Good afternoon everyone,
I am enclosing below in summary the main points of our review and the questions that the model could answer about these diseases.
Many people wonder why EBV, the Epstein-Barr virus, and not another virus, is the main trigger of the symptomatic picture of ME/CFS and Long COVID, when there are other factors, such as different infections, metal intoxication, among others. In the following lines, I will explain the fundamentals of this phenomenon, summarizing the essential points of the review article we recently published.
The common denominator of all the triggering factors of both diseases is their capacity to immunosuppress. Any intracellular infection, whether bacterial, viral or parasitic, that is not controlled, leads to immunosuppression due to chronic exposure to antigens. Usually, the ability to control an infection is due to genetic factors, particularly the HLA genes (I and II). These genes encode proteins called human leukocyte antigen (HLA), which are essential for distinguishing self from non-self in our body. If this "alert" does not function properly, the immune system cannot efficiently eliminate pathogens. HLAs are like a scanner that allows us to identify things that are not from the body and respond to them. If this scanner is not working properly and does not recognize something that is bad, it would prevent your immune system from eliminating it and therefore prevent it from moving freely through your body without being eliminated.
In the context of ME/CFS, there are two possible scenarios: the individual may have a direct genetic predisposition to EBV, or they may lose control over EBV due to an underlying immune deficiency caused by another infection or exposure to chemicals or metals. If it is another infection, we would also be talking about a "genetic weakness" (HLA) to those specific pathogens.
If the individual is genetically susceptible to EBV, it is because he or she has old HLA-II haplotypes, to which EBV has co-evolved. This is mainly because EBV infects by binding to HLA-II proteins in cells. This virus is cunning: when it infects a cell, it introduces its DNA into it latently without generating new virions, avoiding detection by the immune system and using B cells as "Trojan horses".
While 95% of the world's population has EBV, only a minority develop problems. This is where the "weak" HLA-II haplotypes against EBV come into play again.
Although it is said that the majority of the population does not have problems with this virus, this is not entirely true. Think that this virus takes advantage of every time you become immunosuppressed for any reason. An example is its brother herpes labialis, that every time that person is immunosuppressed for any reason, it takes advantage and infects more cells, making the lesion visible on the lips. But every time the immune system recovers from the first event that immunosuppressed him, this virus is controlled again and the lesion disappears. This is exactly the same thing that happens in healthy people who are able to control EBV.
The main difference between these healthy people and ME/CFS patients who have problems with EBV, is that by having strong HLA-II haplotypes against EBV they are able to recognize all EBV latency types and control them. In contrast, patients with EBV ME/CFS, having weak haplotypes against EBV, their TCD4 cells are not able to recognize EBV latency I cells. The rest of the latency types are able to be recognized since they are controlled by TCD8 cells, as they would not have weak HLA-I haplotypes against EBV.
Let us explain this better. TCD4 cells recognize antigens presented on HLA-II proteins and TCD8 cells recognize antigens presented on HLA-I proteins. Normally, any intracellular infection is controlled by TCD8 cells because the infected cells present on the HLA-I proteins of their membrane the antigens of the pathogen inside. On the other hand, HLA-II proteins are found mostly on antigen-presenting cells that take antigens from outside the cell and present them on their HLA-II proteins so that they are recognized by T-CD4 cells. So, we would think that EBV, being an intracellular pathogen, its antigens should always be presented on the HLA-I proteins of the infected cell. This is not always the case; this virus has evolved to evade this system by generating latency. One of the evasion mechanisms to remain unrecognized is to prevent a latency antigen, called EBNA-1, from being presented on HLA-I proteins and from being presented on HLA-II proteins. This is of utmost importance for the virus because it prevents, for example, latency I cells (only expressing EBNA-1 from the virus) from being recognized by TCD8 cells. On the other hand, the rest of the latency cells (II and III) and lytic cells without would be recognized and eliminated by CD8 T cells. So we would think that no one would be able to control the latency I cells if they evade CD8 T cells. Here our immune system is also intelligent and this is where CD4 T cells play the differential role between healthy and sick people with this virus. The importance of HLA-II haplotypes reappears. Those individuals with EBV-resistant HLA-II haplotypes will be able to present the EBNA-1 antigen well on latency I cells and will be recognized and eliminated by TCD4 cells. In contrast, those with EBV-weak HLA-II haplotypes will not be able to present EBNA-1 well on HLA-II proteins and therefore CD4 T cells will not recognize the latency I cells. These latency I cells, when left unchecked, will multiply and cause inflammation and damage. But every time they go to another type of latency or lytic phase they will be recognized by CD8 T cells.
So what happens to those individuals who have been infected with other pathogens (such as Long COVID) and fail to control them? Well, in the end the same thing happens. Being genetically weak against these pathogens, they also end up presenting an immunodeficiency due to chronic exposure to antigens, decreasing the effective response of CD4 T cells. As these cells are the main cells that control EBV latency I, cells with latency I end up evading the immune system and multiplying, generating the same problems as in the case of EBV ME/CFS.
Therefore, in any subtype of patient with ME/CFS and in Long COVID, they end up presenting a viral syndrome due to EBV. Once EBV latency I cells are out of control, it allows any inflammatory stimulus in any tissue to recruit leukocytes (including EBV latency cells), ultimately leading to the formation of EBV-infected ectopic lymphoid aggregates.
These formations are "ectopic" because they are outside their usual location, i.e., they do not form in primary (such as thymus and bone marrow) or secondary (such as lymph nodes and spleen) lymphoid tissues. They form transiently to cope with infection or inflammation and disappear when the stimulus is resolved.
The B cells with EBV latency use these lymphoid aggregates to their advantage, since as there is antigen presentation in these structures, they take advantage of it to pass from latency to lytic phase, generating foci of viral reactivations in these inflamed tissues. This causes that, although the initial inflammatory stimulus that provoked the formation of these aggregates has been resolved, these aggregates remain continuously in these tissues due to another inflammatory stimulus due to the molecules released by the cells with latency, as well as the viral reactivations. This would occur mainly in the mucous membranes of our organism but can occur in different tissues and would be the basis for the development of autoimmune diseases.
These autoimmune diseases are generated due to the presentation of cellular autoantigens from those tissues or by the presentation of viral EBNA-1 through HLA-II proteins. The antigens when presented on HLA-II proteins undergo a series of modifications that can lead to the formation of new antigens "different" from the previous ones. In addition, EBNA-1 has a sequence similar to different proteins in our body, which can confuse our immune system and generate an autoimmune response. Here again appears the implication of having weak HLA-II haplotypes against EBV, since most of the diseases associated with this virus such as multiple sclerosis, lupus, rheumatoid arthritis, Sjรถgren's, etc. are associated with the same old HLA-II haplotypes as those weak against EBV. So having these autoimmune diseases implies that they do not control well these cells with EBV latency and therefore are responsible for the development of their autoimmunity.
Why do women have a higher prevalence of ME/CFS, Long COVID and autoimmune diseases?
Hormones play a crucial role. Estrogens, in particular, affect the CD4/CD8 T-cell ratio by reducing it, increase B-cell longevity, enhance antibody release and amplify the expression of HLA-II proteins. Under normal conditions, this increase in antibody levels in women enhances their resistance to viral infections. However, under pathological circumstances, this hormonal balance leads to a prolonged survival of B cells and a decrease in CD4 T cells, in addition to intensifying the expression of HLA-II. This situation leads to increased vulnerability to EBV due to increased survival of virus-transformed B cells and increased expression of HLA-II, which facilitates infection of a greater number of cells. In addition, elevated HLA-II expression can lead to a more robust presentation of cellular autoantigens or viral antigens that, after undergoing post-translational changes, generate neoantigens. These can activate autoreactive cells. Therefore, both the increased survival of transformed B cells and the increased antigenic presentation generated by the increased expression of HLA-II by estradiol may favor an increase in the presentation of both self and foreign antigens during an infectious process, and those abnormal plasma cells that produce autoantibodies survive longer, which consequently increases the likelihood of women developing autoimmune diseases or even cancer.
On the male side, testosterone modulates the immune system by promoting CD4 Th1 (antiviral) response and CD8 T-cell activation, while inhibiting NK cell response and HLA-II expression. Since antigen-presenting cells are essential for the differentiation of CD4 T cells toward Th1 or Th2, based on the cytokines they release, sex hormones may influence this differentiation. Women, having higher levels of antibodies (Th2 response), show a more efficient response to extracellular infections. However, against intracellular pathogens, their immune system may not be as efficient as the male immune system, which benefits from a stronger Th1 cellular response to fight virus-infected cells.
Does this model explain the overactive yet ineffective immune response?
Yes, this model describes a situation in which the body's immune system is working excessively, but inefficiently, against the EBV virus:
1. Deficient adaptive response: CD4 T cells, are not correctly recognizing and dealing with EBV latency I cells. This leads to more infected cells circulating and, at the same time, to a fatigue or exhaustion of the T cells, reducing their ability to fight the virus.
2. Over-activation of innate immunity: Because of this failure of the adaptive response, another part of the immune system, called innate immunity, becomes over-activated because it continually detects that there is an infection but that it cannot be resolved by adaptive immunity. This results in the constant production of inflammatory substances that, instead of helping, can generate more problems and maintain chronic inflammation.
3. Imbalance in immune responses: The body tends to favor an immune response (known as Th2) that is not best suited to fight this type of infection. This is due in part to the production of a substance called IL-6, which redirects the body's defensive response towards the production of antibodies instead of an antiviral cellular response (Th1). The increased Th2 response favors the latency and lytic cycles of EBV by activating more B cells.
Does this model explain viral reactivations and that of other latent pathogens?
Yes, the model explains that, due to decreased activation and function of cytotoxic CD4 T cells, there is a loss of immune surveillance over latent infections of other pathogens. These CD4 T cells are necessary to control latent or lytic phase cells of pathogens such as Parvovirus B19, EBV, cytomegalovirus and other herpesviruses. As a result, increased viral reactivation will be observed, especially in individuals with a higher degree of immunodeficiency.
Does this model explain how there could be increased metal intoxication in these patients?
If there is increased expression of MTs due to elevated intracellular zinc levels, as described in the model, those MTs will be busy binding and regulating zinc and, potentially, copper. As a result, there would be fewer MTs available to bind and detoxify heavy metals that may be present. This could lead to an accumulation of unregulated and potentially toxic heavy metals (such as cadmium and mercury) in the body.
Does this model explain the increased oxidative stress in these diseases?
Yes, the model explains the increased oxidative stress. Infected ectopic lymphoid structures trigger inflammatory responses by releasing certain viral components. This activation induces the release of proinflammatory cytokines, which, in turn, promote excessive production of reactive oxygen species, leading to marked oxidative stress. In addition, perturbation in the homeostasis of certain metals contributes to the disruption of intracellular antioxidant responses. Specifically, there is evidence that an antioxidant enzyme (superoxide dismutase) is affected by altered copper and zinc concentration. Briefly, the model describes how the combination of chronic inflammatory responses, together with imbalances in the homeostasis of certain metals and the persistent release of proinflammatory agents, culminates in a significant increase in oxidative and nitrosative stress in the body.
Does this model explain exercise intolerance and post-exertional malaise?
Yes, this model explains exercise intolerance and post-exertional distress in the context of persistent EBV infection and its metabolic, immunological and neurophysiological interactions. The following is a breakdown of how the model addresses this phenomenon:
1. Metabolic alterations: the model describes how EBV infection can lead to insulin resistance through elevated IFN-ฮณ production. This resistance, accompanied by compensatory hyperinsulinemia, can lead to transient hypoglycemia and decreased peripheral tissue metabolism. These factors contribute to exercise intolerance, as muscles are unable to obtain the necessary energy efficiently, resulting in early fatigue.
2. Alterations in cardiovascular function: High levels of serotonin and activation of certain receptors, such as TLR3 and TLR2, can alter cardiovascular function, affecting blood distribution and the body's ability to meet oxygen demands during exercise.
3. Compromised thermoregulation: The body's ability to dissipate heat generated during exercise may be impaired, which could lead to overheating.
4. Oxidative stress: Chronic infection with EBV generates constant oxidative stress, which can impair mitochondrial function and reduce the ability of muscle tissue to generate energy efficiently. This oxidative stress exacerbated during exercise can lead to cell damage and muscle fatigue.
5. Alterations in respiratory function: Respiratory function may be impaired, limiting adequate oxygenation during exercise and contributing to fatigue.
6. Systemic inflammation: Activation of certain receptors, release of proinflammatory cytokines and other mechanisms associated with chronic infection can generate systemic inflammation. This inflammation can negatively affect the body's ability to recover after exercise, contributing to post-exertional malaise.
7. Alterations in neurological function: Metabolic changes and systemic inflammation can have an impact on the central nervous system. Reduced serotonin availability and other alterations may contribute to feelings of fatigue and lethargy.
Does this model explain the dysautonomia present in these patients?
Yes, here is a breakdown of how the model can generate dysautonomia:
1. EBV infection: the inability to adequately control EBV latency I cells could result in chronic inflammatory responses, which disrupts immune system homeostasis and, by extension, affects the autonomic nervous system (ANS).
2. Inflammatory responses: proinflammatory cytokines released in response to EBV, such as IL-1ฮฒ, IL-6 and TNF-ฮฑ, can act on the brain and other organs, disrupting ANS function, leading to symptoms of dysautonomia.
3. Metabolic alterations: Hypozincemia and alterations in copper transport can imbalance the function of key enzymes, such as DAO. Impaired DAO function leads to an accumulation of histamine, a mediator that can cause symptoms of dysautonomia, such as vasodilatation and arrhythmias.
4. Gastrointestinal disturbances: Serotonin accumulation in the gut can stimulate the vagus nerve, a primary connection between the gut and the brain. Overstimulation of the vagus nerve can trigger symptoms of dysautonomia, such as bradycardia.
5. Neurological alterations: A decrease in brain extracellular serotonin and an increase in neurotoxic metabolites of kynurenine may alter neuronal and ANS function, which could manifest as fatigue, exercise intolerance and other symptoms of dysautonomia.
6. Vascular alterations: Microclot formation can affect adequate blood perfusion in organs and tissues, including the brain. Inadequate perfusion can result in neurological and autonomic symptoms.
7. Endocrine disturbances: Hyperinsulinemia and possible reduction in cortisol secretion may affect the balance of the ANS. For example, hypoglycemia may trigger an acute sympathetic response, while decreased cortisol may affect the body's ability to handle stress.
Does this model explain neuroinflammation, mental fog and cognitive impairment?
Yes, this presented model could explain neuroinflammation, mental fog and cognitive impairment as follows:
1. Neuroinflammation: In patients with ME/CFS and LC, there is evidence of chronic viral infection or virus reactivation, especially EBV. When viral genetic material is present, especially EBV EBERs, TLR3 receptors in microglia (immune cells of the central nervous system) are activated. This activation results in the release of proinflammatory cytokines such as IL-1ฮฒ and TNF-ฮฑ. These cytokines may contribute to chronic inflammation of the central nervous system, characterizing neuroinflammation.
2. Mental fog and cognitive impairment: several pathways mentioned in the model may contribute to these symptoms. For example:
- Viral infection can cause damage to the blood-brain barrier, allowing entry of viral genetic material that could further activate microglia and contribute to neuroinflammation.
- Increased IDO activity and decreased tryptophan levels lead to a reduction in serotonin (5-HT) and melatonin synthesis. Since serotonin plays a role in the regulation of mood, cognition and alertness, its reduction could contribute to mental fog.
- Quinolinic acid, a metabolite of tryptophan, has neurotoxic properties by binding to the NMDA receptor, which may increase nitrosative stress and contribute to cognitive impairment.
- Increased oxidative and nitrosative stress in EBV-infected cells, together with neuroinflammation, may interfere with proper neuronal functioning and contribute to cognitive impairment.
- Alterations in the serotonergic system may also directly affect cognitive function and perception of fatigue.
Does this model explain the occurrence of digestive problems, food intolerances and alterations in the microbiota in these patients?
Yes, I will summarize the key points below:
1. Digestive problems:
- The accumulation of 5-HT (serotonin) in the intestinal mucosa causes chronic inflammation.
- This intestinal inflammation leads to a decrease in stomach acid secretion and in the expression of enzymes needed to digest carbohydrates. As a result, more carbohydrates reach the intestinal microbiota without being digested or absorbed, which can cause digestive problems such as bloating, gas and diarrhea.
- The serotonergic alteration, together with the increase in proinflammatory cytokines, causes an alteration in acid secretion, breakdown of the intestinal barrier and decreased expression of enzymes needed to digest carbohydrates.
2. Food intolerances:
- Dysfunction of adaptive immunity, combined with increased nutrient input for commensal bacteria and decreased acid secretion, leads to bacterial proliferation, resulting in small intestinal bacterial overgrowth (SIBO) and the development of food intolerances.
- Alterations in the intestinal barrier allow substances and microorganisms that should not normally cross it to do so, further activating innate immunity and leading to increased accumulation of 5-HT, which aggravates symptoms.
3. Alterations in the microbiota:
- The disruption of tight junctions between enterocytes, caused by increased proinflammatory cytokines, leads to increased intestinal permeability. As a result, bacteria and substances that should not cross the barrier do so, which alters the microbiota and leads to increased activation of the innate immune system.
- SIBO has other consequences, such as bacterial deconjugation of bile salts, leading to poor micelle formation and fat malabsorption, as well as deficiencies in fat-soluble vitamins (A, D, E, and K). In addition, competitive absorption of vitamin B12 by bacteria results in less binding to intrinsic factor and, therefore, less absorption in the terminal ileum.
Does this model explain the metabolic alterations and mitochondrial dysfunction present in these patients?
Yes, let's see how:
1. Metabolic alterations:
- EBV infection, especially in individuals with "weak" HLA-II haplotypes, leads to immune evasion, which promotes inflammatory responses in the body. This inflammation can affect various metabolic pathways.
- Increased release of proinflammatory cytokines, such as IL-1ฮฒ, IL-6, IL-8, IL-12, TNF-ฮฑ, and IFN-ฮณ, has metabolic consequences. These cytokines can alter the balance of certain minerals such as zinc and copper, which can disrupt several essential enzymatic functions.
- Insulin resistance induced by elevated levels of IFN-ฮณ affects glucose metabolism. To compensate, the pancreas produces more insulin, leading to hyperinsulinemia, which has various consequences, including an effect on hepatic glycogen metabolism.
2. Mitochondrial dysfunction:
- Serotonergic disturbances caused by infections can affect mitochondrial function. Serotonin depletion in the central nervous system (CNS) plays a role in the regulation of appetite and energy metabolism.
- Constant activation of the anaerobic glycolytic pathway, either due to the Warburg effect in infected cells or due to mitochondrial dysfunction, results in elevated lactic acid production.
- The generation of quinolinic, a metabolite of tryptophan, may be neurotoxic and contribute to nitrosative stress, which may further impair mitochondrial function.
- Overstimulation of NMDA receptors, whether by quinolinic acid or other pathways, can lead to increased nitric oxide/peroxynitrite levels, which has direct consequences on mitochondrial function and health.
3. Global consequences:
- Energy depletion, as a result of metabolic alterations and mitochondrial dysfunction, can manifest as chronic fatigue and other associated symptoms.
- Alterations in the serotonergic system, along with metabolic imbalances and chronic inflammation, may contribute to neurological symptoms, including fatigue and depression.
Does this model explain the formation of microclot formation?
Yes, the following are the key points of this process according to the model:
1. Proinflammatory cytokines and hypercoagulation:
- Overproduction of proinflammatory cytokines, such as TNFฮฑ, IL-6 and IL-1ฮฒ during infectious processes, leads to hypercoagulation, platelet activation, leukocyte infiltration and vascular hyperpermeability.
2. Platelet activation:
- Platelets, when activated through 5-HT2A receptors due to increased 5-HT in peripheral blood or by binding of EBERs to TLR3, bind fibrinogen, which enhances aggregation and coagulation processes.
- Activated platelets can release ฮฒ-amyloid (Aฮฒ) peptide, which, interacting with fibrinogen, causes fibrinogen oligomerization, fibrin deposition and Aฮฒ fibrillation, favoring the formation of abnormal microclots resistant to degradation by fibrinolytic enzymes.
3. Amyloidogenesis and fibrinogenesis:
- Elevated levels of IL-1ฮฒ, IL-6 and TNF-ฮฑ stimulate the production of serum amyloid A (SAA) protein in hepatocytes.
- Increased SAA in the blood may favor its interaction with fibrinogen, leading to amyloidogenic changes in fibrinogen, resulting in the formation of fibrin amyloid microaggregates resistant to fibrinolysis.
4. Capillary obstruction and endothelial damage:
- The formation of these micro-clots leads to capillary obstruction, which compromises blood flow and increases inflammation, contributing to the appearance of various symptoms.
- In addition, endothelial damage caused by EBV infection, either through positive activation of NOX2 by EBNA-1 in EBV-transformed endothelial cells or through activation of TLR3 by EBERs, may influence microclot formation. NOX2 activation may cause vasoconstriction and thrombosis through platelet aggregation via overproduction of hydrogen peroxide, isoprostanes, or inactivation of nitric oxide.
Does this model explain the alteration in cortisol levels?
Yes. The following are the key points of this process according to the model:
1. Initial stimulus:
- Under acute conditions, proinflammatory cytokines such as IFN-ฮณ, TNFฮฑ, IL-1 and IL-6 stimulate the hypothalamic-pituitary-adrenal (HPA) axis by activating ACTH secretion. IFN-ฮณ, for example, not only activates macrophages, but also allows an increase in glucocorticoid receptor expression for subsequent feedback inhibition. So that the inflammatory response is not exaggerated, there is a stimulation in cortisol secretion due to the increase in ACTH, which results from the action of IFN-ฮณ and the direct stimulation of the adrenal gland by IL-6.
2. Suppression of cortisol secretion during persistent infections:
- During persistent infections, chronic exposure to IL-10, TGF-ฮฒ1 and TNFฮฑ could suppress ACTH-stimulated cortisol secretion in the adrenal gland, leading to relative hypocortisolism.
- The anti-inflammatory and immunosuppressive cytokines, IL-10 and TGF-ฮฒ1, are elevated in EBV infections. These cytokines are secreted by EBV latent cells and regulatory T cells to counteract proinflammatory cytokines and evade CD4 T cells. Therefore, the greater the number of EBV reservoir-infected tissues, the greater the secretion of these anti-inflammatory cytokines and thus the greater the negative feedback on cortisol secretion.
3. Possible infection in the adrenal or pituitary glands:
- Disease progression and acquired immunodeficiency in CD4 T-cell function may lead to an increase in the replicative rate of the virus and infection in the adrenal or pituitary glands, depleting cortisol stores.
4. Impact of chronic insulinism:
- Chronic high insulin may also play a role in the development of hypocortisolism, as insulin may inhibit the secretion of corticotropin-releasing hormone in the hypothalamus, which in turn would inhibit ACTH secretion in the pituitary gland.
๐๐๐ ๐๐๐๐๐๐๐ ๐๐๐๐๐๐๐๐๐!
๐๐๐ ๐๐ฌ ๐ ๐ฅ๐ข๐ง๐ค: This review article suggests that EBV may be a catalyst, inducing similar symptoms in Long COVID and Myalgic Encephalomyelitis, and orchestrating far-reaching immune challenges.
๐๐ฆ๐ฆ๐ฎ๐ง๐จ๐๐๐๐ข๐๐ข๐๐ง๐๐ฒ ๐๐ง๐ ๐๐๐ญ๐จ๐ฉ๐ข๐ ๐๐ฒ๐ฆ๐ฉ๐ก๐จ๐ข๐ ๐๐ ๐ ๐ซ๐๐ ๐๐ญ๐๐ฌ: One of the most intriguing and alarming findings regarding EBV is its ability to induce the formation of structures called ectopic lymphoid aggregates in tissues. These structures are not benign; in fact, they can be potent instigators of inflammatory responses that disrupt normal tissue function. Why does this occur? This review suggests that in individuals with certain genetic characteristics - specifically those with "weak" HLA-II haplotypes against EBV - this virus can become more easily established, leading to the formation of these aggregates. Most worryingly, these aggregates not only cause inflammation, but may also contribute to a form of acquired immunodeficiency, further weakening the body's defenses and even developing autoimmune diseases.
๐๐จ๐ง๐ฌ๐๐ช๐ฎ๐๐ง๐๐๐ฌ:
๐๐๐ฑ ๐๐ข๐๐๐๐ซ๐๐ง๐๐๐ฌ: The role of gender differences is critical in affecting EBV interaction and symptom manifestation. Biological sex may influence the interaction with EBV. Estrogens in women increase B-cell survival and antibody release, but may also amplify risks with EBV, potentially promoting autoimmune conditions.
๐๐ซ๐๐๐ญ๐ฆ๐๐ง๐ญ๐ฌ ๐ญ๐ก๐๐ญ ๐๐จ๐ฎ๐ฅ๐ ๐ข๐ฆ๐ฉ๐ซ๐จ๐ฏ๐ ๐จ๐ซ ๐ฐ๐จ๐ซ๐ฌ๐๐ง ๐ฌ๐ฒ๐ฆ๐ฉ๐ญ๐จ๐ฆ๐ฌ:
๐๐ฐ๐ข๐ญ๐ญ๐๐ซ ๐ญ๐ก๐ซ๐๐๐ ๐๐๐ฌ๐๐ซ๐ข๐๐ข๐ง๐ ๐ฆ๐จ๐ซ๐ ๐๐๐ญ๐๐ข๐ฅ๐ฌ ๐จ๐ ๐ญ๐ก๐ ๐๐ซ๐ญ๐ข๐๐ฅ๐: https://x.com/manruipa/status/1703705886286344336?s=20 
If you find this information of value, I invite you to spread this post and the article to your contacts - together we can make this valuable information reach more people!
