Que el 90-95% tenga el EBV no implica estrictamente que hayan desarrollado patologías asociadas al EBV tras años de la infección y estando “sanos” ese periodo (que también ocurre). Significa principalmente que cierta población con predisposición genética (HLA-II) desarrollan patologías asociadas al EBV justo tras la infección de la cual no se recuperan. Estos también se incluyen dentro de ese 90% porque presentan la infección. Luego tienes que añadir aquellos pacientes que “controlaban” bien la infección latente pero por cualquier motivo se inmunodeprimen. Por ejemplo, cuando se llega a la vejez aumenta la senescencia inmune provocando que se dejen de controlar patógenos latentes como el EBV y dando lugar a enfermedades asociadas a este virus, como carcinomas y linfomas. O cualquier otra infección por otro patógeno que provoque inmunosupresión o agotamiento inmunológico, llevará también al desarrollo de enfermedades asociadas al EBV porque no pueden controlarlo. Por ejemplo, los pacientes con SIDA también desarrollan enfermedades asociadas al EBV por la ineficacia en el control del virus. O pacientes a los que se les está realizando un transplante de órganos y están inmunodeprimidos. Y todos ellos también se incluyen por tanto en ese 90-95% de personas que tienen el EBV.

El aumento de casos de cáncer en jóvenes en los últimos años está directamente relacionado con el incremento de infecciones, y hay razones científicas para poder afirmarlo. Lo primero que hay que entender es que estamos viendo un incremento de cáncer respecto a años anteriores, y en ese mismo período también ha aumentado la tasa de infecciones. Antes, las infecciones respiratorias eran más estacionales, con mayor incidencia en invierno, pero en los últimos años hemos visto brotes constantes de diferentes cepas de SARS-CoV-2 y otras infecciones virales a lo largo de todo el año. El problema es que la exposición repetida a infecciones genera agotamiento inmunológico, un fenómeno en el que el sistema inmune pierde eficacia para responder a nuevas agresiones. Un mecanismo clave en esto es el aumento de PD-L1 en linfocitos T, lo que impide que el sistema inmune controle adecuadamente infecciones y células anormales. Esto permite que patógenos latentes, como los herpesvirus oncogénicos (por ejemplo, el virus de Epstein-Barr o el HHV-8), se reactiven y contribuyan al desarrollo de cáncer. ¿Por qué afecta más a los jóvenes? Porque son la población con mayor movilidad y contacto social, lo que los expone a infecciones recurrentes con más frecuencia que otros grupos de edad. Este contexto de infecciones persistentes, inflamación crónica y agotamiento inmunológico crea un entorno ideal para el desarrollo de neoplasias. Por eso, pensar que la causa principal es la contaminación o la alimentación o el estrés no tiene tanto sentido. La polución lleva décadas en niveles similares, y la alimentación, aunque mala, no ha cambiado radicalmente en los últimos años como para explicar este incremento específico. En cambio, lo que sí ha cambiado en este período es el aumento de infecciones frecuentes y prolongadas, lo que refuerza la relación entre infecciones y cáncer en jóvenes. Por ejemplo, tienes ejemplos recientes de pacientes con COVID persistente que han desarrollado cáncer. Puede preguntar en las asociaciones de pacientes si quiere.

Igual os suena:

🦠 🔍 𝐃𝐢𝐝 𝐲𝐨𝐮 𝐤𝐧𝐨𝐰 𝐭𝐡𝐚𝐭 𝐄𝐬𝐩𝐭𝐞𝐢𝐧-𝐁𝐚𝐫𝐫 𝐯𝐢𝐫𝐮𝐬 𝐜𝐨𝐮𝐥𝐝 𝐛𝐞 𝐚 𝐭𝐫𝐢𝐠𝐠𝐞𝐫 𝐟𝐨𝐫 𝐬𝐲𝐦𝐩𝐭𝐨𝐦𝐬 𝐢𝐧 𝐌𝐄/𝐂𝐅𝐒 𝐚𝐧𝐝 𝐋𝐨𝐧𝐠 𝐂𝐎𝐕𝐈𝐃? A thread 🧵 Below, I summarize the points of our recent published review and how it could explain the development of 𝐝𝐲𝐬𝐚𝐮𝐭𝐨𝐧𝐨𝐦𝐢𝐚, 𝐦𝐢𝐜𝐫𝐨𝐜𝐥𝐨𝐭𝐬, 𝐚𝐮𝐭𝐨𝐢𝐦𝐦𝐮𝐧𝐞 𝐝𝐢𝐬𝐞𝐚𝐬𝐞𝐬, 𝐞𝐱𝐞𝐫𝐜𝐢𝐬𝐞 𝐢𝐧𝐭𝐨𝐥𝐞𝐫𝐚𝐧𝐜𝐞, 𝐦𝐢𝐭𝐨𝐜𝐡𝐨𝐧𝐝𝐫𝐢𝐚𝐥 𝐝𝐲𝐬𝐟𝐮𝐧𝐜𝐭𝐢𝐨𝐧, 𝐡𝐲𝐩𝐨𝐜𝐨𝐫𝐭𝐢𝐬𝐨𝐥𝐢𝐬𝐦 𝐚𝐧𝐝 𝐦𝐨𝐫𝐞 𝐜𝐨𝐧𝐬𝐞𝐪𝐮𝐞𝐧𝐜𝐞𝐬. Share with other patients so they can understand their illness. 𝐊𝐧𝐨𝐰𝐥𝐞𝐝𝐠𝐞 𝐢𝐬 𝐩𝐨𝐰𝐞𝐫! 📚 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, Sjögren'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: 1️⃣ 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. 2️⃣ 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. 3️⃣ 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: 1️⃣ 𝐌𝐞𝐭𝐚𝐛𝐨𝐥𝐢𝐜 𝐚𝐥𝐭𝐞𝐫𝐚𝐭𝐢𝐨𝐧𝐬: the model describes how EBV infection can lead to insulin resistance through elevated IFN-γ 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. 2️⃣ 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. 3️⃣ 𝐂𝐨𝐦𝐩𝐫𝐨𝐦𝐢𝐬𝐞𝐝 𝐭𝐡𝐞𝐫𝐦𝐨𝐫𝐞𝐠𝐮𝐥𝐚𝐭𝐢𝐨𝐧: The body's ability to dissipate heat generated during exercise may be impaired, which could lead to overheating. 4️⃣ 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. 5️⃣ 𝐀𝐥𝐭𝐞𝐫𝐚𝐭𝐢𝐨𝐧𝐬 𝐢𝐧 𝐫𝐞𝐬𝐩𝐢𝐫𝐚𝐭𝐨𝐫𝐲 𝐟𝐮𝐧𝐜𝐭𝐢𝐨𝐧: Respiratory function may be impaired, limiting adequate oxygenation during exercise and contributing to fatigue. 6️⃣ 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. 7️⃣ 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: 1️⃣ 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). 2️⃣ 𝐈𝐧𝐟𝐥𝐚𝐦𝐦𝐚𝐭𝐨𝐫𝐲 𝐫𝐞𝐬𝐩𝐨𝐧𝐬𝐞𝐬: proinflammatory cytokines released in response to EBV, such as IL-1β, IL-6 and TNF-α, can act on the brain and other organs, disrupting ANS function, leading to symptoms of dysautonomia. 3️⃣ 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. 4️⃣ 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. 5️⃣ 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. 6️⃣ 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. 7️⃣ 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: 1️⃣ 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-1β and TNF-α. These cytokines may contribute to chronic inflammation of the central nervous system, characterizing neuroinflammation. 2️⃣ 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. 𝐋𝐢𝐧𝐤: 𝐂𝐨𝐧𝐭𝐢𝐧𝐮𝐞 𝐭𝐡𝐞 𝐭𝐡𝐫𝐞𝐚𝐝 🧵👇🏽 #EpsteinBarrVirus #EBV #LongCovid #MECFS #MyalgicEncephalomyelitis #Health #Research #News #microE2324 #medicine #Microbiology #VIRUS #ChronicDiseases #SARSCOV2 #COVID19 #LongHaulers #MCAS #ME #MyE #CFSME @microbeminded2 @MVGutierrezMD @elisaperego78 @TomKindlon @Dan_Wyke @research_long @agy_lena @SarahOC_MECFS @joshuamcclure @Lymenews @JanetDafoe @EricTopol @SGriffin_Lab

🦠 🔍 𝐃𝐢𝐝 𝐲𝐨𝐮 𝐤𝐧𝐨𝐰 𝐭𝐡𝐚𝐭 𝐄𝐬𝐩𝐭𝐞𝐢𝐧-𝐁𝐚𝐫𝐫 𝐯𝐢𝐫𝐮𝐬 𝐜𝐨𝐮𝐥𝐝 𝐛𝐞 𝐚 𝐭𝐫𝐢𝐠𝐠𝐞𝐫 𝐟𝐨𝐫 𝐬𝐲𝐦𝐩𝐭𝐨𝐦𝐬 𝐢𝐧 𝐌𝐄/𝐂𝐅𝐒 𝐚𝐧𝐝 𝐋𝐨𝐧𝐠 𝐂𝐎𝐕𝐈𝐃? A thread 🧵 Below, I summarize the points of our recent published review and how it could explain the development of 𝐝𝐲𝐬𝐚𝐮𝐭𝐨𝐧𝐨𝐦𝐢𝐚, 𝐦𝐢𝐜𝐫𝐨𝐜𝐥𝐨𝐭𝐬, 𝐚𝐮𝐭𝐨𝐢𝐦𝐦𝐮𝐧𝐞 𝐝𝐢𝐬𝐞𝐚𝐬𝐞𝐬, 𝐞𝐱𝐞𝐫𝐜𝐢𝐬𝐞 𝐢𝐧𝐭𝐨𝐥𝐞𝐫𝐚𝐧𝐜𝐞, 𝐦𝐢𝐭𝐨𝐜𝐡𝐨𝐧𝐝𝐫𝐢𝐚𝐥 𝐝𝐲𝐬𝐟𝐮𝐧𝐜𝐭𝐢𝐨𝐧, 𝐡𝐲𝐩𝐨𝐜𝐨𝐫𝐭𝐢𝐬𝐨𝐥𝐢𝐬𝐦 𝐚𝐧𝐝 𝐦𝐨𝐫𝐞 𝐜𝐨𝐧𝐬𝐞𝐪𝐮𝐞𝐧𝐜𝐞𝐬. Share with other patients so they can understand their illness. 𝐊𝐧𝐨𝐰𝐥𝐞𝐝𝐠𝐞 𝐢𝐬 𝐩𝐨𝐰𝐞𝐫! 📚 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, Sjögren'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: 1️⃣ 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. 2️⃣ 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. 3️⃣ 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: 1️⃣ 𝐌𝐞𝐭𝐚𝐛𝐨𝐥𝐢𝐜 𝐚𝐥𝐭𝐞𝐫𝐚𝐭𝐢𝐨𝐧𝐬: the model describes how EBV infection can lead to insulin resistance through elevated IFN-γ 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. 2️⃣ 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. 3️⃣ 𝐂𝐨𝐦𝐩𝐫𝐨𝐦𝐢𝐬𝐞𝐝 𝐭𝐡𝐞𝐫𝐦𝐨𝐫𝐞𝐠𝐮𝐥𝐚𝐭𝐢𝐨𝐧: The body's ability to dissipate heat generated during exercise may be impaired, which could lead to overheating. 4️⃣ 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. 5️⃣ 𝐀𝐥𝐭𝐞𝐫𝐚𝐭𝐢𝐨𝐧𝐬 𝐢𝐧 𝐫𝐞𝐬𝐩𝐢𝐫𝐚𝐭𝐨𝐫𝐲 𝐟𝐮𝐧𝐜𝐭𝐢𝐨𝐧: Respiratory function may be impaired, limiting adequate oxygenation during exercise and contributing to fatigue. 6️⃣ 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. 7️⃣ 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: 1️⃣ 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). 2️⃣ 𝐈𝐧𝐟𝐥𝐚𝐦𝐦𝐚𝐭𝐨𝐫𝐲 𝐫𝐞𝐬𝐩𝐨𝐧𝐬𝐞𝐬: proinflammatory cytokines released in response to EBV, such as IL-1β, IL-6 and TNF-α, can act on the brain and other organs, disrupting ANS function, leading to symptoms of dysautonomia. 3️⃣ 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. 4️⃣ 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. 5️⃣ 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. 6️⃣ 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. 7️⃣ 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: 1️⃣ 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-1β and TNF-α. These cytokines may contribute to chronic inflammation of the central nervous system, characterizing neuroinflammation. 2️⃣ 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. 𝐋𝐢𝐧𝐤: 𝐂𝐨𝐧𝐭𝐢𝐧𝐮𝐞 𝐭𝐡𝐞 𝐭𝐡𝐫𝐞𝐚𝐝 🧵👇🏽 #EpsteinBarrVirus #EBV #LongCovid #MECFS #MyalgicEncephalomyelitis #Health #Research #News #microE2324 #medicine #Microbiology #VIRUS #ChronicDiseases #SARSCOV2 #COVID19 #LongHaulers #MCAS #ME #MyE #CFSME @microbeminded2 @MVGutierrezMD @elisaperego78 @TomKindlon @Dan_Wyke @research_long @agy_lena @SarahOC_MECFS @joshuamcclure @Lymenews @JanetDafoe @EricTopol @SGriffin_Lab