Hypothesis Hypocortisolemic ASIA: A vaccine-and chronic infection-induced syndrome behind the origin of long COVID and ME, 2024, Ruiz-Pablos et al

I did a remote long covid study at Mt. Sinai where they were looking at cortisol levels and all you had to do was report to labcorp in the AM. I did and N=1 but my levels were completely normal.

 

To my knowledge, no one knows how/if it’s relevant to ME/CFS fatigue.

 

ICI-treated individuals who develop hypophysitis may hold the key to the development of ME/CFS, Long COVID and post-vaccinal syndromes


In the field of immunology and cancer treatment, Immune Checkpoint Inhibitors (ICIs) have revolutionized cancer therapy by activating the immune system to attack cancer cells. However, this immune hyperactivation can have significant side effects, known as immune-related adverse events (irAEs), including hypophysitis, an inflammation of the pituitary gland.


Immune Hyperactivation and Hypophysitis.
ICIs work by blocking immune regulatory proteins, such as CTLA-4 and PD-1, which boosts the immune response against cancer. This dysregulation can, however, lead to immune hyperactivation that not only attacks cancer cells, but also healthy tissues. A clear example is hypophysitis, where the pituitary gland becomes inflamed due to the uncontrolled action of the immune system. Inflammation and damage of the pituitary gland affects the production and secretion of pituitary hormones, which can lead to a variety of clinical symptoms depending on the hormones affected (such as ACTH, TSH, GH, among others).


Similarity with Long COVID, ME/CFS and Post-Vacunal Syndromes.
Current research suggests that similar immune hyperactivation may be involved in conditions such as Long COVID, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-vacunal syndromes. These conditions share features such as chronic inflammation, autoimmunity and immune depletion.


Long COVID
Long COVID, a condition that persists in some individuals after acute SARS-CoV-2 infection, shows signs of a dysregulated immune response similar to that seen in patients treated with ICI. Prolonged inflammation and possible reactivation of latent viruses, such as Epstein-Barr, may contribute to persistent symptomatology, including chronic fatigue, cognitive dysfunction, and hormonal imbalances.


ME/CFS
ME/CFS is a debilitating disease characterized by extreme fatigue following infection that is not relieved by rest and worsens with physical or mental activity. As in ICI-induced hypophysitis, it has been proposed that a chronic dysregulated immune response may play a crucial role in the development of ME/CFS. This immune response may be directed not only against infectious agents, but also against the body's own tissues, resulting in a state of persistent inflammation and dysfunction.


Post-vaccinal syndromes
Post-vaccinal syndromes, although rare, have been reported in some individuals after receiving certain vaccines, including COVID-19 vaccines. These syndromes can include symptoms similar to those of ME/CFS and Long COVID, such as chronic fatigue, muscle aches, and neurological problems. It is believed that in these cases, a vaccine-induced hyperactivation of the immune system could trigger autoimmune and inflammatory responses that contribute to these symptoms.


Hypophysitis as a Study Model
ICI-induced hypophysitis provides a useful model for understanding how a dysregulated immune response can lead to systemic disease. The study of this condition may offer crucial clues to the mechanisms underlying ME/CFS, Long COVID and post-vaccinal syndromes. For example:

• Chronic Inflammation: persistence of inflammation in hypophysitis may mirror the chronic inflammation seen in ME/CFS and Long COVID.
• Hormonal Dysregulation: hypophysitis may cause hormonal deficiencies, similar to the imbalances observed in ME/CFS and Long COVID.
• Autoimmunity: The autoimmune nature of hypophysitis may parallel the autoimmune responses suspected in ME/CFS, Long COVID and post-vaccine syndromes.
• HLA-DRB1 allele: Both hypophysitis in ICI-treated patients and ME/CFS conditions, Long COVID and post-vaccinal syndromes, could be associated with susceptible HLA-DRB1 alleles. In patients treated with ICI, the immune hyperactivation is due to the therapy itself, and upon termination of ICI treatment, the problem usually resolves. In contrast, in ME/CFS, Long COVID and post-vaccinal syndromes, persistence of viral antigen perpetuates hyperactivation and autoimmune damage.

Conclusion
Hyperactivation of the immune system, whether induced by ICI treatments, viral infections such as SARS-CoV-2 or herpesviruses, or even vaccines, can result in a variety of immune-related adverse events (irAEs) and chronic conditions such as hypophysitis, ME/CFS, Long COVID, and post-vaccinal syndromes. Understanding these shared mechanisms, especially in individuals with susceptible HLA-DRB1 alleles, may be the key to developing effective treatments and improving the quality of life for patients affected by these debilitating diseases.


More information in this thread:

https://twitter.com/user/status/1810664159354192253

 

Old Articles that, if Published Today, Would Be the Key to the Development of Long COVID, Myalgic Encephalomyelitis and Post Vaccinal Syndromes

Study on Hypothalamic-Pituitary-Adrenal Axis (HPA) in SARS Survivors
An article in (2005) investigated endocrine sequelae in SARS survivors, revealing that 39.3% of patients had hypocortisolism. The low-dose Synacthen test (1 μg) was crucial in detecting subtle HPA axis dysfunctions, showing that many patients recovered HPA axis function within 1 year after treatment. In addition, transient thyroid dysfunction was observed in some patients, resolving between 3 and 9 months. These findings suggest that SARS-CoV can cause long-lasting endocrine dysfunction, which is relevant to understanding Long COVID, Myalgic Encephalomyelitis and post-vaccinal complications. The improvement in serum cortisol levels and resolution of symptoms such as fatigue and postural dizziness suggest that cortisol replacement was effective in most cases.

https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2265.2005.02325.x


Study on Molecular Mimicry of ACTH in SARS and its Treatment with Corticosteroids.
Another study, published in ℎ (2004), proposes that SARS and other coronaviruses employ molecular mimetic strategies to evade the host immune response. The SARS virus expresses amino acid sequences that mimic host adrenocorticotropic hormone (ACTH). This induces the production of autoantibodies against ACTH, limiting the host stress response and leading to relative adrenocortical insufficiency.

Corticosteroid treatment can mitigate these effects by providing the corticosteroid levels needed to fight infection. According to the study, initiating corticosteroid treatment as early as possible allows the use of lower doses, whereas a delay in treatment requires higher doses to suppress virus-induced inflammatory cytokine dysfunction. In addition, prophylactic use of moderate doses of corticosteroids could prevent clinical infection with SARS by preventing the ACTH mimetic strategy of the virus from becoming active.

The results show that SARS patients treated with corticosteroids experienced clinical improvements, supporting the hypothesis that autoantibodies against ACTH play a crucial role in the pathogenesis of SARS. Also, these findings could be applicable to the treatment and prevention of complications in Long COVID, post-vaccinal syndromes and Myalgic Encephalomyelitis, given that SARS-CoV-2 and other viruses may employ similar immune evasion mechanisms.

https://www.sciencedirect.com/science/article/pii/S0306987704002828?via=ihub


Study on Anti-ACTH Antibodies in Critically Ill Patients with COVID-19.

A recent study published in (2021) evaluated the presence of anti-ACTH antibodies in critically ill patients with COVID-19. The authors, D. Pérez-Torres, C. Díaz-Rodríguez, and A. Armentia-Medina, investigated whether anti-ACTH antibodies were detectable in these patients and measured plasma cortisol and ACTH levels.

The study found that 60% of critically ill COVID-19 patients had anti-ACTH antibodies, and half of these patients showed low cortisol and ACTH levels. These findings support the theory that SARS-CoV-2 may use molecular mimetic strategies to evade the host immune response. The presence of these antibodies may block the immune response and attenuate the natural HPA axis response to stress, leading to relative adrenal insufficiency.

https://www.sciencedirect.com/science/article/pii/S0210569121001960?via=ihub


Implications for Long COVID, Myalgic Encephalomyelitis and Post-Vaccinal Syndromes.

The findings of these studies are highly relevant to understanding the complications of Long COVID, Myalgic Encephalomyelitis, and post-vaccinal syndromes. HPA axis dysfunction and the production of autoantibodies against ACTH could explain some of the persistent symptoms observed in these patients. The use of stimulation testing and early treatment with corticosteroids could be useful strategies to diagnose and treat these complications.



All of this is detailed in our : https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full

 

Why is autoimmunity triggered by viral antigens the most likely cause of Long COVID, Myalgic Encephalomyelitis and Post-vaccinal Syndromes?

New articles published this July support our hypothesis:


Increased proinflammatory cytokines.
Elevation of cytokines such as IL-6 leading to muscle deterioration
https://www.science.org/doi/10.1126/sciimmunol.adm7908

Our model: elevated IL-6, caused by poor control of infected cells and viral reservoirs, contributes to muscle deterioration.

Increased IFN-γ is linked to symptoms in Long COVID, and its reduction with IFN-γ inhibitors improves symptoms.
https://www.science.org/doi/10.1126/scitranslmed.adn0136

Our model: Interferon gamma (IFN-γ) is a proinflammatory cytokine that increases during chronic infections. Normally, cortisol controls IFN-γ levels. A decrease or dysregulation of cortisol can keep IFN-γ levels chronically elevated. If autoimmune hypophysitis is present, caused by infection or vaccine viral antigen, cortisol levels will be reduced, allowing continued T-cell activation and a persistent increase in IFN-γ. Thus, chronic inflammation and constant activation of the immune system, caused by persistent elevated levels of IFN-γ, can promote reactivation of latent viruses and an increase in infected cells. For example, IFN-γ increases the expression of MHC-II, facilitating the binding of Epstein-Barr virus to this receptor and its entry into cells. The improvement of symptoms with IFN-γ inhibitors suggests that restoring cortisol levels could alleviate symptoms, indicating a possible dysregulation of cortisol due to autoimmunity against the pituitary gland.

Viral persistence.
The continued presence of viral reservoirs in the mucous membranes and the increase of activated T cells in those same areas indicate continued reaction to infection and a subsequent exhaustion of T cells in blood.
https://www.science.org/doi/10.1126/scitranslmed.adk3295

Our model: this increase in activated T cells may lead to the development of autoimmune diseases, such as hypophysitis in genetically susceptible patients, similar to the risk in immune checkpoint inhibitor (ICI) patients with susceptible HLA-II alleles.

Autoimmunity.
Patients with #LongCOVID have autoantibodies against neural tissues, correlated with neurological symptoms. Transfer of these antibodies to mice induces similar symptoms.
https://www.medrxiv.org/content/10.1101/2024.06.18.24309100v1

The authors propose treatments based on therapies used in other autoimmune diseases.

* Intravenous immunoglobulin (IVIg): neutralizes and eliminates autoantibodies.
* FcRn inhibitors: Degrade antibodies by blocking their interaction with the neonatal Fc receptor.
* BC 007: Neutralizes autoantibodies against β1, β2, and M2 adrenergic receptors.
* Plasmapheresis: Temporarily removes antibodies from blood plasma.
* Anti-CD20 or CAR-T monoclonal antibodies: Attack and destroy antibody-producing B cells.

Our model: genetically predisposed patients (HLA-II alleles) may develop autoimmunity against various tissues, including the pituitary gland. If such autoimmunity is not treated in time, it can lead to irreversible damage.

Current treatments for autoimmune diseases can be effective in temporarily reducing or eliminating autoantibodies and controlling symptoms. However, these approaches have important limitations: they only address the effects of autoimmunity without eliminating the underlying cause, such as a persistent viral infection. If the viral antigen responsible for the autoimmunity is still present, autoantibody production can resume, reactivating the disease. CAR-T therapy shows promising potential, as it could eliminate autoantibody-producing B cells and, in the future, infected cells.

However, it should be crucial to combine these treatments with antivirals to reduce the viral load and the production of viral antigens that can induce molecular mimicry with self antigens. This could help to decrease the underlying autoimmune stimulus and improve disease control.

In addition, if treatment of autoimmunity is delayed and has caused damage to the pituitary gland, symptoms may persist due to irreparable damage to this organ, despite efforts to control autoimmunity. For that reason, some patients treated with these therapies may continue to have symptoms by having, for example, irreparable damage to the pituitary gland with cortisol depletion. In this case, treatment with hydrocortisone in replacement doses should be added.

Do you want to know more about how this autoimmunity develops and what treatments could improve symptoms?
Read this thread about our review article:
https://twitter.com/user/status/1810664159354192253

 

New Article Could Reveal the Origin of the Long COVID!



Model of the new article.

1. Immune Sensitization and Inflammatory Response:

* Proposition: the S1 subunit of SARS-CoV-2 can induce a form of “sensitization” in the immune system. This means that, following exposure to the S1 protein, the immune system becomes more reactive to future inflammatory stimuli. This sensitization leads to a more intense and longer lasting inflammatory response compared to a normal response to an inflammatory stimulus.

* Mechanism: Sensitization is associated with an increase in the expression of antigen-presenting molecules such as MHC-II in brain microglial cells. This suggests that the S1 protein alters the activation threshold of immune cells, making them more likely to respond in an exaggerated manner to future exposures to pathogens or inflammatory stimuli.

2. Impact on HPA Axis and Cortisol Production:

* HPA Axis: Unlike pathogen antigens, such as LPS, which stimulate the HPA axis to increase cortisol production, the S1 subunit does not follow this pattern. Instead of increasing cortisol levels, exposure to S1 causes a decrease in basal cortisol levels in the brain and does not activate the HPA axis in the expected manner. This may contribute to down-regulation of inflammation and an uncontrolled immune response.

* Cortisol: The decrease in cortisol observed after S1 exposure suggests that the immune system becomes less regulated, which may lead to exacerbated inflammation and increased sensitivity to future inflammatory stimuli.

3. Consequences:

* Symptoms and Behavior: S1-triggered sensitization manifests in symptoms such as changes in physical activity, eating behavior, and fever response. These effects are related to alterations in the functioning of the hypothalamus, which regulates multiple physiological and behavioral functions.

* Disease Model: Results suggest that exposure to S1 may induce long-lasting changes in the immune system and hormonal regulation, contributing to increased vulnerability to inflammation and symptoms similar to those seen in disorders such as Long COVID.


: https://www.sciencedirect.com/science/article/pii/S0889159124005105?via=ihub



Model Proposed in Our Review Article.

1. Molecular Mimicry and Autoimmunity:

* Proposed: SARS-CoV-2 protein S induces molecular mimicry with ACTH, generating an autoimmune response against ACTH. This results in hypophysitis and cortisol depletion.

* Mechanism: HLA-DRB1 alleles, such as DR15, can promote immune hyperactivation against the SARS-CoV-2 S protein. This hyperactivation may lead to an autoimmune response due to molecular mimicry with ACTH. In individuals with these susceptible alleles, the exacerbated immune response can result in pituitary damage and reduced ACTH production.

2. HPA Axis and Hormonal Dysfunction:

* HPA Axis: Autoimmune hypophysitis and decreased ACTH lead to reduced cortisol production. Prolonged exposure to these viral antigens causes pituitary dysfunction and contributes to symptoms such as chronic fatigue and hormonal disturbances. Decreased cortisol levels lead to immune exhaustion by not decreasing T-lymphocyte activation.

: https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full



Model Comparison and Support for the Autoimmune Hypothesis.

The new article indirectly supports our hypothesis by demonstrating that the S1 subunit of SARS-CoV-2 protein S induces a neuroinflammatory priming and increases MHC-II expression in microglial cells. This priming elevates S1 protein presentation through MHC-II, which may lead to prolonged hyperactivation of the immune system. This sensitization could increase the propensity of the immune system to respond in an exaggerated manner to future exposures to pathogens or inflammatory stimuli and to attack self-antigens with molecular mimicry, such as ACTH, particularly in individuals genetically predisposed via HLA-II alleles.


Furthermore, the reduction in brain corticosterone following S1 exposure, together with dysfunction in the HPA axis, supports the idea that neuroinflammatory priming contributes to a dysregulated immune response and increased activation of autoimmune processes.


Parallelism with Autoimmune Hypophysitis Induced by Immune Checkpoint Inhibitors (ICIs)

Immune Checkpoint Inhibitors (ICIs) provide a relevant example of how immune hyperactivation can induce autoimmune hypophysitis in genetically susceptible individuals (HLA-II alleles). ICIs, by blocking immune regulatory proteins, can cause uncontrolled inflammation of the pituitary gland. This phenomenon is particularly notable in patients with susceptible HLA-II alleles, who may experience an autoimmune response directed against the pituitary gland. ICI-induced autoimmune hypophysitis illustrates how immune hyperactivation can result in significant pituitary damage, similar to that seen in conditions such as ME/CFS, Long COVID and post-vaccinal syndromes.



Comparison with Long COVID Post-Vaccination Cases.

The immune hyperactivation observed in ICI-induced autoimmune hypophysitis and in the SARS-CoV-2 model in individuals with susceptible HLA-II alleles may provide an explanation for Long COVID cases developed after vaccination. In these cases, exposure to SARS-CoV-2 protein S by vaccination may induce the same immune hyperactivation. This hyperactivation may result in persistent inflammation and autoimmune responses similar to those seen in viral infection-induced hypophysitis, due to molecular mimicry with ACTH and altered regulation of the HPA axis.



Treatment .

1. Eliminate Viral Antigen: Use antivirals or strategies to eliminate SARS-CoV-2 protein S and reduce immune hyperactivation.

2. Corticosteroids: Apply corticosteroids to reduce inflammation and, if pituitary damage is present, consider corticosteroids in replacement doses for hormone deficiency.

3. Assess Cortisol: Morning cortisol tests may not be reliable for detecting hypocortisolism. Perform saliva cortisol testing in several shots throughout the day for accurate assessment of hypocortisolism.

4. Supplements and Additional Support: Use anti-inflammatory and antioxidant supplements to support treatment and reduce residual inflammation.



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