Monday, 2 April 2018

MS Suceptibility Genes may link to EBV viral Loads

Genetic variants found in people with MS appear to be associated with viral infection with EBV.
Is this genetic locus making understanding of MS susceptibility clearer

The number one set of genes linking to MS susceptibility reside within the major histocompatibility complex (MHC = transplantation antigens used in DNA fingerprinting). These are called HLA in humans and H-2 in mice. The major MS susceptibility locus is HLA-DRB1*1501.  So in this study they find that that HLA-DRB1*15 is associated with higher viral loads. They also find that HLA-B*07 is associated with a higher viral load and HLA-A*02 with lowest viral load. 
This possibly suggests that people who express HLA-A*02 variant of HLA-A (MHC class I) may be good at mounting a CD8 T cell anti-viral response. In other studies it has been found that  that HLA-A*02 mediates a modest, but none the less stronger, EBV-specific CD8 T cell response than non-HLA-A*02 alleles related to the EBV proteins expressed in the latency programme in cells such as memory B cells and germinal centre cells, which make memory B cells. People with MS may have less HLA-A*02 meaning that they won't make the best anti-EBV response.
Likewise this suggests that the HLA-B variant 7 creates a worse anti-viral response. Indeed this has been reported before where it has been found that more people with MS have the HLA-B*07 variant and this notably the HLA-B*0702 variant gives a poorer anti-EBV response.
Now to HLA-DRB1*15 (MHC class II variant of the DR molecule the Beta chain of the alpah beta pair in MHC class II and vatinat number 15.), which is the main MS susceptibility gene. There appears to be a link between EBV and HLA-DRB1*15. but in this study it suggests that this variant would be associated with a poorer anti-EBV response by CD4 T cells, that may influence the capacity of T cells to help B cells make anti-EBNA1. 
However maybe this relates to the infection of B cells by EBV. It is known that HLA-DR , in addition to CD21 and sometimes CD35, is required for EBV to infect B cells. 
I am speculating that the HLA-DRB1*15 variant may help virus infect B cells more. There would be other variants that this effects are there are other DR variants associated with other autoimmune diseases, where EBV has been implicated as a susceptibility trigger
Is this the biological link?.
Agostini S, Mancuso R, Guerini FR, D'Alfonso S, Agliardi C, Hernis A, Zanzottera M, Barizzone N, Leone MA, Caputo D, Rovaris M, Clerici M.
J Transl Med. 2018 Mar 27;16(1):80. doi: 10.1186/s12967-018-1450-6.

BACKGROUND:

The aetiopathology of multiple sclerosis (MS) is believed to include genetic and environmental factors. Human leucocyte antigen (HLA) alleles, in particular,  are associated with disease susceptibility, whereas Epstein Barr Virus (EBV) infection has long been suspected to play a role in disease pathogenesis. The aim of the present study is to evaluate correlations between HLA alleles and EBV infection in MS.

METHODS:

HLA alleles, EBV viral load (VL) and serum anti-EBV antibody titres were evaluated in EBV-seropositive MS patients (N = 117) and age- and sex-matched healthy controls (HC; N = 89).

RESULTS:

Significantly higher DNA viral loads (p = 0.048) and EBNA-1 antibody titre (p = 0.0004) were seen in MS compared to HC. EBV VL was higher in HLA-B*07+ (p = 0.02) and HLA-DRB1*15+ (p = 0.02) MS patients, whereas it was lower in HLA-A*02+ (p = 0.04) subjects. EBV VL was highest in HLA-A*02-/B*07+/DRB1*15+ patients and lowest in HLA-A*A02+/B*07-/DRB1*15- individuals (p < 0.0001). HLA-B*07 resulted the most associated allele to EBV VL after multiple regression analysis considering altogether the three alleles, (p = 0.0001). No differences were observed in anti-EBV antibody titers in relationship with HLA distribution.

CONCLUSIONS:

Host HLA-B*07 allele influence EBV VL in MS. As HLA-class I molecules present antigens to T lymphocytes and initiate immune response against viruses, these results could support a role for EBV in MS.

8 comments:

  1. Dear prof. G's Team,

    3,5 year ago you've posted something similiar about HERV
    [http://multiple-sclerosis-research.blogspot.com/2014/01/endogeneous-viral-genes-are-associated.html].

    It seems that everything is going in the right direction.

    Please, take a look at the abstract of https://www.ncbi.nlm.nih.gov/pubmed/25505955.

    Dr Pender notes that before the study, all the patients had very low T cell reactivity to Epstein-Barr — about 0.1%. "This changed to up to 48% after the T cells were multiplied with the Epstein-Barr fragments. Importantly, the patients who have shown the most clinical improvement were the ones whose T cells showed the highest reactivity to Epstein-Barr virus after their incubation.

    Maybe soon #CharcotProject will use a "forgotten key" to effectively treat MS (antivirals) and prof. G with his whole team will land in the history books.

    When the third GNbAC1 trial will be completed?

    Regards,
    Chris

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  2. autoimmunity, after MS, that I most saw studies interconnecting it with a genetic susceptibility and EBV infection was SLE.

    http://acrabstracts.org/abstract/epstein-barr-virus-interluekin-10-vil10-in-systemic-lupus-erythematosus/

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    Replies
    1. Yes there is good evidence for EBV and SLE...also good evidence for memory B and SLE.

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    2. Interesting that you show that EBV creates an IL-10 mimic...most immunologists view this as an immunosuppressive cytokine, so EBV suppresses the immune response to EBV, the other way to view this is that EBV makes IL-10 which is a B cell growth and differentiation factor and so it helps with the B cell infection

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  3. Would a course of spironolactone which blocks EBV replication be beneficial for MS suffers? Has anyone tried this?

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    Replies
    1. The dose required to inhibit EBV in humans would give you renal failure.

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    2. Thanks for the reply Spironolactone has quite a few side effects

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