Review Epstein-Barr virus-acquired immunodeficiency in myalgic encephalomyelitis-Is it present in long COVID?, 2023, Ruiz-Pablos et al

Epstein-Barr virus-acquired immunodeficiency in myalgic encephalomyelitis-Is it present in long COVID?

Abstract
Both myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) and long COVID (LC) are characterized by similar immunological alterations, persistence of chronic viral infection, autoimmunity, chronic inflammatory state, viral reactivation, hypocortisolism, and microclot formation. They also present with similar symptoms such as asthenia, exercise intolerance, sleep disorders, cognitive dysfunction, and neurological and gastrointestinal complaints. In addition, both pathologies present Epstein–Barr virus (EBV) reactivation, indicating the possibility of this virus being the link between both pathologies. Therefore, we propose that latency and recurrent EBV reactivation could generate an acquired immunodeficiency syndrome in three steps: first, an acquired EBV immunodeficiency develops in individuals with “weak” EBV HLA-II haplotypes, which prevents the control of latency I cells. Second, ectopic lymphoid structures with EBV latency form in different tissues (including the CNS), promoting inflammatory responses and further impairment of cell-mediated immunity. Finally, immune exhaustion occurs due to chronic exposure to viral antigens, with consolidation of the disease. In the case of LC, prior to the first step, there is the possibility of previous SARS-CoV-2 infection in individuals with “weak” HLA-II haplotypes against this virus and/or EBV.


https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04515-7

 

The author Manuel Ruiz-Pablos seems to have a general interest in EBV related diseases and published https://pubmed.ncbi.nlm.nih.gov/35894054/ and https://pubmed.ncbi.nlm.nih.gov/34867935/. He is also a patient that sufferes from ME/CFS https://twitter.com/manruipa.

 

Schematic model of the development of acquired immunodeficiency following EBV infection

 

Development of Epstein–Barr Virus (EBV)-induced acquired immunodeficiency in patients with genetic susceptibility

 

He has done a long Twitter thread on it

 

Interesting conjecture. I think it deserves more investigation and I would encourage the authors to continue their studies of this.

I blogged a bit about EBV in 2014 myself and I feel this avenue rings true for me.
https://boolyblog.blogspot.com/2014/05/why-viruses-immunoevasins-and-mixed.html

The real need imho is to prove / detect these processes in patients and find ways to distinguish cohorts as subtypes of CFS and then do something to help them.

I would question the terminology of "depletion" as a form of exhaustion, used in this paper. As a general rule I tend to disbelieve exhaustion theories about symptoms as I think that if the symptoms persist despite attempts to convalesce then they are more likely due to dysregulation.

In this case, given what we know about the pathological production of IL-10 (as discussed in the paper) and EBV's immunoevasive viral analogue of vIL-10 and its suppressive effect on T cells, I dont think we need to invoke chronic exposure to viral antigens to account for the downregulation of T cell activity.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355093/
"The EBV Immunoevasins vIL-10 and BNLF2a Protect Newly Infected B Cells from Immune Recognition and Elimination"

So I think there is a lot to understand about this and plenty to discuss, with the overriding priority being to find a way apply this kind of understanding clinically.

 

https://twitter.com/user/status/1703750287725306327


The main reason is that the HPA axis hypofunction is a consequence, not a cause, of immunological alteration. Also, using hydrocortisone could aggravate immunodeficiency and EBV reactivation.

 

I can’t read the science as I’m in a crash. But my experience since COVID 2020 has been that my immune system can’t fully handle infections anymore and I get more infection symptoms when I have to use my steroid inhaler, which I do as asthma worse post COVID too. I’m an anecdote in agreement.

 

Thank you very much to these authors for this research, that may implicate EBV in ME and LC.

Those who are aware of the history of ME will know that EBV as a culprit in acquiring this disease has been viewed before.

Medicine is gradually (too gradually) learning that there is more to EBV than a short-lived, uncomfortable illness.

I hope science can soon definitively answer whether EBV is one of the villains in the cause of ME, and now LC.

(As a study subject of n=1, I have had several documented EBV reactivations.)

 

The abstract is a word salad of non-facts. I cannot be bothered to look in more detail.
The ideas are so old that even that man dug out of a Danish bog would have been familiar with them.

 

NEW ARTICLE PUBLISHED!
Unraveling the Connections Between EBV, Long COVID, and Myalgic Encephalomyelitis

After months of meticulous review and analysis, I am proud to present a study that explores the deep connections between Epstein-Barr virus (EBV), Long COVID and Myalgic Encephalomyelitis. The findings, while fascinating, urge us to rethink our current understanding of these conditions:

1️⃣ EBV as a link: 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.

2️⃣ Immunodeficiency and Ectopic Lymphoid Aggregates: 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.

3️⃣ Consequences:

• Development of Autoimmune Diseases: EBV, by interacting with certain genetic haplotypes, can increase the risk of autoimmune diseases. The infection triggers an immune response that, in combination with genetic predispositions, can confuse the body's own tissues with foreign agents, leading to an autoimmune attack.
• Chronic Innate Immune Response: EBV infection weakens the T-cell response, causing persistent inflammation due to a constant activation of the innate immune system.
• Reactivation and Transient Autoantibodies: T-cell dysfunction leads to viral reactivations. During these reactivation episodes, the body may produce transient autoantibodies that may contribute to clinical symptoms. These autoantibodies may come and go depending on the stage of infection and viral reactivation.
• Abortive Lytic Replications: EBV cells can begin, but not complete, lytic replications, releasing proteins that intensify inflammation.
• Hypocortisolism: A reduction in cortisol levels. This hormone is essential for numerous functions in the body, including stress management. An imbalance can have profound effects on overall health.
• Microclot formation: These tiny clots can hinder blood flow, which in turn affects the delivery of oxygen and nutrients to tissues.
• Insulin Resistance: There is a connection between EBV infection and insulin resistance, which may contribute to metabolic complications.
• Serotonergic Disruption: It is notable how EBV affects serotonin levels, with an increase in the gut and a decrease in the central nervous system. This dichotomy may be at the root of several symptoms.
• Hypozincemia and Decreased Ceruloplasmin: Infection can lead to decreased levels of zinc and ceruloplasmin in the body, affecting immune function and other processes.
• Oxidative Stress and Inflammation: EBV infection intensifies oxidative stress and inflammation, depleting the body's antioxidant defenses and contributing to a vicious cycle of cellular damage.
• IDO Pathway Activation: This metabolic pathway, essential for tryptophan degradation, is impaired, which may have implications for mood and neurological function.
• Nitrosative Stress: Increased nitrosative stress may contribute to cellular damage and alter mitochondrial function.
• Altered Microbiota: Chronic EBV infection of the intestinal mucosa compromises the intestinal barrier. Increased serotonin in the gut causes inflammation, which combined with an increase in proinflammatory cytokines, leads to increased intestinal permeability. This results in an overgrowth of bacteria in the small intestine and development of food intolerances. Vitamin deficiencies may also occur due to inadequate absorption.
• Transactivation of Human Endogenous Retroviruses (HERV): EBV can activate genes in HERVs, specifically the env gene of HERV-K18, through their latent proteins. These superantigens may contribute to immune fatigue and a state of anergy in T lymphocytes.

4️⃣ Sex Differences: 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.

Women's menstrual cycles further complicate this situation, as phases such as ovulation cause potential immunosuppression and increase vulnerability to viral reactivations.

In men, testosterone shapes the immune response differently, often favoring a more effective defense against intracellular pathogens. This distinction may affect the progression and manifestation of conditions such as ME/CFS and Long COVID.

5️⃣ Treatments that could improve or worsen symptoms:

Hydrocortisone:

• Advantage: Potential to address hypocortisolism.
• Disadvantage: May have limited or adverse effects in patients with ME/CFS, as HPA axis hypofunction is a consequence, not a cause, of immune impairment. In addition, it could worsen immunodeficiency and EBV reactivation. Therefore, it would not be recommended.

Selective Serotonin Reuptake Inhibitors (SSRIs):

• Advantage: They could help restore serotonergic impairment, especially at the CNS level.
• Disadvantage: At the peripheral level, they could exacerbate hypoglycemia and hyperinsulinemia. In addition, they could worsen intestinal symptoms due to increased serotonin at the intestinal level. Other alternatives are better.

Metformin:

• Advantage: May be beneficial by reducing ROS production, improving insulin sensitivity, and not associated with risk of hypoglycemia.
• Disadvantage: Side effects of the drug.

N-acetylcysteine (NAC) and other antioxidants:

• Advantage: Help reduce oxidative stress. They may decrease the risk of developing EBV-associated cancer and also inhibit NF-κB activation.
• Disadvantage: No specific adverse effects are mentioned at normal doses.

Hydroxychloroquine:

• Advantage: May be useful by increasing intracellular zinc and decreasing SARS-CoV-2 replication.
• Disadvantage: Promotes reactivation of EBV and other herpesviruses, which may contribute to long-term development of lymphomas. In addition, it limits T-cell responses and may increase oxidative stress. Its use would not be recommended.

Antivirals such as valganciclovir or valacyclovir:

• Advantage: May reduce reactivation, inflammation, appearance of temporary autoantibodies and insulin resistance.
• Disadvantage: Side effects of the drug.

Hyperbaric Oxygen Therapy:

• Advantage: May increase pathogen clearance, synthesis of various growth factors, and angiogenesis.
• Disadvantage: Increased oxidative stress may generate higher levels of ROS and reactive nitrogen species, leading to more oxidative and nitrosative damage. Therefore, this therapy could be useful for those viruses that do not generate latency, such as SARS-CoV-2, but could be detrimental for viruses that do generate latency, such as EBV, as it promotes the increase of latent cells by increasing oxidative stress.

In summary, the symptoms of individuals with EBV-acquired immunodeficiency could be improved with the combined use of antioxidant supplements, antivirals, and metformin. The use of anticoagulants could also be considered.

I hope this study will serve as an aid to all professionals and sufferers seeking answers in the maze of symptoms and treatments associated with these conditions.

Twitter thread describing more details of the article: https://twitter.com/user/status/1703705886286344336


Read the full study here: https://link.springer.com/article/10.1186/s12967-023-04515-7

I appreciate the opportunity to share these findings with you and look forward to your feedback and comments.

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!

If you are interested in helping the ongoing research on EBV, ME/CFS and Long COVID, please consider contributing. Your donation can make a difference. Help us advance research by donating here: https://helpify.es/comunidades/todo-por-la-causa-del-sindrome-de-la-fatiga-cronica/

 

A quick search for "ectopic lymphoid aggregates" came up with this 2017 hypothesis paper "The spread of EBV to ectopic lymphoid aggregates may be the final common pathway in the pathogenesis of ME/CFS" which we don't seem to have a thread on (paywalled but available on sci-hub).
It's ref #194 in the current paper.

Haven't read either paper.

 

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 MS/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:

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-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.

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-1β, IL-6 and TNF-α, 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-1β and TNF-α. 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-1β, IL-6, IL-8, IL-12, TNF-α, and IFN-γ, 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-γ 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 TNFα, IL-6 and IL-1β 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 β-amyloid (Aβ) peptide, which, interacting with fibrinogen, causes fibrinogen oligomerization, fibrin deposition and Aβ fibrillation, favoring the formation of abnormal microclots resistant to degradation by fibrinolytic enzymes.

3. Amyloidogenesis and fibrinogenesis:

- Elevated levels of IL-1β, IL-6 and TNF-α 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-γ, TNFα, IL-1 and IL-6 stimulate the hypothalamic-pituitary-adrenal (HPA) axis by activating ACTH secretion. IFN-γ, 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-γ 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-β1 and TNFα could suppress ACTH-stimulated cortisol secretion in the adrenal gland, leading to relative hypocortisolism.

- The anti-inflammatory and immunosuppressive cytokines, IL-10 and TGF-β1, 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.

 

This is a sweeping claim.

 

There are other scenarios, I fear, not the least of which is the infection - whatever it may be - persists by virtue of its own voracity and immune evasion capacity.

 

It is written so that it can be understood by the general public.
Clearly thousands of pathways are involved in the immune response. But in terms of genetic factors involved in weakness against infections, the development of autoimmune diseases and their relationship in distinguishing the self from the foreign, HLAs are the main ones involved. That is what the review is about.

 

But is it accurate, Manuel?
Do you have experience as a physician on which to base the assertion - or indeed reliable data from the literature?

I am pretty sure that the main determinants of inability to control infection are:

malnutrition
nowhere warm to sleep at night
diabetes
alcoholism and drug dependence
old age
corticosteroid therapy
coexistent leukaemia or lymphoma

and so on.

HLA has an effect time to developing AIDS but not great deacon other infections as far as I know, even if the equivalent in mice does.

The problem with immunological theories like this is that you can make up a theory to explain anything - or its opposite, by pretty much anything.

I don't think there are any ectopic lymphoid follicles in ME. I spent years studying ectopic follicles in rheumatoid disease and to be honest I see no relevance to ME.