Okay, keep in mind here that I'm just a badly brain fogged patient who's terribly out of his league, but I wanted to try rambling a bit and see if anything good comes of it, either by something worthwhile accidentally popping out of my mouth, or by maybe introducing anyone to concepts that might turn out to be important pieces of the picture. Maybe I can keep from misleading anyone if everyone will remember that I don't even know what direction I'm pointed in. Don't follow me, I'm lost, okay? I'm just going to make it up as I go along. Please feel free to disagree, or to add to the references included, or whatever you may please.

Keep in mind I'm hoping to inspire perhaps a little cautious optimism rather than burden or overwhelm anyone here - I find it cause for optimism to think we might have gotten this far.

Since my psychiatrist has me thinking about tryptophan and serotonin again, I was reminded of some of the CFS research referring to tryptophan. Tryptophan might be one of the subjects where there may be something important offered to us. Someone I admire greatly is CFS patient researcher Paolo Maccallini, whose website has some extensive information about metabolic and possible auto-immune issues with CFS. There are other angles to CFS that might be considered, but some of Paolo's work with antibodies to glycolytic enzymes might just turn out to be of particular importance, and sometimes I have tried to pick up where he left off with them and in doing so have been encouraged about where these topics might lead.

https://paolomaccallini.com/2018/04/15/glycolytic-enzymes-as-autoantigens

So I am reminded that issues with tryptophan metabolism are sometime presented in the context of a "metabolic trap" in CFS - I don't know if I think this is quite on-target, but perhaps it could turn out to be close. Maybe in the course of this I will be able to clarify that remark somewhat, although I still have a very poor understanding of some of it.

https://paolomaccallini.com/2018/10/08/is-it-a-trap

Metabolic fates of tryptophan, and the kynurenine pathway: You can see in Figure 1 at the last link above how important tryptophan metabolism ultimately is, at the bottom of the figure are essential aspects of metabolism like the citric acid cycle, oxidative respiration and ATP production. Some other versions of diagrams of tryptophan metabolism seem suggestive that whether tryptophan is being devoted to producing serotonin and its products could, among other things, depend on whether tryptophan needs to be diverted down the kynurenine pathway for the biosynthesis of niacin. I have never been able to understand why niacin deficiency couldn't result in deficiency of tryptophan or serotonin for this reason.

It might also eventually be of importance that there are several forms of niacin - niacinamide, which is cheaper to produce and is typically used to enrich or fortified foods, and nicotinic acid, which between the two is the form we might expect to find in nature. While the two may be interchangable for a number of important purposes, there are some differences, including that the niacinamide form may lack the anti-cholesterol benefits associated with nicotinic acid form. I made the mistake of taking niaciniamide ("no-flush" or "flush-free" niacin) for months instead of nicotinic acid, before I realized my error and my doctor eventually gave me the nicotinic acid form as "Niaspan" in hopes of lowering my cholesterol. I generally try to avoid the flushing associated with nicotinic acid by starting with a very low dose, just a sliver off a tablet, maybe an eighth, and gradually working my way up to more over the course of a week or two as I get used to it and the flushing stops being so dramatic.

However, there are more things that might be able to interfere with the citric acid cycle or ATP production as seen in the diagram on Paolo's page, notably including microbial toxins, some of which can be made at the expense of our own ATP. The extent to which they are able to do this may in part depend on how much the human body can be tricked into participating. (I've posted some things about this before, anything relating CFS to hibernation particularly comes to mind).

Because there can be many steps to the processing of tryptophan for various purposes, there might be many possible inhibitors for enzymes involved in these pathways, or numerous opportunities for co-factor deficiencies for some of these enzymes, that might also be able to pose problems? As per the diagram, however, supplementation that directly promotes NAD+ synthesis might bypass enzymes of the kynurenine pathway and any irregularities therein.

I still have mixed feelings about Dr. Davis' comments about "not trying this at home", about not trying to experiment with the pathways for tryptophan metabolism on the grounds it could be dangerous. On the one hand, I agree - pharmaceuticals that have targets related to these pathways may often carry some sobering inherent risks associated with them and caution is advisable on that count alone. On the other hand, many aspects of daily life might have some impact on these pathways, including high- or low-tryptophan diets or nutritional status, such that we may not be really able to avoid some experimentation, but perhaps might only hope to become more knowledgeable and more careful experimenters.

I still don't think everything is entirely clear here - Paolo notes that metabolites of the kynurenine pathway can have immunosuppressive effects, so there might be room for irregulaties along these pathways to be the idea of a patient's own body, if immunosuppression were going to undermine a patient's ability to fight the infection that may be present. Even then it may be a bit of a challenge to understand why immunosuppressives can sometimes be helpful in diseases where research reports routine findings of infection, at the same time immunosuppressive medications still carry warnings about the risk they may promote or aid infection.

Autoimmunity and infection: There seems to a significant amount of research out there associating numerous medical problems with possible auto-immunity, and in a number of these cases there are some fairly precise insights into this. It's often proposed that because of their similarity to human proteins, some proteins belong to infections of various types might generate antibodies that are able to cross-react with human proteins, resulting in autoimmune disease. This process is often called "Molecular Mimickry", which suggests that microbes are able confuse the immune system by imitating us at the molecular level although the similarities may not be something they actively work at.

I often refer to antibodies involved as "so-called autoantibodies" or "auto"-antibodies, in hopes of balancing out the notion that the human proteins are the true and intended targets of these antibodies or that the human immune system is prone to such mistakes. What in autoimmune disease may be called an "inappropriate" immune response to self, may turn out to often be first and foremost an appropriate immune response to a microbial pathogen that may not be taken into consideration in the discussion. Some microbes can still be very hard to detect without going as far as genetic fingerprinting, and may have often been overlooked by older studies that lacked such capabilities, and may still be often overlooked in clincal situations for the same reason - so they may still tend to get left out of discussions.

Sadly, even some of Dr. Davis' comments on tryptophan metabolism might be drifting toward this category, since he seems as if he may see tryptophan or its metabolism as pivotal in "inappropriate" B- and T-cell responses, whereas perhaps this is logical recruiting of B- and T-cells against infection in spite of any collateral autoimmune damages to the host that may result, particularly if an infection that is accomplished at thwarting the reponses of other immune cells such as phagocytes (macrophages and neutrophils, the "first responders"), which some evidence implies that microbial biofilms might be particularly good at doing.

Antibody effects: The subject also starts to touch on "Functional antibodies", which are antibodies that may not only have normal functions like attaching themselves to unwanted things like microbes in order to guide the immune system in disposing of them, but may be able to perform other functions such as blocking or agonising receptors thereby potentially acting like neurotransmitters or drugs and affecting neurological function. There are already numerous examples of this that have been discovered and reported, and no doubt there will be more. Antibodies may also be able to neutralize or otherwise alter the function of their target proteins, in addition to their better known function of labelling things for immune recognition. Antibodies such as anti-B-adrenergic antibodies reported in CFS occur in a number of other conditions, and may occur in some of these conditions as functional antibodies.

Autoantibody targets: One of the things that intrigues me about Paolo Maccallini's work with autoimmune aspects of CFS is the role of antibodies to glycolytic enzymes. I've found few researchers speaking up on what this actually means in real-life to have such antibodies, but there may be just enough to keep the idea afloat that antibodies to some of these enzymes that recognize the human forms of thse proteins may be able to exert effects that could compromise human metabolism at the cellular level and weaken the host.

One of the more notable things I've seen in literature on autoimmune diseases is that occasionally someone points out that in order for antibodies to recognize a target, the target should be readily available to them, whereas the rightful and usual domain of many proteins including glycolytic enzymes, may be in the interior of cells where they are not available for antibodies to recognize and attach to. In order for enzymes as these to be significant autoantigens might require possible relocation of these enzymes to cell surfaces so they can be readily recognized by antibodies.

I think there was just enough reference to the possibility to inspire a tentative hypothesis that impairment of normal cellular function, for example though mitochondrial impairment, decoupling, loss, or poisoning, or through disruption of the citric acid cycle, might cause the relocation of glycolytic enzymes to the cell surface in order to continue functioning, at which time they might be recognized by antibodies with an corresponding autoimmune response, or have their normal functions interfered with by antibodies. Perhaps there could also be unusual consequences to their operating in what may be such an unusual mode if indeed they are able to do this.

Suspects: Ideally, we might be able to link an autoantibody to a microbial cause, but there may be some problems with this in that a number of microbial proteins that may set off an immune response are not only similar to our own, but to one another, so that a number of different microbes might be able to cause them rather than there being only one possible microbial cause. Perhaps it may even turn out that what we're really looking at is molecular modelling of why infections make people feel weak, sick, and fatigued and why plenty of rest rather than plenty of exercise turns out to frequently be doctors' orders for infections. All a doctor may have to do here is ignore the role of infection, or be discourged by a trusted source of granting a role for infection, and doctors' orders may come out very different indeed.

It may be worth noting however, that certain fungal proteins may conserve the greatest similarity to human proteins, which is not necessarily surprising considering that according to the classifications of organisms, humans and fungi are both eukaryotes whereas bacteria are prokaryotes. In other words, we are a yeast infection's distant cousin before a bacteria is a yeast infection's distant cousin, so to speak - and sometimes the similarities in human and fungal proteins can be so striking that even someone who's never seen a protein sequence before can spot them and guess the significance.

Even while this might make a number of antibodies poor choices as biomarkers, it might help make them a key to our understanding of numerous medical conditions, and might provide us with important therapeutic targets in the event we are unable to effectively address the possible presence of infection. It might be noted that are at least enough reports to such an effect that they might keep the possibility afloat that successful removal of infection capable of generating antibodies that cross-react with the host, may be capable of alleviating the symptoms of autoimmune disease.

Another thing that may cloud the issue of suspects beside some some possible interchangeability of causative organisms, may be the ability of diverse groups of organisms forming microbial biofilms. Iranian researchers discovered that the biofilm formed by a non-albicans Candida species was capable of playing host and protector to Herpesvirus 6 (PubMed Article:PMC5686830, while other research reports that Candida biofilms can preferrentially play host to certain anerobic bacteria (PubMed Article:PMC4252622. Renowned biofilm expert Dr. Randall Wolcott didn't seem to think we should expect to find such a thing as biofilms of a only single species at all in human hosts.

Dr. Wolcott also warns us against "Koch's Postulates" - specifically the "One organism, one disease" part, and will tell you how "Koch's Postulates set us back 100 years". Indeed, many well known diseases may turn out to be the work of such collections of multiple and diverse species, which may help account for some of the diversity of microbial findings seen in research into various diseases, and some of the confusion over it. If it takes 3 particular microbes to cause the spectrum of symptoms of a particular disease but we insist that it only takes 1, how far will we ever really get with our understanding?

Biofilms can also exhibit unusual resistance to antibiotics, and we may still be getting to the bottom of why and how even after having already worn out as many as half a dozen theories about this. We continue to live and learn.

Sequence similarity: Paolo Maccallini has done a significant amount of work looking at the amino acid sequences that make up certain key proteins, and I've also done some unpublished work in this area. Amino acids are the "letters" that make up the "words" of protein sequences, and different letters of the alphabet are used to represent their occurence in proteins. On the one hand, if we find amino acid sequences in a protein to be virtually identical to the sequence that an antibody recognizes, we might have made an important if rather obvious finding. On the other hand, small differences in amino acid sequences can sometimes make the difference whether or not the protein is an actual antibody target or alter the outcome of targeting by an antibody, and we also already know that antibodies can recognize two different proteins whose composition can be so radically different that it's difficult for us to recognize their similarity and might never guess that the same antibody can recognize both, were it not for the research.

Paolo has pointed out some possible cross-reactivity that might cloud the results of testing for Borrellia or other infections, which as most of know seems a very likely candidate for Lyme Disease (that's found on some of the pages of his site including this one: False Positive, and this is a journal article by Paolo on Lyme: PMID:29317049)

Anti-tryptophan and anti-serotonin: One of the most surprising things to me after looking at similarities between the amino acids sequences of different proteins that might contribute to unwanted autoimmune effects, is finding out there can be antibodies that might recognize a single amino acid like tryptophan, or its downstream products like serotonin. Antibodies to serotonin have been reported in, for example, psychiatric disorders (PubMed ID:14572623), and fibromyalgia (PubMed ID:8868152, PubMed ID:1287679). Antibodies to tryptophan metabolites of the "IDO/THO" pathway (see diagram of tryptophan metabolism) have been noted in neurodegenerative diseases (PubMed Article:PMC2915656), which may therefore be another possible source of trouble with tryptophan metabolism in conditions such as CFS. Paolo Maccallini's materials claim that antibodies to serotonin are among the "auto"-antibodies confirmed in CFS.

One question I'm still looking for an answer to, is whether antibodies to tryptophan or its metabolites such as serotonin might also cross-react with similar neurotransmitters, or with melatonin or even certain melanins. Not only are pathogenic fungi increasingly being seen as possible suspects in neurodegenerative diseases (see the work of Diana Pisa and colleagues), but fungi can also be notable sources of melanin pigments - hence, could fungal infections play a role in the generation of antibodies that accidentally also recognize human neurotransmitters or tryptophan metabolites? 

One case in point might be the study by Uran et al (PubMed Article:PMC3187017) which seems to confirm the existence of anti-melanin antibodies generated in reponse to the fungal pathogen, Paraccocidiodes brasiliensis. The authors also support the idea of cross-reactivity between different types of fungal melanins.

Could this actually turn out to be where the research into tryptophan and the research into autoimmunity really meet?

Granted that without my reviewing some of the materials more carefully, some of this might remain pure speculation on my part (the possible relocation of human glycolytic enzymes or the possible cross-reactivity between anti-fungal antibodies and tryptophan metabolites), but that's about as optimistically cutting-edge as this particular badly brain-fogged individual has been able to get about the subject of CFS and the mystery of if it's why it's so hard to stay out of my chair. To tell the truth, for some reason I'm still having trouble sorting out whether I could have CFS, asthma that's very intolerant of activity, some form of orthostatic intolerance (although Maccallini states that orthostatic intolerance is a common clincal feature of ME/CFS on the "Metabolic Trap" page), or if it could be something else entirely, but I can certainly sympathize with anyone who deals with any of these.

Sometimes I'm inspired thinking about the sort of things my grandparents might have said to be inspiring: "If you know what you're fighting, maybe you've got a fighting chance" or "The questions won't get answered if nobody asks them" - so I don't really know what any of the answers are, I'm just a sick guy with a lot of questions.