Discussion in 'Multiple Sclerosis' started by Kyla, Apr 9, 2015.
Epstein-Barr virus genetic variants are associated with multiple sclerosis.
Mechelli R1, Manzari C1, Policano C1, Annese A1, Picardi E1, Umeton R1, Fornasiero A1, D'Erchia AM1, Buscarinu MC1, Agliardi C1, Annibali V1, Serafini B1, Rosicarelli B1, Romano S1, Angelini DF1, Ricigliano VA1, Buttari F1, Battistini L1, Centonze D1, Guerini FR1, D'Alfonso S1, Pesole G1, Salvetti M2, Ristori G1.
We analyzed the Epstein-Barr nuclear antigen 2 (EBNA2) gene, which contains the most variable region of the viral genome, in persons with multiple sclerosis (MS) and control subjects to verify whether virus genetic variants are involved in disease development.
A seminested PCR approach and Sanger sequencing were used to analyze EBNA2 in 53 patients and 38 matched healthy donors (HDs). High-throughput sequencing by Illumina MiSeq was also applied in a subgroup of donors (17 patients and 17 HDs). Patients underwent gadolinium-enhanced MRI and human leucocyte antigen typing.
MS risk significantly correlated with an excess of 1.2 allele (odds ratio [OR] = 5.13; 95% confidence interval [CI] 1.84-14.32; p = 0.016) and underrepresentation of 1.3B allele (OR = 0.23; 95% CI 0.08-0.51; p = 0.0006). We identified new genetic variants, mostly 1.2 allele- and MS-associated (especially amino acid variation at position 245; OR = 9.4; 95% CI 1.19-78.72; p = 0.0123). In all cases, the consensus sequence from deep sequencing confirmed Sanger sequencing (including the cosegregation of newly identified variants with known EBNA2 alleles) and showed that the extent of genotype intraindividual variability was higher than expected: rare EBNA2 variants were detected in all HDs and patients with MS (range 1-17 and 3-19, respectively). EBNA2 variants did not seem to correlate with human leucocyte antigen typing or clinical/MRI features.
Our study unveils a strong association between Epstein-Barr virus genomic variants and MS, reinforcing the idea that Epstein-Barr virus contributes to disease development.
© 2015 American Academy of Neurology.
Please note that the variants for which they looked were in the genes which produce early nuclear antigens. We already know that EBV has several latent states, and only one of these is completely inactive. Most latent EBV is still capable of producing early nuclear antigens, but stops short of producing proteins which lead to lytic replication.
Most medical thinking has been that the dangerous activity is confined to active, lytic replication which releases virions into the bloodstream. This is easy to detect because it causes cell death and significant antibody response. Early DNA replication inside a cell has been neglected because it is assumed to be incapable of transmission to other cells. The exception to this takes place when those cells are produced by clonal expansion of infected immune cells. Cells with multiple EBV episomes inside the nuclear membrane are capable of producing infected daughter cells via mitosis. If DNA replication inside these cells continues there is nothing to prevent a huge expansion in the number of infected immune cells. This is the normal way immune systems amplify a response to a tiny quantity of a particular antigen to produce a powerful immune response. If that response is being misdirected, serious pathology can result.
We have several problems here with standard medical thinking: 1) all EBV infecting people is not the same, it can even differ between physiological compartments in a single individual; 2) lytic replication is not the only dangerous activity; 3) genetic variants which change early nuclear antigens may escape detection entirely.
There was a study in 2012 which found that in EBV-associated ME/CFS, there is partial reactivation of EBV which can generate at least two viral proteins, namely DNA polymerase and dUTPase.
Discovery could lead to faster diagnosis for some Chronic Fatigue Syndrome cases
Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset
Thank you @anciendaze, great explanation
That is a very interesting observation, anciendaze.
What I find intriguing is how ME/CFS is mostly linked to pathogens that can form chronic intracellular infections, which do not destroy cells, rather than infections that destroy cells via lysis.
In the case of EBV, we find that this virus can produce proteins inside the cell even in latent states of this virus. Enterovirus, a virus strongly linked to ME/CFS, is another example of a pathogen which produces chronic intracellular infections (non-cytolytic enterovirus infections as they are called in this case).
Then in the case of the two bacteria which are known to cause ME/CFS, namely Chlamydia pneumoniae and Coxiella burnetii, are both obligate intracellular bacteria, which means in their normal lifecycle, they only form intracellular infections, inside cells.
My hunch is that these chronic intracellular infections may all have one thing in common: they may all give rise to abnormal immune responses, such as autoimmunity or unexplained chronic inflammation, because these infections are active inside human cells, and so will likely elect immune responses.
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