Tuesday, 17 April 2018

EBV and the not so magnificant 7. A cause of autoimmunity

New genetic research has linked EBV infection to seven autoimmune diseases and include multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis, celiac disease and SLE

What do they have in common?



Simple...they all respond to CD20-depletion therapy and are all driven by memory B cells. OK that's not the paper below, that's me explaining it. 


In this paper, they looked at the genes associated with susceptibility to autoimmune disease, namely Lupus, and asked what transscription factors (things that make genes to be made into proteins) were associated with these genes. They did this for other autoimmune diseases also. They found that one was a molecule made by Epstein Barr Virus.


 This protein is called EBNA2. This implicates further that this virus is at the centre of infection. ProfG will comment on this. But before you do that read this.


The Epstein–Barr virus nuclear antigen 2 (EBNA-2) is one of the six (EBV viral nuclear proteins expressed in latently infected B lymphocytes is a transactivator protein. EBNA2 is involved in the regulation of latent viral transcription and contributes to the immortalization of EBV infected cells.

EBNA2 has an acidic activation domain, which can interact with many different general transcription factors and co-activators. 

EBNA-LP and EBNA2 are the first two proteins expressed in latent infection of primary B lymphocytes. EBNA-LP stimulates EBNA2 activation of the LMP1 promoter and of the LMP1/LMP2B bidirectional transcriptional regulatory element whereas EBNA-LP alone only has a negative effect.

LMP1 mimics the effect of stimulating CD40, which is needed to activate the B cell. LMP2 mimics the effect of stimulating the B cell antigen receptor (i.e. the target for B cells). So if you have LMP1 and LMP2 a B cell can be activated in the absence of antigen and absence of T cells and perhaps macrophages.

Harley JB et al. Transcription factors operate across disease loci, with EBNA2 implicated in autoimmunity.Nature Genetics (2018)
doi:10.1038/s41588-018-0102-3



Explaining the genetics of many diseases is challenging because most associations localize to incompletely characterized regulatory regions. Using new computational methods, we show that transcription factors (TFs) occupy multiple loci associated with individual complex genetic disorders. Application to 213 phenotypes and 1,544 TF binding datasets identified 2,264 relationships between hundreds of TFs and 94 phenotypes, including androgen receptor in prostate cancer and GATA3 in breast cancer. Strikingly, nearly half of systemic lupus erythematosus risk loci are occupied by the Epstein–Barr virus EBNA2 protein and many coclustering human TFs, showing gene–environment interaction. Similar EBNA2-anchored associations exist in multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, juvenile idiopathic arthritis and celiac disease. Instances of allele-dependent DNA binding and downstream effects on gene expression at plausibly causal variants support genetic mechanisms dependent on EBNA2. Our results nominate mechanisms that operate across risk loci within disease phenotypes.


This study shows that EBNA2 and its associated human transcription factors occupy a substantial fraction of autoimmune risk loci. In particular, Nuclear Factor Kappa B (NF-κB) subunits strongly intersect many of these loci, suggesting that NF-κB is important in the mechanisms that confer risk in these inflammatory diseases. NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. This is present in all cells but is particularly important in B cells.

Further analyses suggest that multiple causal autoimmune variants may act through allele-dependent binding of these proteins, resulting in downstream alterations in gene expression. In this scenario, the relevant transcription factors and gene expression changes must occur in the cell type that alters disease risk. 

Collectively, the data identify the EBV infected B cell as a possible site for gene action at select loci in multiple autoimmune disease, with the caveat that existing data are biased, having been predominantly collected in this cell type. 

Why could this be so?

Here is a hypothectical. EBV and Humans have co-evolved. The vast majoirty of people in the world are infected by EBV. Infection of B cells by EBV leads to the production of memory B cells. The virus produces IL-10, whilst some think this is an immune inhibitor it is a B cell growth factor. 

In the memory cells the virus goes to sleep and gets transported round the body and avoids immune destruction. When it gets in the area around the mouth the virus activates and the cells turn into plasma cells, which are killed when the cell bursts and liberates virus to infect someone else. Infected B cells will get destroyed by the immune system. So the virus lives in humans.

However does the human benefit from this.

Virus produces LMP1 and LMP2 and this will cause the memory B cells to be expanded outside control of regulator control. The advantage would be that humans would be able to respond to infections quicker because you won't need T cells specific for the pathogen to be made in addition to the specific B cells. This would give survival advantage to infected humans. 

On the down side (a) there may be some cancers that could develop as EBV can immortalise B cells. Indeed humans develop EBV related cancers like Hodgkins lymphoma and Burkitts Lymphoma. On the other side the problem would be Autoimmunity.

The EBV makes the B cells T cell independent/less-dependent possibly able to be autoreactive. In our history we would be infected by EBV in the first few years and this would expand the memory B cell pool and we don't notice this is as a problem. However in western Socieities the majority of people do not get infected until adolescence, the immune repertoire has different selection pressures, therefore you get massive proliferation of B cells and these then get kill by the CD8+ immune system causing glandular fever and puts us at risk from MS in late adult life. 

Historically, we would have had children before this time and our life span would not be that long, so the evolutionary pressure to remove this problem is not there. The specificity of the B cell will determine which type of autoimmunity develops so some people develop arthritis, others MS.

Targeting EBV many be important so you may have an interest in this.

Yan Y, Ren Y, Chen R, Hu J, Ji Y, Yang J, Shen J, Hu L, Pei H, Wang J, Qiu Y, Lu H, Huang L. valuation of Epstein-Barr Virus Salivary Shedding in HIV/AIDS Patients and HAART Use: A Retrospective Cohort Study. Virol Sin. 2018. doi: 10.1007/s12250-018-0028-z. [Epub ahead of print]

Little data is available on the evaluation of the occurrence rates of Epstein-Barr virus (EBV) in saliva and relationship with highly active antiretroviral therapy (HAART) use in HIV/AIDS patients in China. We conducted a retrospective cohort study of EBV serological tests for HIV/AIDS patients who were treated in the hospitals for infectious diseases in Wuxi and Shanghai, China from May 2016 to April 2017. The EBV-seropositive samples were identified by ELISA. EBV-specific primers and probes were used for the quantitative detection of viral DNA from saliva via quantitative real-time polymerase chain reaction. CD4 cell counts of the HIV/AIDS patients were detected by a flow cytometry. A total of 372 HIV/AIDS patients were ultimately selected and categorized for this retrospective cohort study. For EBV IgG and IgM, the HIV/AIDS HAART use (H) and non-HAART use (NH) groups had significantly higher seropositive rates than the HIV-negative control group. The HIV/AIDS (NH) group had the highest seropositive rate (IgG, 94.27%; IgM, 68.98%) and the highest incidence of EBV reactivation or infection. For salivary EBV DNA-positive rates and quantities, the HIV/AIDS (H) (73.69%) and the HIV/AIDS (NH) (100%) groups showed significantly higher values than the HIV-negative control group (35.79%, > twofold). Further, the salivary EBV DNA-negative population had significantly higher CD4 cell counts than the EBV DNA-positive population in the HIV/AIDS (H) group and the HIV/AIDS (NH) groups. Thus, HAART use is beneficial in decreasing the EBV salivary shedding in HIV/AIDS patients and indirectly decreases EBV transmission risk.

So HIV treatment reduces EBV can it inhibit MS, first question would be can it effect infectious mononucleosis?



14 comments:

  1. Since it's nearly impossible to avoid EBV infection, should we think about deliberate infection (vaccination?) at an early age for children at risk of overactive immune systems? What about unintended consequences?

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  2. http://multiple-sclerosis-research.blogspot.com/2017/11/who-needs-t-cellsnot-ebv-infected.html?m=1

    I thought it was EBNA-LMP1 that mimics CD40 ie allows B cell activation in the absence of T cell help?

    Whichever it is, I guess end result is the same ie B cell activation in the absence of T cell help/regulation = autoimmunity :( and you're right about evolution. Evolution cares nothing for us once we've had children.

    But why only some of us get MS or other ai disease???




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    Replies
    1. Quite right AM, just testing:-) You passed with flying colours and the post is now changed.

      The MHC is probably going to dictate, which type of autoimmunities we get.

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  3. The evidence for EBV in MS is growing.Shouldn't we be treating patients with anti-virals and get to the root of what is responsible for memory B-cell activation? HAART have shown to decrease EBV DNA in saliva. I think that medical professionals don't see IM as a serious disease since it is self limiting in the majority of patients, mostly adolescents.

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    1. About that, the "funny" thing with EBV is that even mono is neglected from doctors. Patients complain that they never overcame the fatigue and a load of other symptoms after they had mono -which can persist for years-, and even the mono relapses are hard to believe for doctors. No, a swollen liver and lymph nodes are not enough to convince them, and when the blood tests come back positive they consider it an isolated case. This is where the mainstream pathology is still today. I really dont get how EBV is so understudied.

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    2. I know how you feel. I have been told many times by doctors you cannot have full mono twice, each time I point to my medical notes and tell them it was their colleagues who diagnosed it using blood tests. After the second episode I had fatigue starting every winter and stopping in late summer for 4 years. When the fatigue stopped I developed a new set of enlarged lymph nodes, which grew in the winter and shrunk in the summer. In the winter of the 5th year I developed Hodgkin's Lymphoma. EBV should be sent the same way as smallpox.

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  4. Exhausted cytotoxic control of Epstein-Barr virus in human lupus.

    Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

    https://www.ncbi.nlm.nih.gov/pubmed/22028659

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  5. Thank you for this paper, Mouse Doctor!

    When Prof. G is going to comment on this?

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    Replies
    1. Not sure, he has been taking advice from EBV experts

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  6. How common is it to have Hodgkin lymphoma and MS ? I am a possible candidate although MS is questionable for me

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  7. I have been reading a lot about the possible and real connection of autoimmunity, and in this it is necessary the genetic factors of predisposition, and the EBV infection, tbm necessary for the autoimmunity to eclode. I haven't been so much on the blog these last few times that it's not to look like "EBV maniac as a direct trigger of MS," but I do not "understand" how Big Pharma has not yet admitted, and decided to face it in form of a "drug." If MS depended only on genetic factors, heredity, I wouldn't see a case of MS so active in one twin, the other twin being healthy, it has absolutely nothing.

    There's some "thing" that happens "during the course" and that is determinant for the triggering of the disease.

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  8. Any idea if EBV correlates with CIDP? Or if CIDP responds to CD20-depletion therapy? My step mom has CIDP and I’m curious if she may one day end up on Alemtuzimab like me, her MSer step daughter. It seems there’s so little research and study completed on CIDP because it’s prevalence is so much lower than MS. It’s possible she may never get a different treatment for it other than IVIG, which seems to be losing effectiveness for her and steroids which have other consequences.

    Apologies if this is a bit off topic but I figured that some of the researchers here may have a finger on the pulse of other research areas that may have some potential overlap in terms of treatment. :)

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    1. Patients with CIDP respond well to HSCT

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  9. "We compared the
    salivary EBV DNA of patients undergoing HAART and
    those who do not; we concluded that HAART could play a
    pivotal role in indirectly decreasing the possibility of EBV
    co-infection with HIV or promoting EBV immune clearance
    in saliva."

    ReplyDelete

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