The initiation and prevention of multiple sclerosis

Abstract

Although there are strong genetic determinants of multiple sclerosis, the results of migration studies support a role for the environment, and through rigorous epidemiological investigation, Epstein-Barr virus infection, vitamin D nutrition, and cigarette smoking have been identified as likely causal factors for multiple sclerosis. In this review, we discuss the strength of this evidence, as well as the potential biological mechanisms underlying these associations. Both vitamin D nutrition and cigarette smoking are modifiable and as such, increasing vitamin D levels and smoking avoidance have the potential to substantially reduce MS risk and influence its progression.

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

“…One of the unresolved mysteries in MS is its association with EBV infection (44). Mechanistic studies need to help explain how a virus that infects .90% of the adult human population can be the trigger of a relatively uncommon disease, such as MS, on the appropriate genetic susceptibility background.…”

“…12, 45) show that LCV-infected B cells have a central pathogenic role in the activation of highly pathogenic MHC-E-restricted effector memory cytotoxic T cells that, upon activation with the MOG34-56 peptide (core epitope [40][41][42][43][44][45][46][47][48], can elicit MS-like pathology and disease. Notably, similar autoaggressive CTLs were found in MS lesions, where they seemed to be engaged in cytotoxic interactions with HLA-E + oligodendrocytes (5).…”

“…In addition to this core motif, the presence of an acidic residue (E, D, S, T) close to the N-terminal site of the LIR motif is important. Using this algorithm, we scanned the rhMOG sequences of marmoset and rhesus monkeys and found three potential LIR motifs: residues 3-6 (FRVI), [44][45][46][47] In conclusion, based on the results of this study we propose a physiological role for B cells in the protection against autoimmunity in MS. They take up autoantigens and neutralize them via destructive processing; in this way, activation of autoaggressive CD8 + T cells is avoided.…”

“…Although CatG of marmosets has a mouse-like narrow specificity for aromatic (chymotryptic) cleavage sites (Trp, Phe, Tyr), a double mutation in the specificity-determining residues (Ala-189-Ser and Glu-226-Ala) broadens the activity of rhesus monkey and human CatG to basic (tryptic) cleavage sites (e.g., Arg and Lys) (42). To test the proteolytic degradation of the pathogenically dominant Mm-MOG34-56 peptide we used the shorter peptide MOG35-51 to avoid interference of the Arg residue at position 52, which is outside the epitope of interest (residues [40][41][42][43][44][45][46][47][48]. The reported in vitro data show that native Mm-MOG35-51 peptide is rapidly degraded in cellfree lysates of noninfected and LCV infected B cells of rhesus monkeys as well as in LCV-infected B cells of marmosets.…”

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

“…There is strong evidence for a pathogenic role of EBV infection, but the discrepancy between the high prevalence of EBV infection in the human population (> 90 %) and the low incidence of MS (±0.1 %) is unexplained (Ascherio et al, 2012). The risk for MS increases 2-3-fold with development of infectious mononucleosis compared to EBVseropositive people, and an increased IgG1 titer against EBV proteins EBNA-1 is predictive of disease exacerbation (Ascherio and Munger, 2015).…”