Epstein-Barr virus behind the development of autoimmune diseases, cancer, ME/CFS and Long COVID

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I would like to share with you my latest review article. The Epstein-Barr virus (EBV) has long been known to be behind the development of autoimmune diseases, cancer and is even suspected to be behind the development of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Long COVID. But it is still unclear what pathways it uses.

In this review I describe how the possession of certain ancestral HLA-II alleles (a system used by our immune system to recognize which proteins are foreign, such as pathogens, and which are not) makes the individual genetically weak to control EBV latent cells, thus developing different diseases. EBV infects B cells through a protein on its surface called gp42, which allows it to bind to HLA-II molecules on the B cell surface. If the individual possesses ancestral HLA-II alleles susceptible to EBV, it will cause that after the infection of B cells and the establishment of the latent form, the antigen presentation of these cells will be altered, since gp42 would remain bound to HLA-II molecules interfering in the presentation of antigens to T lymphocytes (necessary to eliminate infected cells), and in the activation of these. This protects the cell from being recognized by CD4+ T lymphocytes and thus surviving, since B cells are one of the main cells that regulate our immune system. But the consequence of possessing these weak alleles against EBV is the development of a type of immunodeficiency, by preventing the activation of CD4 T cells by the interaction of gp42.

Another advantage of infecting B cells is that they have the ability to form ectopic lymphoid aggregates in any tissue. This, under normal conditions, is useful to fight infections in the affected tissue better and faster, since these cells are responsible (among others) for presenting antigens to CD4 T cells and generating antibodies. But EBV takes advantage of this pathway to survive, since any inflammatory process (due to infection or for any other reason) occurring in any tissue recruits both healthy B cells and B cells with latency to the inflamed tissue. In this inflamed tissue they form ectopic lymphoid aggregates similar to germinal centers (central factories for the generation of high affinity immunoglobulins against pathogens). Finally, these ectopic lymphoid aggregates become reservoirs of EBV latent cells generating a chronic infection with viral reactivations in these tissues. Moreover, being B cells, they have the capacity to present antigens. Therefore, those B cells and epithelial cells modified by EBV could present antigens from that tissue as foreign proteins and thus cause the development of autoimmune diseases. This occurs by presenting self-antigens on HLA-II molecules altered by gp42. Thus, depending on the tissue infiltrated by these cells with EBV latency, one type of autoimmune disease or another will be generated. For example, if they infiltrate the thyroid they could generate autoimmune thyroiditis, in the intestinal mucosa they could generate celiac disease, if they infiltrate the pancreatic islets they would generate type 1 diabetes, if they do so in the central nervous system they would generate multiple sclerosis, in the exocrine glands they would generate Sjögren's syndrome, in the thymus they would generate myasthenia gravis, in the synovial joints they would generate rheumatoid arthritis and so on with the rest of the tissues. In addition, if these latent cells are not controlled, cancer may develop after a few years. For this reason, patients with autoimmune diseases have a higher risk of developing them.


This model not only explains the development of the diseases described here, but also others, such as EBV-associated gastric carcinoma, in which the formation of these ectopic lymphoid structures in the gastric mucosa in response to Helicobacter pylori infection or another inflammatory process causes the infiltration of B cells with EBV latency in the lymphoid aggregates, and the subsequent infection of epithelial cells when expressing MHC-II, due to an increase in IFN-γ. Finally, the immune evasion microenvironment generated by these EBV-transformed cells and the clonal growth of EBV-latent epithelial cells would lead to the development of the disease. This model could even explain the involvement of EBV in the development of chronic fatigue syndrome or myalgic encephalomyelitis and Long COVID. Both diseases present similar EBV reactivations and chronic symptoms, which could suggest a common EBV immunopathology. In the case of Long COVID, inflammation caused by SARS-CoV2 infection of tissues would recruit B cells with EBV latency, where ectopic lymphoid aggregates could form and lead to viral reactivations. Likewise, it could also help us understand why EBV-associated autoimmune diseases, Long COVID and chronic fatigue syndrome/myalgic encephalomyelitis are more common in women. Estrogens, by increasing B-cell survival, would allow a greater permanence of these ectopic lymphoid aggregates with EBV latency in the inflamed tissues of patients with "ancestral" HLA-II alleles and, therefore, a chronification of symptoms.


Attached is the link to the manuscript with some treatment proposals:

https://www.mdpi.com/2076-0817/11/8/831


You can also read this other article to understand how EBV can develop Chronic Fatigue Syndrome or Myalgic Encephalomyelitis:

https://www.frontiersin.org/articles/10.3389/fimmu.2021.656797/full

You can enter in this twitter thread where I am answering your questions:

Best regards,
Manuel.
 

Violeta

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Thank you, Manuel, for your article and also for bringing it here.

Do you have any extended information about:

"The only difference between these patients and healthy people who have also had EBV without problems is that they have increased levels of IgGs (especially EBNA IgGs), indicating that there is an erroneous response against EBV,...( 9)"

"by having an elevated Th2 humoral response (favors the production of antibodies) instead of the Th1 cellular response (necessary to eliminate virus-infected cells) . (10)"

Thank you for taking the time to answer questions.
 

Violeta

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I had to look up ectopic lymphoid aggregates and found this:
Uses the word 'structures' instead of 'aggregates' but I assume they are the same thing.
I had seen something about viruses and lymphatics so this got my attention.

Ectopic lymphoid structures (ELS) often develop at sites of inflammation in target tissues of autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, myasthenia gravis, and systemic lupus erythematosus."

I guess you would want to break up the aggregates and help drain lymphatics.
 
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Violeta

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This is interesting about the ectopic lymphoid aggregates that Manuel mentions so often in his article.

"Ectopic (or tertiary) lymphoid structures (ELS) are organized aggregates of lymphocytes resembling secondary lymphoid organs and developing in chronically inflamed nonlymphoid tissues during persistent infections, graft rejection, autoimmune conditions, and cancer."

Can you picture that say in your knee if you have rheumatoid arthritis, or as he says in his article, on your thymus. I just don't know how you would clear them out.
 

CSMLSM

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ancestral HLA-II alleles susceptible to EBV
Excellent!
How may I get tested for this?

I myself am controlling my ME/CFS with a selective CB2 agonist and believe I am keeping down the EBV through the apoptosis of infected B cells.
Microlglia have been shown to be activated in an M1 state in ME/CFS. I also control this with CB2 activation in microglia as it makes them express the M2 state.
I use Caryophyllene from Copaiba essential oil.
It is amazing I am almost normal. Maybe you could do some research into it.
Here is some information on why I use Caryophyllene-

CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents - PubMed (nih.gov)
Taken from the abstract
In this study, we investigated the immunosuppressive properties of JWH-015, a synthetic CB2-selective agonist. We found that JWH-015 triggered apoptosis in thymocytes in vitro and inhibited the proliferative response of T and B cells to mitogens through induction of apoptosis. JWH-015 induced cross-talk between extrinsic and intrinsic pathways of apoptosis involving caspase-8, caspase-9, and caspase-3 as well as loss of mitochondrial membrane potential. Finally, administration of JWH-015 in vivo caused thymic atrophy, apoptosis, and decreased peripheral T cell response to mitogens. Together, this study suggests that CB2-selective agonists, devoid of psychotropic effect, may serve as novel anti-inflammatory/immunosuppressive agents.

The protective effects of β-caryophyllene on LPS-induced primary microglia M1/M2 imbalance: A mechanistic evaluation | Request PDF (researchgate.net)
Taken from the abstract
Scientific evidence propounds both of the neuromodulatory and immunomodulatory effects of CB2 in the immune system. β-Caryophyllene (BCP) is a dietary selective CB2 agonist, which deserves the anti-inflammatory and antioxidant effects at both low and high doses through activation of the CB2 receptor. Methods In this study, we investigated the protective effects of a broad range concentration of BCP against LPS-induced primary microglia cells inflammation and M1/M2 imbalance and identifying the portion of the involvement of related signaling pathways on BCP effects using pharmacological antagonists of CB2, PPAR-γ, and sphingomyelinase (SMase). Key findings The protective effects of BCP on LPS-induced microglia imbalance is provided by the M2 healing phenotype of microglia, releasing the anti-inflammatory (IL-10, Arg-1, and urea) and anti-oxidant (GSH) parameters and reducing the inflammatory (IL-1β, TNF-α, PGE2, iNOS and NO) and oxidative (ROS) biomarkers. Moreover, we showed that BCP exerts its effects through CB2 receptors which overproduction of ceramides by SMase at middle to higher concentrations of BCP reduce the protective activity of BCP and results in the activation of the PPAR-γ pathway. Significance In conclusion, the low concentration of BCP has higher selective anti-inflammatory effects rather than high levels. On this occasion, BCP by modulating the microglia is able to have potential therapeutic effects in neuro-inflammation conditions and microglia cells such as MS and AD.

Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells - PMC (nih.gov)
Taken from abstract
Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

Dr. Jarred Younger - Neuroinflammation in ME/CFS - YouTube


Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology | Journal of Translational Medicine | Full Text (biomedcentral.com)

Leptin modulates cell morphology and cytokine release in microglia - PubMed (nih.gov)

Leptin Activates the Anandamide Hydrolase Promoter in Human T Lymphocytes through STAT3 - ScienceDirect

Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB - PubMed (nih.gov)


Best regards,
Daniel
 

CSMLSM

Senior Member
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This is interesting about the ectopic lymphoid aggregates that Manuel mentions so often in his article.

"Ectopic (or tertiary) lymphoid structures (ELS) are organized aggregates of lymphocytes resembling secondary lymphoid organs and developing in chronically inflamed nonlymphoid tissues during persistent infections, graft rejection, autoimmune conditions, and cancer."

Can you picture that say in your knee if you have rheumatoid arthritis, or as he says in his article, on your thymus. I just don't know how you would clear them out.
With a CB2 agonist to cause apoptosis and enzymatically destroy everything inside the B cells including EBV is my hypothesis and appears to be working excellently in practice for me.
 

Violeta

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With a CB2 agonist to cause apoptosis and enzymatically destroy everything inside the B cells including EBV is my hypothesis and appears to be working excellently in practice for me.
Thank you for all the information. I can't calm my brain down to read it all right now, but I am very interested.

Which caryophyllene and copaiba essential oil do you use? Do you take the copaiba essential oil internally?