Autoimmune autonomic ganglionopathy is a very rare disease. So why feature it in a blog on chronic fatigue syndrome  (ME/CFS), fibromyalgia (FM), and postural orthostatic tachycardia syndrome (POTS)? Because it could provide a preview of the future. All these diseases feature problems with the autonomic nervous system (ANS). While we know quite a bit about ANS (and other) problems in these diseases, we still don’t know why they’ve occurred. Autoimmunity is a possibility for each of these diseases.

Ganglion high mag

The nerve ganglion – characterized by the dark dots – is the center of the picture

The ANS affects blood flows, digestion, the immune system, heart rate, sleep, etc. When the body needs to respond to a stressor, the fight or flight (sympathetic nervous system (SNS)) is activated. When the stressor is gone, the “rest and digest” (parasympathetic nervous system (PNS)) returns the body to normal functioning. In ME/CFS, POTS and FM, the fight or flight system has become unusually activated.

There was a talk on autoimmune autonomic gangliopathy (AAG) given by Steven Vernino at the recent Dysautonomia Conference.

Autoimmune autonomic gangliopathy (AAG) is interesting because it demonstrates how the immune system can take a two-by-four to the autonomic nervous system. Given the many people with ME/CFS, FM and POTS whose diseases were triggered by an infection; i.e. an immune response – that’s an intriguing fact.

Steve Vernino related how one 50 year old woman’s AAG began with a cold! Four days later, she was admitted to hospital with severe nausea, abdominal pain, tingling, blurry vision, and dizziness. Her blood pressure was doing weird things: lying down, her blood pressure was high normal, but standing up, it dropped to 80/56 (!).

Since the ANS regulates blood pressure, those strange blood pressure readings suggested that her ANS wasn’t functioning properly. Other signs – dry mouth, enlarged pupils, and lack of sweating – also pointed to problems with the ANS. Her sensory and motor nerves – which run alongside ANS nerves – on the other hand, were normal.

What had happened? Autoimmune autonomic ganglionopathy (AAG) is a rare disease, but researchers ultimately uncovered what was going on. The ANS produces two kinds of nerve “ganglia” – areas where the nerves collect together. The parasympathetic nerve ganglia are found near the organs, while the sympathetic ganglia are found close to the spinal cord. Acetylcholine is used to open up a channel between one neuron and another – and activate the nerves.

Studies uncovered the presence of antibodies in AAG patients which attack the anti-nicotinic acetylcholine receptors (AChR) that are responsible for opening up the channel between two autonomic nerves. With the channel blocked, the signal cannot pass and the ANS cannot work. That’s why her blood pressure dropped severely when standing up. It’s why she had so many gut problems.

She had something characterized as acute pandysautonomia; i.e. a rapid onset of autonomic nervous system failure. It’s been known since 1969 that Epstein-Barr virus (EBV) – the same virus responsible for triggering ME/CFS in many people – can trigger it. Some people with this experience a partial spontaneous (i.e. untreated) recovery, but full recoveries are rare. A simple cold had changed this person’s life forever.

In AAG, both sides of the ANS fail. The sympathetic nervous system fails to kick in during standing, resulting in low blood pressure (orthostatic hypotension) and problems with gut motility. Parasympathetic failure, on the other hand, leads to dry eyes and mouth, bladder problems, sexual impairment, low heart rate variability, and big pupils which do not respond to light.

People with AAG experience “autonomic failure”, which is rare. In autonomic failure, their nerves simply stop working. In dysautonomia, which is much more common, the autonomic reflexes work but the balance between the SNS and the PNS is off. Some people have a combination of both.

As so often occurs in autoimmunity, there was a lot of grey area that took time to clear up. AAG was originally diagnosed when the AChR antibody levels were .05, but the diagnostic criteria are stricter now, and the cutoff for the disease is 4 times higher (from .2 up to 5). At lower than .2, 50% of those with the antibodies have no autonomic symptoms at all.

Over time, doctors learned that only the higher antibody levels were causing problems.

This reveals another tricky aspect of antibodies and autoimmune disease: deleterious antibodies can be present without causing many problems; i.e. it’s often the level of the antibody which counts. Researchers now know that AChR antibodies become “clinically significant” when they’re .2 and over, and generally don’t cause problems at lower levels.

They’ve also learned that different grades of AAG exist. People with very high levels of antibody levels early typically get sick very rapidly and experience severe autonomic failure. People who present with lower levels of antibodies early on typically have limited autonomic failure. As it may be in ME/CFS, the ferocity of the early immune response apparently makes a big difference. The damage, in other words, is done early.

As in ME/CFS, FM, and POTS, most of those afflicted with AAG are women. As in these diseases, many (50%) report a viral onset, but gradual onsets also occur. The disease is also associated with joint hypermobility, MCAS, other autoimmune diseases, and higher levels of autoantibodies in general.

Treatments often involve immunosuppression (IVIG, plasma exchange, Rituximab, steroids) and can be very effective in some cases, but can come with side effects as well. Symptoms improve when antibody levels drop. Other treatments include standard treatments for orthostatic intolerance (droxidopa, pyridostigmine, midodrine.)

In what’s surely another potential lesson for heterogenous diseases like ME/CFS, FM, and POTS, some people with acute autonomic failure don’t have any antibodies. Instead, they have an inflammatory neuropathy: the receptors for their autonomic nerves are being destroyed by inflammation. Same outcome – different pathway.

Autoimmunity in POTS and ME/CFS

In AAG, autoimmune or inflammatory processes prevent the autonomic nervous system receptors from relaying messages from autonomic nervous system nerves. That results in autonomic “failure” – something that’s not generally seen in ME/CFS or POTS. Instead, these diseases generally feature dysautonomia – a failure to properly regulate the ANS.

Adhesion-GPCR receptor family

This is one subset of the huge family of GCPR receptors.

Still, some of the symptoms and signs seen in AAG (problems standing, gut issues, small fiber neuropathy, low heart rate variability), are also found in ME/CFS, FM, and POTS. Plus, just as with AAG, most patients are women, the diseases are often triggered by an infection, and they’re allied with other disorders such as Ehlers Danlos Syndrome (EDS) and mast cell activation syndrome (MCAS).

Given the similarities present, the question arises if an autoimmune or inflammatory process is also targeting the autonomic nervous systems of ME/CFS, POTS, and FM patients?

The big target right now is the GPCR family of receptors. This large family contains several receptors that have been associated with autonomic disorders such as AAG, Sjogren’s Syndrome, POTS, and possibly ME/CFS.

Chronic Fatigue Syndrome (ME/CFS)

There’s much grey area in ME/CFS. It should be noted that the autoantibodies that may play a role in it are believed to be natural regulators of autonomic functioning. They become pathological when they’re too prevalent and either overactive or inhibit ANS functioning.

Elevated M3 and M4 muscarinic and β2 adrenergic autoantibodies that were associated with immune abnormalities have been found in ME/CFS. A recent study suggested that B1 and B2 adrenergic antibodies were associated with structural changes in the brain.

Another study found elevated autoantibodies in the plasma, but not the cerebrospinal fluid. It did not, however, find that they were associated with increased symptoms – an essential requirement for an autoimmune disease. Whelan introduced some more mystery when he recently reported at the IACFS/ME conference that he did not find that the antibodies that have been associated with POTS were elevated in ME/CFS patients with POTS. He did find a correlation between autoantibody levels and the presence of small fiber neuropathy (SFN).

Small studies suggest that immunoadsorption may be able to reduce the levels of these antibodies – and reduce symptoms. Rituximab has taught us, though, to be wary of the findings of anything but larger placebo-controlled studies. It’s not easy to validate autoimmunity in disease and the search for an autoimmune cause of the ANS problems in ME/CFS is still in its infancy.

Recently, though, a group of researchers including Carmen Scheibenbogen and Manual Martinez-Lavin proposed that chronic fatigue syndrome (ME/CFS), POTS, and complex regional pain syndrome (CRPS) belong to a new category of diseases they called “autoimmune neurosensory dysautonomias”, defined by problems with the GPCRs.

Wirth and Scheibenbogen have also proposed that these autoantibodies are narrowing or vasoconstricting the blood vessels, reducing blood flows and oxygen consumption. They believe the blood flow problems may lead to an increase in vasodilators such as bradykinin, which produce pain, fatigue and other symptoms.

Postural Orthostatic Tachycardia Syndrome (POTS)

3d rendered illustration of an artery with streaming blood

Much more evidence of GPCR issues is present in POTS, but the studies have tended to be small. Still, several studies have found increased levels of antibodies against alpha and beta-adrenergic and/or muscarinic receptors. Last year, a study found elevated autoantibodies against the alpha 1 adrenergic receptor (89%) and the muscarinic acetylcholine M4 receptor (53%). As with AAG, an exposure to EBV was noted. Sympathetic nervous system activation, problems with blood flows, reduced blood volume could all be explained by problems with GPCRs.

Last year as well, the autoimmunity hypothesis in POTS took a step forward with the production of an animal model. The study was small, but it nevertheless suggested that an autoimmune response to A-1 and B1 adrenergic receptors would be likely to produce the high heart rates and reduced blood pressures seen in POTS. While recognizing that substantial work remains to be done, two researchers asserted that the production of the animal model was “crucial for future POTS research“.

Another step forward was taken with the publication of a paper showing that the serum (blood) from POTS patients produced an unusual activation of the receptors under question. That activation was, in turn, associated with problems standing and walking. POTS needs larger studies, and comparisons with different disease groups, but POTS seems like it’s getting closer.

Recently, a fibromyalgia study that used IgG from FM patients to create a fibromyalgia-like mouse, suggested an autoimmune process may be activating pain-producing neurons found just outside the spinal cord and producing small fiber neuropathy.

Study Suggests Something in the Blood is Causing Fibromyalgia


AAG is a rare disease in which autoantibodies target autonomic nervous system receptors and produce autonomic failure – and quite a few symptoms which overlap with ME/CFS, POTS, and FM. It took some time to understand which levels of autoantibodies had clinical significance. Over time, it also became clear that some cases of AAG are inflammatory in origin – not autoimmune.

ME/CFS and POTS are different and similar. All three diseases feature problems with the autonomic nervous system and have some connection with joint hypermobility and mast cell activation syndrome. The dysautonomia problems in ME/CFS and POTS appear to be the result of autonomic regulation, not autonomic failure. If an autoimmune process is present, it’s likely causing increases in naturally occurring antibodies which dysregulate the autonomic nervous system.

Research more and more suggests that a subset of POTS is autoimmune in nature. An animal model has been produced and POTS researchers have gone beyond measuring antibody levels to assessing the effect blood from POTS patients has on receptor responsiveness. Larger studies are needed, though, to validate the finding – and potentially blow open the door to the possibility of using autoimmune drugs in POTS.

The hunt for an autoimmune cause of the autonomic problems in ME/CFS is on. Interestingly, one of the same autoantibodies found in POTS also appears to be found in ME/CFS. While some results are promising, others are puzzling. We’re still at the beginning of understanding the role autoimmunity may play in the autonomic nervous system issues in ME/CFS.


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