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It’s getting exhausting keeping up with these immune exhaustion studies. Avindra Nath has proposed that B-cell exhaustion is driving ME/CFS, but in “Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis“, Spanish researchers propose another suspect – exhausted T-cells. Both researchers start with an infection, identify an immune weakness that leads to exhausted immune cells –  end up with chronic fatigue syndrome (ME/CFS).

While Nath ends up in the temporal-parietal junction (TPJ) in the brain, these researchers end up at the pituitary gland in the brain: two immune hypotheses – two brain issues…Interesting!

The Pituitary Gland

The pituitary gland has hovered on the fringes of ME/CFS research but is getting a bit more attention – at least from doctors – and they explore spinal issues more. This little gland, found just down from the hypothalamus, has an outsize effect on the body.

The pituitary gland is part of the HPA axis – one of two major stress response systems in the body. It produces adrenocorticotropic hormone (ACTH) which stimulates the adrenal glands to produce cortisol. In hypopituitarism – the pituitary problem these researchers believe is present in ME/CFS, the pituitary gland doesn’t produce enough ACTH – resulting in low cortisol levels and probably fatigue, inflammation, etc.

Low cortisol levels were one of the first abnormalities found in ME/CFS. Dr. Kaufman stated that virtually everyone with ME/CFS (@90%) has a problem with the hypothalamic-pituitary axis – which could result from intracranial hypertension pounding away at the pituitary. Low cortisol levels have also popped up again several times in long COVID.

It’s never been clear, however, how important a role the various HPA axis abnormalities found in ME/CFS are. HPA axis research in ME/CFS flourished early but slowly petered out over time as few firm conclusions were drawn. HPA axis readings continue to pop up but one gets the feeling that researchers were never really able to wrap their hands around what’s going on in the HPA axis in ME/CFS.

Even the low cortisol findings have come under suspicion lately in both ME/CFS and long COVID because of concerns that researchers have not taken into account that altered circadian rhythms may have thrown morning cortisol levels off. (Janet Mullington is exploring this issue in ME/CFS in an Open Medicine Foundation-funded study (blog coming up).

Epstein-Barr Virus

These researchers propose it all begins with a blunted immune response to EBV.

The new paper starts with the recognition that herpes and other viruses can inhibit HPA axis activity, that the pituitary gland’s location makes it particularly vulnerable to infections, and that depending on which way the HPA axis bends, either immunosuppression (high cortisol), or inflammation, or autoimmune diseases (low cortisol) may result.

As with the HPA axis, whether EBV reactivation plays an important role in ME/CFS is still unclear. Increased anti-EBV-dUTPase antibodies, defective B and T cell responses to EBV, increased rates of active EBV infection, and elevated IgM antibodies have all been found, but variable antibody findings, questions regarding active infection, and normal viral EBV loads have made it unclear what effect EBV is having.

The authors propose, though, that EBV provides the crucial connection in ME/CFS. In their 2021 paper, “Epstein-Barr Virus and the Origin of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome“, the same authors proposed that the Th2 immune shift sometimes seen in ME/CFS has left ME/CFS patients vulnerable to EBV reactivation.

It turns out EBV may, in some individuals, target specific cells in the pituitary which regulate ACTH secretion when infections are present. A direct EBV infection of these pituitary cells could decrease ACTH production and thus produce low cortisol levels.

ASIA

Indeed, a 2021 Stanford study found increased rates of antipituitary (APA) (33%) and antihypothalamic (AHA) (56%) antibodies that were associated with reduced HPA axis responses. Those antibodies could produce a condition called autoimmune hypophysitis, or inflammation of the pituitary gland. The authors believe that some people with ME/CFS have a condition called adjuvant-induced autoimmune/inflammatory syndrome (ASIA) that’s damaging the pituitary gland.

ASIA popped up in the scientific literature in 2011 when an Israeli immunologist, Yehuda Shoenfeld, proposed that it occurs when genetically susceptible individuals react to one of the “adjuvants” or substances added to vaccines or other compounds to increase their effectiveness. These adjuvants may include things like aluminum salts, emulsions, oils, spike (S) protein, Toll-like receptor agonists, mRNA vaccine lipids, and polyethylene glycol.

Over time, Shoenfield proposed that ASIA is present in diseases like “post-vaccination symptoms”, Gulf war syndrome, sick building syndrome, Sjogren’s Syndrome, and siliconosis – all of which produce some familiar symptoms: low cortisol, chronic fatigue, unrefreshing sleep, sleep disturbances, cognitive problems and memory loss. The authors of this paper propose that long COVID, ME/CFS and post-COVID-19 vaccine syndrome be added to that list.

One of the most common manifestations of ASIA is autoimmune hypophysitis and adrenocorticotropic hormone (ACTH) deficiency.

Front and Center – Genetic Susceptibility

The authors believe that when a variety of factors (infections, foreign agents, adjuvants in vaccines) interact in a person with a certain genetic makeup (ancestral HLA-II alleles – HLA-DR15), trouble results. Specifically, an inability to ramp up T-helper cells (CD4) not only lets the pathogen replicate but results in compensatory immune responses that produce their own complications.

With the T-helper cells – which alert the immune system to the presence of invaders – unable to recognize the invaders, the latent herpesviruses found in the B-cells come out of hiding and reactivate. The cytotoxic T-cells (CD8) jump in, but lacking the T-helper cells to guide them to the invaders, shoot wildly, become hyperactivated and eventually exhausted. Meanwhile, B-cells start churning out antibodies designed to target the intruder or antigen (pathogen, toxin). Ultimately, they lose their way and attack the pituitary, producing a condition called autoimmune hypophysitis (inflammation of the pituitary).

The authors believe a genetic susceptibility in HLA genes makes it difficult for T-cells to find and fight off EBV.

In a last-ditch effort to bring the pathogens into check, the innate immune system roars into action – producing inflammation and more havoc – but is never able to vanquish the pathogen. (The innate immune system is not designed to rid the body of infections). (A similar scenario of innate immune system activation driven by an underperforming adaptive immune system has been proposed by Avindra Nath – but with dysfunctional B-cells. Since B and T-cells drive the adaptive immune response, one can assume it’s not doing so well in ME/CFS.)

A world of trouble results. The persistent chronic inflammation increases the immune system’s need for vitamin D, and may result in insulin resistance if the vitamin D situation is not addressed. Low zinc and copper levels can also result. Along the way, the authors find a way to hook in mast cell activation, transient hypoglycemia, and exercise intolerance.

The autoimmune hypophysitis produced suppresses ACTH secretion in the pituitary – resulting in low cortisol, and by reducing DHEA and DHEA-s, potentially low testosterone levels as well. The low cortisol produces symptoms like intense fatigue, dizziness, difficulty concentrating, difficulty exerting oneself, and a generalized feeling of malaise.

The pro-inflammatory cytokines unleashed by the innate immune system in combination with the compensatory CD8 T-cell activation may even result in muscle breakdown and the strange pattern found in ME/CF of amino acids being preferentially used to provide energy.

The authors even manage to bring in gut dysfunction, leaky gut syndrome, SIBO, disruption of the blood-brain barrier, reduced tryptophan, oxidative stress, mitochondrial problems, calcium accumulations, anaerobic metabolism, microglial activation, neurotoxicity, and, of course, neuroinflammation.

In shades of Dr. Naviaux’s Dauer hypothesis, the authors believe the immune exhaustion found in post-infectious diseases is not a failure of the immune system but is a compensatory mechanism designed to prevent the spread of intracellular pathogens by denying them the tryptophan they need to replicate.

It’s quite the tour-de-force! By the time we’ve gotten to citation 231, we’re onto the treatment section.

Treatment

The authors say no to checkpoint inhibitors. (Image by Alexandre-Perrier,-Audrey-Didelot,-Pierre-Laurent-Puig,-Hélène-Blons-and-Simon-Garinet,-CC-BY-4.0. Wikimedia Commons)

No to Checkpoint Inhibitors – In contrast to Avindra Nath, who proposes using checkpoint inhibitors (ICIs) to get the immune system back in gear, these authors think ICIs will make the problem worse. Getting the exhausted T-cells back into action will exacerbate the pituitary inflammation (hypophysitis) and/or the autoimmune disease that caused it. If no infection is present, they believe the treatment can work but if it is present

Depending on what situation a patient is in, the authors recommend different solutions.

In All Cases – Use supplements to reduce oxidative stress and replenish the compounds depleted by inflammation or malabsorption and to revive the exhausted T-cells. These include vitamin C, n-acetylcysteine (NAC), alpha-lipoic acid (ALA), S-adenosylmethionine (SAM-e), selenium and B-complex vitamins.

Early Disease Onset Caused by Infection – Use corticosteroids and antivirals at disease onset for a short period of time to reduce the production antibodies that attack the pituitary, knock down the virus, and reduce the T-cell exhaustion. Knocking down the pathogen is crucial, as they believe it’s the pathogen that is spurring the production of antibodies that are attacking the pituitary.

Consider supplementing with DHEA to assist with ACTH production. Add supplements (see above).

In Inflammatory and Immunosuppressive States – consider glutamine and nicotinamide mononucleotide (NMN) to restore cytotoxic T-cell functioning, astragalus to help with T-helper cell functioning and EBV reactivation, protein supplementation to maintain protein synthesis, vitamin D supplementation to reduce T-cell hyperactivation and improve insulin sensitivity, and melatonin to protect neurons, reduce oxidative stress and improve sleep. Use antibiotics and antihistamines to reduce inflammation in people with small intestinal bowel overgrowth (SIBO).

Disease Onset Not Caused by Infection – use corticosteroids for a short period of time to reduce the production antibodies that attack the pituitary. Consider supplementing with DHEA corticosteroids to inhibit ACTH secretion. Add supplements (see above).

Pituitary Damage has Occurred – If the pituitary has been damaged, corticosteroids may be needed long term to preserve the functioning of the adrenals. Consider supplementing with DHEA corticosteroids to inhibit ACTH secretion. Add supplements (see above).

No Pituitary Damage, Normal ACTH levels, and hyporesponsive HPA axis (low cortisol) is present – try supplements that reduce inflammation, and oxidative stress, and stimulate cortisol production, such as ginseng. Add other supplements (see above).

Since studies have found low salivary cortisol in ME/CFS but at times normal ACTH levels in some people with ME/CFS, long COVID will fit into this category.

It’s gone! (Image – Empty Sella Syndrome from the Brain by Nevitt_Dilman_CCA_3_Wikimedia_Commons)

The Spinal Connection

Although it’s not mentioned in this paper, the spinal-pituitary connection comes from a condition called empty sella syndrome (ESS) – which occurs when the bony structure that holds the pituitary in place becomes flattened. This usually results from high cerebrospinal fluid pressure (intracranial hypertension) – which appears to be common in ME/CFS.

Hulens believes Intracranial hypertension plays a significant role in some people with ME/CFS and/or fibromyalgia and can be associated with blunted adrenocorticotropic hormone (ACTH), cortisol, growth hormone, luteinizing hormone, and thyroid stimulating hormone responses and an increased prolactin response in these diseases.

In an Unraveled podcast, Dr. Ruhoy reported that she sees ESS or partially empty Sella in 80-90% of her craniocervical instability patients. She has also found elevated prolactin in many of her patients which could be linked to the pituitary problems via compression of the hypothalamus stalk as well.

A dysfunctional pituitary gland is the outcome.

Conclusion

Two hypotheses that start from the same place – an infection – propose that an immune defect (in B or T-cells) results in an inability to tackle the infection, immune exhaustion, and autoimmunity/inflammation, and ultimately results in a problem in the brain (TPJ, pituitary gland).

One proposes an immune approach (checkpoint inhibitors) that the other believes will make things much worse (!). Instead of checkpoint inhibitors, the Spanish researchers focus more on the temporary use of corticosteroids, plus antivirals and a range of supplements to restore T-cell functioning and the HPA axis, reduce oxidative stress, etc.

With B and T-cells, and even neutrophils and monocytes, in ME/CFS all showing signs of immune exhaustion and/or difficulties producing energy, one wonders if problems producing energy is the tie that binds these together.