EBV and MS: Lessons from hepatitis and HIV
Nolan, D. and Mallal, S. (2009) EBV and MS: Lessons from hepatitis and HIV. In: 10th Biennial Scientific Conferene on "Progress on MS Research" - MSRA Conference 2009, 15 - 17 October 2009, Sydney, Australia.
Lessons from other viruses: HLA molecules bind preferentially to evolutionarily conserved and functionally important peptide sequences. DNA viruses such as EBV have evolved in a symbiotic host-viral relationship with an extensive use of “host mimicry” in which viral peptides maintain close similarity to self peptides. This allows DNA viruses to exploit “holes” in the T-cell repertoire created through thymic deletion of auto reactive T-cells. Of the class I genes, HLA-A appears to target the self peptides and DNA viruses while most HLA-B alleles target RNA viruses most efficiently. RNA viruses such as HIV and Hepatitis C can evade HLA-restricted responses by “classic” escape mutations. However more recently it has also been recognised that in some cases these viruses may also adapt to induce HLA-restricted immune responses which favour viral replication. The mechanisms for this are not as yet understood. EBV infection is also known to be associated with vigorous HLA-restricted immune responses that may be ineffective in limiting the virus. Such examples illustrate the importance of determining any viral sequence variation in parallel with measurement of specific HLA-restricted immune responses to both the non-adapted and adapted virus. This information is needed to dissect the relative contribution of host and viral genetics and to determine the likelihood that the immune response is: 1) beneficial to the host, 2) Ineffective/neutral or 3) actively beneficial to viral replication or survival.
A contemporary model for the pathogenesis of Multiple Sclerosis to account for some of the known interacting genetic and environmental risk factors will be described and the implications of recent observations from HIV and Hepatitis viruses considered. The development of Multiple Sclerosis may require a three step process involving 1) permissive genetics followed by 2) relative vitamin D deficiency around the birth and 3) appropriately timed EBV infection later in life. As with HIV infection allelic variation within the MHC has been shown to be the primary host genetic determinant of the risk and outcomes of MS in the era of whole genome screening. Genetics The risk of disease conferred by HLA-DRB1*1501/DQB1*-0602 can be normalised by the presence of “protective” DR14, DR10 and DR01 alleles. The combination of DRB1*1501 and DR8 in particular confers the greatly increased risk. On the other hand HLA-A*02 alleles are associated with protection against MS while HLA-A*03 and HLA-B*07 increase disease risk. Low levels of sun exposure and vitamin D around the time of birth may be associated with increased risk. The HLA-DRB1*1501 promoter specifically lacks sensitivity to the effects of vitamin D via a highly conserved VDRE. It has been proposed that low levels of vitamin D in early life could therefore reduce HLA-DRB1*1501 expression and allow HLA-DRB1*15 restricted auto-reactive T-cells to escape thymic deletion. EBV Infection: EVB appears to be necessary but not sufficient for the development of MS and cases of MS appear to be more specifically predicted by a serological response to EBNA-1. EBV infected B cells and plasma cells have been found to accumulate in the meninges, ectopic lymphoid follicles and perivascular cuffs of acute and chronic demyelinated lesions. Furthermore EBV specific IgG antibodies in the CSF result in the oligoclonal bands observed. EBNA-1 is critical to establish and maintain latent B cell EBV infection and can elicit both class I-dependent CD8 and class II-dependant memory CD4 T-cell responses. The CD8 responses involved involve interferon gamma secretion but not vigorous cytotoxicity and the CD4 responses have greater cytotoxic potential but both limit EBV driven B cell proliferation. CD8+ T-Cell cytotoxic responses directed against EBNA-1 expressing B cells or plasma cells are believed to occur in MS affected brains. As the disease progress a more prominent memory CD4 T-cell response to EBNA-1 appears involving the production of pro-inflammatory cytokines. Controversy exists as to whether damage to white and grey matter occurs directly or as a result of bystander effects. There is currently little evidence to support a model in which MS initiation and/or progression depends on “reactivated” EBV infection.
Potential implications for the study of host-pathogen interactions in MS
Whether or not EBV or another pathogen is implicated in MS, it is likely it will be necessary to examine pathogen sequence variation within known or potential HLA- restricted epitopes and the relevant specific Class I and II restricted immune responses to these variants in order to understand both the normal responses and the potential ways an aberrant host-pathogen interaction might be implicated in the pathogenesis of MS. Studies of patients enrolled in the Perth Demyelinating Diseases Cohort are underway to examine these hypotheses.
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|Murdoch Affiliation:||Institute for Immunology and Infectious Diseases|
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