HYPOTHESIS: Could autoantibodies to muscarinic acetylcholine receptors cause or underpin ME/CFS? People who develop ME/CFS from a viral infection often also have conditions such as irritable bowel syndrome (IBS), interstitial cystitis (IC), Sjögren's syndrome (SS) or orthostatic hypotension (OH). These conditions may be present prior to catching the virus that triggered the 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 may precipitate or 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 Sjogren's syndrome, which is linked to anti-muscarinic autoantibodies. Reference here. 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). References here and here (see halfway down page). Orthostatic hypotension has autoantibodies that target both the M2 and M3 subtypes of muscarinic receptors (and in this case, the autoantibodies activate these two subtypes of muscarinic receptor). Autoantibodies to beta-adrenergic receptors β1 and β2 are also found in orthostatic hypotension. Reference here. Sjogren'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). References here and here. In particular, this study demonstrates that these M3 autoantibodies reduce saliva production. Interstitial cystitis may be due to autoantibodies that target the M3 muscarinic receptors (though this is speculation). Reference here. Irritable bowel syndrome is also associated with autonomic nervous system dysfunction. Reference here. 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. References here, here and here.