BCG vaccination may restore normal Notch signaling, which is disrupted in MS, possibly due to infection by Epstein-Barr virus causing auto-immunity
Steven RBrenner, Physician, St. Louis University Dept. Neurology and Psychiatry, retired.SBren20979@aol.com
Submitted January 28, 2014
I read the article on Bacille Calmette-Guerin (BCG) reducing the likelihood of developing multiple sclerosis (MS) after an event of clinically isolated syndrome. [1] BCG upregulates NOTCH-1 signaling through a nitric oxide mediated pathway in macrophages. [2] Notch signaling appears to be involved in the pathogenesis of MS; Notch receptors are abundantly expressed in inflammatory and demyelinating lesions as well as in autoimmune experimental encephalomyelitis (EAE). [3] Modulation of Notch signaling in EAE reduces the severity of immune responses. [3] Recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a protein of the Notch signaling pathway which also is involved in Epstein-Barr virus infection, is a CSF related autoantigen in an MS patient subset. [4] Notch1C (Notch1incracellular domain) trans-activates gene expression by CBF-1/RBPJ tethering to DNA. Transactivation of Notch1C is due in part to eliminating CBF-1/RBPJ mediated repression. The same mechanism utilized by Epstein-Barr virus EBNA2, through molecular mimicry, causes virus driven immortalization of cells. [5] BCG vaccination causing up-regulation of cellular Notch-1 signaling may restore normal cellular Notch-1 mechanisms and prevent Epstein-Barr virus from causing macrophage immortalization with development of the auto -immunity characteristic of MS.
1. Ristori G, Romano S, Cannoni S, et al. Effects of Bacille Calmette-Guerin after the first demyelinating eveng in the CNS. Neurology 2014; 82:41-48.
2. Kapoor N, Naravana Y, Patil SA, Balaji KN. Nitric oxide is involved in Mycobacterium bovis bacillus Calmette-Guerin-activated Jagged1 and Notch1 signaling. J Immunol 2010; 184: 3117-3126.
3. Jurynczyk M. Selmai K. Notch: a new player in MS mechanisms. J Neuorimmunol. 2010; 218 : 3-11.
4. Querol L, Clark PL, Bailey MA, et al. Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 2013; 81:956-963.
5. Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 1996;16: 952-959.
For disclosures, contact the editorial office at journal@neurology.org.
I read the article on Bacille Calmette-Guerin (BCG) reducing the likelihood of developing multiple sclerosis (MS) after an event of clinically isolated syndrome. [1] BCG upregulates NOTCH-1 signaling through a nitric oxide mediated pathway in macrophages. [2] Notch signaling appears to be involved in the pathogenesis of MS; Notch receptors are abundantly expressed in inflammatory and demyelinating lesions as well as in autoimmune experimental encephalomyelitis (EAE). [3] Modulation of Notch signaling in EAE reduces the severity of immune responses. [3] Recombination signal binding protein for immunoglobulin kappa J region (RBPJ), a protein of the Notch signaling pathway which also is involved in Epstein-Barr virus infection, is a CSF related autoantigen in an MS patient subset. [4] Notch1C (Notch1incracellular domain) trans-activates gene expression by CBF-1/RBPJ tethering to DNA. Transactivation of Notch1C is due in part to eliminating CBF-1/RBPJ mediated repression. The same mechanism utilized by Epstein-Barr virus EBNA2, through molecular mimicry, causes virus driven immortalization of cells. [5] BCG vaccination causing up-regulation of cellular Notch-1 signaling may restore normal cellular Notch-1 mechanisms and prevent Epstein-Barr virus from causing macrophage immortalization with development of the auto -immunity characteristic of MS.
1. Ristori G, Romano S, Cannoni S, et al. Effects of Bacille Calmette-Guerin after the first demyelinating eveng in the CNS. Neurology 2014; 82:41-48.
2. Kapoor N, Naravana Y, Patil SA, Balaji KN. Nitric oxide is involved in Mycobacterium bovis bacillus Calmette-Guerin-activated Jagged1 and Notch1 signaling. J Immunol 2010; 184: 3117-3126.
3. Jurynczyk M. Selmai K. Notch: a new player in MS mechanisms. J Neuorimmunol. 2010; 218 : 3-11.
4. Querol L, Clark PL, Bailey MA, et al. Protein array-based profiling of CSF identifies RBPJ as an autoantigen in multiple sclerosis. Neurology 2013; 81:956-963.
5. Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. Mol Cell Biol 1996;16: 952-959.
For disclosures, contact the editorial office at journal@neurology.org.