison of ex vivo samples with in vitro isolates by use of heteroduplex tracking assays. J Infect Dis. 2006;193:287-297.
5. Skalsky RL, Corcoran DL, Gotwein E, et al. The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathogens 2012;
8: e1002484.
For disclosures, please contact the editorial office at journal@neurology.org.
We thank Dr. Brenner for his comments. Prevention of autoimmunity by adjuvant immunotherapy partially depends on inducible nitric oxide synthase [1] and the relationship between NOTCH-signaling and Epstein Barr Virus (EBV). It would be interesting to determine the mechanisms underlying the converging sero-epidemologic evidence that link EBV to MS. [2] This relationship is based on the molecular interaction between Epstein Barr Nuclear Antigen 2 (EBNA2) and Recombination Binding Protein for immunoglobulin kappa J region (RBP-Jk): EBNA2 functions as a transcriptional activator by interacting with DNA-binding RBP-Jk, and relieving the transcriptional repression that is mediated by a large multiprotein complex. [3] The EBNA2 gene is the most polymorphic of all EBV genes [4] and is densely targeted by host and virus micro-RNAs. [5] This interaction may be vital and MS studies on EBNA2 variants are ongoing. The possibility that adjuvant immunotherapy may counteract the pathogenic loop due to EBV or its genomic variants deserves further research. Moreover, future trials with BCG vaccine in demyelinating diseases might include analysis of EBV status (serology, viral load, genotyping) and NOTCH-signaling components.
1. Kahn DA, Archer DC, Gold DP, Kelly CJ. Adjuvant immunotherapy is dependent on inducible nitric oxide synthase. J Exp Med 2001;193:1261- 1268.
2. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007;61:288-299.
3. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer 2004;4:757-768.
4. Tierney RJ, Edwards RH, Sitki-Green D, et al. Multiple Epstein-Barr virus strains in patients with infectious mononucleosis: comparison of ex vivo samples with in vitro isolates by use of heteroduplex tracking assays. J Infect Dis. 2006;193:287-297.
5. Skalsky RL, Corcoran DL, Gotwein E, et al. The viral and cellular microRNA targetome in lymphoblastoid cell lines. PLoS Pathogens 2012; 8: e1002484.
For disclosures, please contact the editorial office at journal@neurology.org.