Hi,
@Moof . Thank you very much for your help.
Translating everything and checking it out, it's going to take me a long time. I was even thinking of paying a medical translation company to do it. I don't know what I'll do in the end.
Meanwhile, I've translated the discussion of the article with a translator. I hope it's understood.
DISCUSSION
Chronic fatigue syndrome or myalgic encephalomyelitis (ME/CFS) is currently a disease of unknown etiology, which appears suddenly in a previously active person and whose onset appears to be related to an acute infection in most cases. Until now, CFS patients have been studied without classification into pathogen subgroups. The aim of this study is to show how the viral cycle of the Epstein-Barr virus and its mechanism of immune evasion can generate CFS and what the metabolic and physiological consequences are that could be responsible for the symptoms of chronic fatigue.
The EBV expresses at least 44 miRNAs, most of them with unknown function, and two non-coding RNAs (EBERs). EBV-coded miRNAs control the expression of various cellular genes with antiapoptotic functions, but also interfere with innate immune responses and inflammation. Some EBV miRNAs act by suppressing, in infected B lymphocytes, the release of pro-inflammatory cytokines such as IL-12, which resulted in suppression of differentiation of CD4 naive + T-cells to Th1 cells (important antiviral effectors that activate macrophages and NK lymphocytes to kill intracellular pathogens).
Several EBV miRNAs modulate the immune recognition of newly infected B cells (preferably EBV target cells). Viral miRNAs, in infected B cells, control the gene expression of HLA class II and three lysosomal enzymes important for proteolysis and epitope presentation to CD4+ T cells. This allows them to interfere with peptide processing and class II HLA antigenic presentation. As a result of the decrease in HLA II antigenic presentation, the activation of EBV-specific cytotoxic effector CD4+ T cells and the death of infected B cells is reduced.
Also, to avoid detection of EBV-specific CD4 T cells, EBV latent membrane protein 2A (LMP2A) was found to play a critical role in the negative regulation of the expression of class II MHC molecules in infected B cells. Functionally, LMP2A mimics constitutively activated BCR signaling; however, the LMP2A-activated PI3K pathway mediates suppression of HCM class II and CD74 in EBV-infected B cells. Previous studies have revealed that CIITA is a major regulator of the expression of MHC class II and CD74 molecules. They demonstrated that LMP2A mediated the reduction of IUPAC levels by decreasing the expression of PU.1 and E47.
EBV-infected B-lymphocytes generate an IL-10 homologue (vIL-10), encoded by the EBV BCRF1 gene during the prelatent and latent phases.9,17 vIL-10 can act on multiple cell types and inhibit cytokine synthesis in T cells (inhibits production of IL-2 and IFN-g by Th1 cells) and NK.19 cells. This allows the antiviral functions of effector CD4+ T-cells to be suppressed and the NK-cell-mediated death of infected B-cells to be reduced.21 It is also a potent inhibitor of antigenic presentation, reducing the expression of MHC II and the accessory co-stimulation molecules CD80 and CD86 in dendritic cells.
Other miRNAs interfere with the recognition and destruction of EBV-infected cells by CD8+ T cells. First, miRNAs directly target TAP2, negatively regulate the entire TAP complex, and reduce HLA class I allotypes that preferentially have TAP-dependent epitopes. Second, they repress EBNA1, a protein expressed in most forms of EBV latency and a target of EBV-specific CD8+ T-cells. Third, miRNAs decrease the release of IL-12 by infected B cells, as IL12B is directly suppressed by these miRNAs in infected cells. This repression of IL12B not only can reduce the differentiation of CD4+ T-cells, it can also regulate the functions of effector T-cells, decreasing the activity of CD8+ T-cells specific to EBV.
EBV can infect the CNS through HBMEC infection. This leads to the rupture of the adhesion molecules or narrow BHE bonds, leading to the passage of leukocytes (including EBV-infected B cells) through the capillaries into the surrounding tissue.30 B cells with EBV latent infection are able to release EBERs (two non-coding RNAs). Where the release of EBER1 induces the activation of TLR3 signaling resulting in an increase in proinflammatory cytokines (inflammation is generated in the tissue).
As with EBV infection of HBMEC, infection of epithelial cells of the intestinal mucosa by EBV leads to the breakdown of the narrow junctions of the intestinal barrier, leading to the passage of bacteria and other substances. At the same time, EBV is able to infect plasma cells in the mucosa. Therefore, B cells with latent EBV infection release EBERs. EBER1 activates TLR3 signaling of enterocytes, resulting in the induction of type I IFNs and proinflammatory cytokines. This activation of TLR3 at the intestinal level reduces the activity of the serotonin transporter (SERT) in enterocytes, thus reducing serotonin uptake and causing an increase of extracellular 5-HT in this tissue. This excess serotonin should be collected and transported by platelets, as platelets get 5-HT mainly from the intestine. But the platelets do not get to collect all this excess, as they also express TLR3 as enterocytes. When these receptors are activated by the infection, the serotonin reuptake of these cells decreases. This eventually allows for a buildup of serotonin in the intestinal mucosa. Platelets activated via TLR3 also excrete the content of their granules (dense granules contain serotonin). The serotonin released by platelets would increase vascular permeability and may promote inflammation in tissues where EBV-infected cells are present. All this results in a decrease of 5-HT levels in platelets.
Add that in fasting conditions the 5-HT plasma levels of these patients are the same as those of healthy patients. This occurs thanks to alternative transports that remove free serotonin from the portal blood (prevents excess 5-HT at the intestinal level from reaching the systemic circulation). But in postprandial conditions by further stimulating the release of serotonin (especially with carbohydrate consumption), transport systems are saturated, thus increasing the levels of free 5-HT in plasma, as has been seen in patients with IBS-D, along with an increase in plasma levels of their 5-HIAA metabolite compared to healthy subjects.
In addition, by breaking down the narrow junctions of the intestinal barrier, bacteria and other harmful substances can pass from the lumen into the bloodstream, activating TLR4, which also decreases SERT activity. Activation of the various serotonin receptors would lead to increased intestinal motility, malabsorption problems along with vitamin deficiencies (vitamin A, E, D, K and B12), diarrhea, dysautonomia by communication of the vagus nerve between the enteric and cardiovascular systems, significant increase in wakefulness and a reduction in slow wave sleep along with cognitive problems. In addition to problems with temperature regulation and hormone secretion.
It should be noted that the environmental factor (EBV infection) not only influences the onset of CFS, but also the age at which the primary infection occurs and the genetic susceptibility to this infection. That is, patients with genes from MHC class I and II molecules that are susceptible to developing EBV-related diseases will have difficulty fighting EBV infection. As most of these diseases have numerous polymorphisms of these susceptibility genes, there is a great genetic heterogeneity among patients who develop one of these diseases, which is manifested as a great phenotypic variability among different patients suffering from the same disease. This is because in all vertebrate species the MHC molecules are highly polymorphic. This polymorphism reflects an immune system strategy to prevent the evasion of immune system pathogens. Having different MHC molecules, individuals deal with microbes in a different way, with individuals in a given population being more susceptible and more resistant to a given disease.
For future research, it would be interesting to start classifying patients into subgroups according to the possible pathogens involved based on understanding and focusing on a possible treatment. Rituximab is currently being studied for this disease and the explanation of why it works in some patients and not in others may be due to the type of pathogen involved. On the other hand, common markers must be found based on a diagnosis of the disease. At the metabolic level, it behaves in a similar way to cancer, all the antioxidants (vitamin C, Q10, E....) are reduced to compensate for the high oxidative stress and the appearance of cachexia and constitutional syndrome is common due to the high energy consumption caused by the Warburg effect. In more advanced disease there may be a decrease in the levels of glutamine, cysteine along with high production of urea and glutamate, this could be a marker of severity and a key point to consider based on supplementing them before implementing any therapy. It should be noted that the role of NK is key to viral infection and therefore key to CFS. Above all, it is essential to evaluate which pathogen is involved in the clinical picture, how it circumvents the immune system and therapeutic strategies to reverse the process and return the system to its initial state. For example, in this case Epstein Barr infection, rituximab could be crucial, since the virus acts by generating latency mainly in B cells. So if the infected B-lymphocytes were lysed, we would reduce the Warburg effect and consequently the chronic fatigue, as well as the immunological problems (there would no longer be a deficit of expression of class II molecules of the MHC). But rituximab treatment may have to be given with antivirals, because by immunosuppressing the patient the EBV could reactivate and continue to infect. There is now a more promising treatment without significant adverse effects, Epstein-Barr virus-specific adoptive immunotherapy. Where the death of EBV-infected B cells is achieved by adoptively transferred CD8+ T cells. This treatment has had promising preliminary results in progressive multiple sclerosis due to EBV, with improvements in the patient's symptoms and signs.
For all these reasons, several markers are proposed to be used in patients with CFS post-infection with EBV:
1. Activated T lymphocytes (CD3+, DR+), (CD4+, DR+): A low level of activated T lymphocytes indirectly indicates a decrease in HLA-II antigenic presentation. This decrease in CD4+ DR+ T-lymphocytes can be seen in other EBV-related diseases, such as children with EBV-associated hemophagocytic lymphohistiocytosis.
2. To verify in laboratory the decrease of the antigenic presentation HLA-II on the part of the antigen-presenting cells.
3. Molecular typing of the HLA system: to verify the existence of certain HLA alleles with a predisposition to develop EBV-related diseases.
4. IgG antibodies to nuclear antigen (antiEBNA IgG): presence of a high number, as in multiple sclerosis.
Tests 1 and 2 should be present in most patients with CFS, as other pathogens also evade the immune system in this way. These pathogens are able to generate an acquired functional immunodeficiency through the deficit of expression of class II molecules of the major histocompatibility complex. Although some also manage to decrease the class I molecules of the MHC, as has been mentioned in this article.