HYPOTHESIS: Could autoantibodies to muscarinic acetylcholine receptors underpin ME/CFS? NOTE: I originally posted this idea in this thread at the Phoenix Rising forum, but thought I'd repost the info here too. The focus of this speculative idea/hypothesis is that autoantibodies to muscarinic acetylcholine receptors might conceivably cause dysautonomia, thereby leading to ME/CFS and some of its co-morbid conditions such as orthostatic hypotension. It is often found that people who developed ME/CFS from a viral infection already had conditions such as irritable bowel syndrome (IBS), interstitial cystitis (IC), Sjögren's syndrome (SS) or orthostatic hypotension (OH) prior to catching the virus that triggered their ME/CFS. These conditions are known co-morbid illnesses for ME/CFS (that is, conditions that are statistically found at higher rates in ME/CFS patients). This statistical association of course suggests the possibility that IBS, IC, SS and OH are not just innocent bystanders, but may play causal roles in the development of ME/CFS. In other words, it suggests that if you had not had IBS, IC, SS and/or OH prior to catching your triggering virus, then perhaps that virus may not have plunged you into ME/CFS at all. But the question remains: what is it about IBS, IC, SS and OH that, in combination with a triggering virus, may lead an individual into ME/CFS? One extremely interesting common denominator I noticed in all these conditions is the presence of autoantibodies to the muscarinic acetylcholine receptors in the parasympathetic nervous system (or just general autonomic nervous system dysfunction). See the summary below for precise details. Could this common denominator of anti-muscarinic autoantibodies in these conditions help explain how these individual illnesses "gang up" together to produce ME/CFS? If each individual condition is promoting anti-muscarinic autoantibodies and autonomic dysfunction, then, if a person suffers from more than one such condition, this may amplify the anti-muscarinic effect and amplify the autonomic dysfunction. Later, when this person catches a viral or bacterial infection, since infections are known to precipitate and ramp up autoimmune processes, this may further exacerbate the anti-muscarinic autoantibodies. Lots of autoantibodies to the muscarinic receptors in the nerves will prevent the proper electrical signals being sent along these nerves to the organs they control (since these signals propagate through the muscarinic receptors), and such dysfunction of the autonomic nerves will lead to many symptoms just on its own. Furthermore, I have seen some suggestions that autonomic dysfunction may cause problems in the Th1/Th2 immune system balance, thus possibly preventing the immune system from fighting off the viral infection, allowing the virus to multiply and spread, leading to more symptoms, and perhaps ultimately to ME/CFS. Might this anti-muscarinic autoantibody hypothesis of ME/CFS explain why rituximab seems to treat ME/CFS? Rituximab can treat of autoimmune diseases, so one might speculate that the reason rituximab improves ME/CFS symptoms is because this drug reduces autoantibodies to muscarinic receptors. Rituximab depletes B cells, and since the main function of B cells is to make antibodies, you would expect rituximab to reduce anti-muscarinic autoantibody production too. Certainly rituximab can treat Sjögren's syndrome, which is linked to anti-muscarinic autoantibodies.1 Summary of autoantibodies to the M1, M2 and M3 muscarinic acetylcholine receptors in ME/CFS and related conditions ME/CFS has autoantibodies that target the M1 subtype of muscarinic receptors, in 50% of patients (the studies do not say whether these autoantibodies activate or block the M1 muscarinic receptors).1 2 Orthostatic hypotension has autoantibodies that target both the M1 and M2 subtypes of muscarinic receptors (and in this case, the autoantibodies activate these two subtypes of muscarinic receptor). Autoantibodies to beta-adrenergic receptors are also found in orthostatic hypotension.1. Sjögren's syndrome has autoantibodies that target the M3 muscarinic receptors (in this case, the autoantibodies block these M3 muscarinic receptors; thus signal transmission in the parasympathetic nerves is inhibited by these muscarinic receptor autoantibodies; this is the likely reason the saliva glands do not get fully activated).1 2 3 Interstitial cystitis may be due to autoantibodies that target the M3 muscarinic receptors.1 Irritable bowel syndrome is also associated with autonomic nervous system dysfunction.1 Interestingly, M1 and M3 muscarinic receptors mediate control of the parietal cells that secrete stomach acid, and mediate control of the pancreas. Autoantibody blockade of these M1 and/or M3 muscarinic receptors might explain why there is often poor stomach acid secretion in ME/CFS, due to the autoantibodies blocking the nerve signals that instigate acid secretion.1 2 3 Possible Treatments that Might Lower Autoantibodies Anything that lowers the overall level of autoantibodies would theoretically help. And anything that specifically lowers anti-muscarinic autoantibodies should be particularly good. Rituximab, which deletes B cells, is probably going to be the best choice for treating treat autoimmunity and autoantibodies in ME/CFS, but this is years away from being employed for ME/CFS patients. So I did search for things other than rituximab that might help combat autoimmunity and autoantibodies, but did not find all that much: • The hormone estriol might help, as estriol has a reasonably strong effect against autoimmunity1 (this is probably why female ME/CFS patients often feel better during pregnancy: estriol is one of the major hormones of pregnancy, being raised around 1000 times its normal level during pregnancy). • Methotrexate should help: this is a drug that suppresses B cell function and thus can treat autoimmunity and autoantibodies.1 The Norwegian researchers Øystein Fluge and Olav Mella, who are conducting the rituximab trials, first noticed the benefits of B cell suppressors for ME/CFS when they gave a patient methotrexate. • Interferon beta ameliorates autoimmunity, so herbs that boost interferon beta (like Bupleurum kaoi and berberine) may help. • Hydroxychloroquine (malaria drug) helps autoimmunity.1 • In enterovirus infections, the cytokines IL-1B and TNF-alpha are linked to the commencement of autoimmunity,1 so taking supplements that counter IL-1B and TNF-alpha may help lower autoimmunity, one might think. Potent natural TNF-alpha inhibitors include cat's claw herb and 5-loxin. • N-acetylglucosamine has been found to suppress the damaging autoimmune response seen in multiple sclerosis and type 1 diabetes mellitus.1 • Linoleic acid, omega-3 and omega-6 fatty acids may help in autoimmune conditions.1 • Royal jelly and raw milk are said to help with autoimmunity. Astragalus decreases nicotinic acetylcholine receptor autoantibodies (in myasthenia gravis)1, but we want something that reduces muscarinic acetylcholine receptor autoantibodies. Dendritic Cells and Autoimmunity When trying to reduce autoimmunity and autoantibodies, one key area that must be considered is dendritic cells, which play a key role in preventing autoimmunity.1 Could a dendritic cell malfunction cause the autoimmunity found in ME/CFS and its related co-morbid conditions? Dendritic cells, when mature, migrate to the lymph nodes, where they start to do their main work — work which includes preventing autoimmunity. It is interesting that in ME/CFS, there is usually lymph node swelling and tenderness, suggesting there is some type of infection, inflammation and possibly dysfunction in the lymph nodes. Could this lymph node swelling prevent the dendritic cells in the lymph nodes from functioning properly, thus thwarting their efforts to control autoimmunity in the body? This makes me wonder whether some type of lymph node treatment may help the dendritic cells there to work better, thus allowing them to do their job of preventing autoimmunity. I am not sure what treatment would help, though. Note that uric acid is low in CFS, and uric acid helps stimulate dendritic cells to their maturation. Also, glutathione may be low in CFS, and this inhibits dendritic cell maturation.1. So these condtions may also hinder dendritic cell function. Combating Autoimmunity in ME/CFS by Boosting Tolerogenic Dendritic Cells Another approach to combating autoimmunity and autoantibodies in ME/CFS and related conditions might be by boosting tolerogenic dendritic cells. Tolerogenic dendritic cells are the specific class of dendritic cells that protect against autoimmunity. The pregnancy hormone estriol, mentioned above, which is a reasonably strong factor that fights autoimmunity, actually works by generating more tolerogenic dendritic cells.1 Estriol treatment has been experimentally given to both women and men with multiple sclerosis (an autoimmune condition), with good results. Transdermal estriol creams are readily available. Other drugs and supplements that boost tolerogenic dendritic cells, and so fight autoimmunity in ME/CFS, include: • Prednisolone induces tolerogenic dendritic cells (in myasthenia gravis).1 Some ME/CFS patients seem to respond very well prednisolone treatment, and perhaps the reason for this is that prednisolone reduces the levels of autoimmunity and autoantibodies in ME/CFS. • Curcumin induces tolerogenic dendritic cells (in the intestines).1 • Vitamin D receptor agonists induce tolerogenic dendritic cells.1 This might explain why using the vitamin D receptor stimulating ARB drug olmesartan (Benicar) in the Marshall protocol has apparently helped some people with ME/CFS. So the Marshall protocol may actually work by reducing autoimmunity (rather than, or in addition to, killing intracellular bacteria, as Trevor Marshall posits). I only have an extremely superficial understanding of how dendritic cells work, but feel that this area is worth investigating. One more tidbit: echovirus (strongly linked to ME/CFS) causes rapid loss-of-function and cell death in human dendritic cells,1 so perhaps this virus causes further dendritic cell dysfunction. Cholinergic Medicines and Supplements It is hard to know whether these would help or not, as it is not clear to me whether the parasympathetic nerves are over-activated or under-activated (or a combination of both at different places). You can see from the above studies on ME/CFS, IC, SS and OH that in some of these conditions, the muscarinic receptor autoantibodies act to jam the muscarinic receptors off (antagonists), and in others, the autoantibodies act to jam these receptors on (agonists). So it is not clear whether you should boost or inhibit the parasympathetic nerves, that is to say, whether you should use muscarinic receptor agonists, or muscarinic receptor antagonists. You also probably want to employ antagonist/agonist supplements that specifically target muscarinic receptors only (which, for the most part, are only found in the parasympathetic branch of the autonomic nervous system), rather than supplements that broadly target both muscarinic and nicotinergic acetylcholine receptors. Better still, you probably want to use antagonists/agonists that only target the appropriate subtype of muscarinic receptor (M1, M2 or M3 subtypes). Here are some muscarinic receptor agonists and antagonists that selectively target specific M1 or M3 subtypes: Selective M1 muscarinic receptor agonists: Muscarine, found in the fly agaric mushroom, agonizes M1 and M2 muscarinic receptors. Cevimeline, for dry mouth in Sjögren's syndrome, agonizes M1 and M3 muscarinic receptors. Pirenzepine, for of peptic ulcers (it reduces gastric acid secretion), agonizes M1 muscarinic receptors. Trihexyphenidyl, a Parkinson's drug, agonizes M1 muscarinic receptors. Xanomeline, for Alzheimer's and schizophrenia, agonizes M1 and M4 muscarinic receptors. Arecoline, found in the betel nut, agonizes M1, M2 and M3 muscarinic receptors (but also has high nicotinic receptor agonism1).Selective M1 muscarinic receptor antagonists: Dicycloverine (aka: dicyclomine), for irritable bowel syndrome, antagonizes M1 muscarinic receptors. Oxybutynin, for overactive bladder, antagonizes M1, M2 and M3 muscarinic receptors. Scopolamine, for treatment of motion sickness (in minute doses), antagonizes M1 muscarinic receptors. Scopolamine is found in plants such as henbane and Jimson weed. Telenzepine, for peptic ulcers (it reduces gastric acid secretion), antagonizes M1 muscarinic receptors. ME/CFS patients often have autoantibodies to M1 muscarinic receptors, though I have no information as to whether these autoantibodies act as agonists or antagonists on the M1 muscarinic receptors.Selective M3 muscarinic receptor agonists: Cevimeline, for dry mouth in Sjögren's syndrome, agonizes M1 and M3 muscarinic receptors. Pilocarpine, for glaucoma, has relatively selective agonism for M3 muscarinic receptors, but also agonizes the other M1 to M5 muscarinic receptors. Arecoline, found in the betel nut, agonizes M1, M2 and M3 muscarinic receptors (but also has high nicotinic receptor agonism1). Ginger agonizes M3 muscarinic receptors. Note that all muscarinic receptor agonists are contraindicated for asthma, coronary insufficiency, gastroduodenal ulcers, intestinal obstruction, hyperthyroidism and incontinence, as they will exacerbate the symptoms of these disorders.Selective M3 muscarinic receptor antagonists: Darifenacin, for overactive bladder, antagonizes M3 muscarinic receptors. Oxybutynin, for overactive bladder, antagonizes M1, M2 and M3 muscarinic receptors.Miscellaneous: Acetylcholine agonizes all M1 to M5 muscarinic receptors. Carbachol, for glaucoma, agonizes all M1 to M5 muscarinic receptors. Atropine, found in deadly nightshade and Jimson weed, antagonizes all M1 to M5 muscarinic receptors. Diphenhydramine, a first-generation antihistamine drug, antagonizes all M1 to M5 muscarinic receptors.References — General: Muscarinic Agonists Muscarinic Antagonists Parasympathomimetic Drug Muscarinic Acetylcholine Receptor M1 Muscarinic Acetylcholine Receptor M3References — Drug Affinities for the Muscarinic Receptor Subtypes M1 to M5: The Muscarinic Acetylcholine Receptor Acetylcholine Receptors (Muscarinic) Muscarinic Receptor Compounds Note: confusingly, the different sources listed here present slightly different data for these drugs' affinities for each muscarinic receptor subtype M1 to M5. So it is hard to know precisely what each drugs' affinities are for the receptor subtypes.