Recently, Health Rising posted a review of an Amy Proal – Tim Henrich interview which noted the formation of a highly active group of researchers at the University of California at San Francisco (UCSF) dedicated to solving long COVID. The group – called the LIINC (Long Term Impact of Infection with Novel Coronavirus) group – has participated in dozens of long-COVID papers over the past three years.
This group published two preprints recently on long COVID – demonstrating what an apparently well-funded research group at a major university can do. The first preprint, “Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2“, involved 30 UCSF researchers.
T-cells
This study focused on one of the most important immune cells – T cells. (Image from NIAID)
The Yin/Peluso study focused on one of the big guns of the immune system – the T-cells. T-cells are part of the adaptive immune system – the part of the immune system that’s tasked with tracking down and eliminating pathogens. (The first part of the immune system – the innate immune system – holds off the pathogens until the adaptive immune system kicks in a couple of days later.)
T-cell both track down pathogen cells and regulate the immune response, and are of major interest in chronic fatigue syndrome (ME/CFS). Mark Davis at Stanford received a rare NIH grant to study them, Derya Unutmaz at Jackson Labs has been very excited about the strange gut-associated mucosal-associated invariant T-cells he’s found, and Lissa Selin and Anna Gill got a big NIH grant (5-year, $2.5 million) to study T-cell exhaustion in ME/CFS.
Cytotoxic (CD8+) T-cells destroy virus-infected and cancerous cells and recruit other immune cells such as macrophages to help them in the attack. Helper T-cells (CD4) tell memory B cells that something is up, as well as activating more killer T-cells. Different subtypes of these cells exist.
Besides cytotoxic and helper T-cells, regulatory T-cells shut down the immune response and are responsible for ensuring that an autoimmune process doesn’t get initiated. Memory T-cells, natural killer T-cells, mucosal-associated invariant T-cells and other T-cells exist.
Since T-cells play such an important role in tracking down and destroying pathogen-infected cells, it makes perfect sense to check them out in long COVID. The longer it takes them to do that, for instance, the deeper the coronavirus could burrow into the tissues, or the more damage it could wreak.
Peluso and Henrich’s 2021 study found that some subsets of killer T-cells decayed more quickly in long-COVID patients; i.e. the killer T-cells tasked with finishing off the coronavirus disappeared at a quicker rate than in COVID patients who did not come down with long COVID.
The Study
This study combined “next-generation” T-cell characterization assays (CyTOF) with antibody studies (apparently “this-generation” :)), as well as gene expression (RNA-Seq (also “next generation” :)) and high-density plasma proteomics (yep, “next generation”) to attempt to figure out what the heck is going on with T-cells and the immune system in long COVID.
The analyses were done on 27 long-COVID and 16 recovered COVID patients 8 months after the infection. Note that this is not necessarily an ME/CFS-like subset. The only requirement for the long-COVID patients was that they have at least one COVID-19-attributed symptom that was new or had worsened since the infection, and was at least somewhat bothersome. Not the most stringent criteria! Most people, however, had at least several symptoms, and the number of symptoms tended to increase from 4-8 months. As this study occurred in 2020-21, nobody had been vaccinated.
Results
The goal – “to identify clues to the immunologic processes that might drive long COVID” – was certainly achieved.
Ongoing Immune Response – First off, the study found “profound changes” in the distribution of t-helper (CD4+) T-cells with particularly high proportions of several subsets (tcm (memory), Tfh (b-helper), and Treg cells.) That indicated that an “ongoing immune response” was present in the long-COVID patients.
Epstein-Barr Virus Reactivation – The fact that the study did not find elevated T-cell responses to the SARS-CoV-2 coronavirus in the long-COVID patients suggested that the immune response was probably directed against another pathogen, such as a herpesvirus (perhaps Epstein-Barr virus), or an auto antigen (autoimmune response directed against a tissue).
Viral Reservoirs – They did, however, find evidence of exhausted SARS-CoV-2-specific CD8+ T-cells in the long-COVID patients. That and higher SARS-CoV-2 antibodies were consistent with a coronavirus viral reservoir that was present in the body. As noted earlier, Selin and Gill are studying T-cell exhaustion they believe could be driving everything in ME/CFS. Their preliminary findings seem pretty close to those found in long COVID and produced a nice tie-in with EBV reactivation – which seemed likely in this study.
In preliminary studies, Selin and Gil found that certain CD8 T-cells were altered in patients with chronic ME/CFS as compared to those who do not have ME/CFS. This suggests that an aberrant response to an immunological trigger, like infection, results in a permanently dysregulated immune system, as a result of CD8 T-cell exhaustion, a phenomenon they previously discovered in patients who developed ME/CFS following an infection with the Epstein-Barr virus.
At this point, two subsets of long COVID appeared to present themselves: one subset driven by high antibody (IgG) expression and another with low antibody expression. A nirmatrelvir-ritonavir clinical trial was underway to attempt to wipe out that reservoir.
THE GIST
- This study from the LIINC group at the University of California at San Francisco examined one of the big guns of the immune system – the T-cells. The T-cells track down virus-infected cells and destroy them, and regulate the adaptive immune response.
- With three large NIH-funded T-cell studies (Mark Davis at Stanford, Selin-Gill Harvard, Derya Unutmaz at Jackson labs) underway, T-cells are potentially a big deal in ME/CFS.
- The UCSF research team brought “next-generation” technology to bear in the T-cell characterization, gene expression, and plasma proteomics sections of the study. The study included long-COVID and recovered COVID-19 patients. The goal was “to identify clues to the immunologic processes that might drive long COVID“.
- That goal appeared to have been met as the study found numerous and significant immune abnormalities. First off, the increased expression of three subsets of T-cells suggested that an ongoing immune process was occurring in the long-COVID patients which wasn’t present in the recovered patients.
- Several subsets of long COVID appear to be present: one was associated with high antibody (IgG) expression and another with low antibody expression. A highly inflammatory response to the virus that could be driving their symptoms was also found in a small group of long-COVID patients.
- Plus, high levels of a subset of activated cytotoxic T-cells in females suggested that increased inflammation could help explain their increased risk of coming down with long COVID.
- The most striking finding, though, was a massive disconnect between the humoral (B-cell) and cellular immune (T-cell) response in the long-COVID patients. These two systems should work together to take care of the virus: the B-cells attach themselves to viral particles to block the virus from entering the cell while the T-cells kill cells that get infected.
- These two systems were coordinated in the recovered COVID patients but not in the long-COVID patients. About half the long-COVID patients who produced coronavirus-specific T-cells produced no antibodies to the virus.
- Putting all the pieces together, the authors found a highly inflammatory state, probably driven by immune dysregulation or problems with immune regulation, was present in long COVID. They concluded the a viral reservoir, reactivation of other viruses, or an autoimmune process could be responsible.
- A second paper using a more effective technique than has been used before from the LIINC found no evidence that increased autoantibodies or an autoimmune issue was in play in long COVID.
Massive Immune Disconnect – The most striking finding, though, was a massive disconnect between the humoral (B-cell) and cellular immune (T-cell) response in the long-COVID patients. These two systems should work together to take care of the virus: the B-cells attach themselves to viral particles to block the virus from entering the cell, while the T-cells kill cells that get infected.
These two systems were coordinated in the recovered COVID patients but not in the long-COVID patients. About half the long-COVID patients who produced coronavirus-specific T-cells produced no antibodies to the virus. This dysregulation also showed up in the gene expression results: genes involved in both the T-cell and B-cell response were upregulated in the recovered COVID cohort but not in the long haulers. With half their adaptive immune response to the virus essentially missing, the long-COVID patients appeared to be trying to fight off the coronavirus with one hand tied behind their back.
The cause was unclear, but the authors posited that a “misalignment” between IL4 and IL5 production by Th2 cells might be the proximate cause, while the ultimate trigger might lie in a persistent coronavirus reservoir, the reactivation of other viruses, or an autoimmune response. The Th2 finding was interesting given indications that an augmented Th2 response is present in ME/CFS.
The Th1 response is focused on killing pathogens while the Th2 response is more skewed toward allergy. It’s been proposed that an overly active Th2 response in ME/CFS is thwarting the immune system from effectively taking care of pathogens such as Epstein-Barr virus (EBV).
Putting all the pieces together, the authors found a highly inflammatory state, probably driven by immune dysregulation or problems with immune regulation, was present in long COVID. Increased expression of heme genes in long-COVID patients also pointed a finger at possible clotting issues including microclots.
Autoimmunity Nixed – For Now
We’re not done with the LIINC group yet, though. They also recently produced another preprint, “Autoantigen profiling reveals a shared post-COVID signature in fully recovered and Long COVID patients“, that digs deep into the autoantibody/autoimmune question in long COVID. The large study (121 long COVID, 64 recovered COVID-19, 57 pre-COVID controls) assessed the levels of autoantibodies (antibodies with the ability to attack the body) present.
We know that acute COVID-19 (the initial response to the virus) provokes the production of many different autoantibodies. Whether those autoantibodies persist in long COVID – and could therefore be driving the illness – is unclear, and study results have been mixed.
The authors noted that methods that can “identify the full range of novel autoantibodies” have not been used thus far and that’s what they and their “high-throughput, unbiased, proteome-wide screens” brought to the table in this study.
Results
Finding little difference between the autoantibodies found in the long-COVID patients and the recovered COVID-19 patients, and no evidence that any of the antibodies were associated with any of the long-COVID symptoms, the study put the brakes on the idea that autoantibodies were driving long COVID or that autoimmunity was present.
They did note that “complex conformational, post-translationally modified, or multimeric protein configurations” might be missed by their assay, thus the results do not completely rule out autoimmunity – and they asserted that more work needs to be done in this area. As of now, though, what appears to be the most rigorous assessment of autoimmunity yet in long COVID didn’t find evidence of it.
The fact that the study did not find elevated T-cell responses to the SARS-CoV-2 coronavirus in the long-COVID patients suggested that this immune response was probably directed against another pathogen, such as Epstein-Barr virus.
Evidence of exhausted SARS-CoV-2-specific CD8+ T-cells and higher SARS-CoV-2 antibodies in the long-COVID patients, were, however, consistent with the idea of a coronavirus viral reservoir being present. Note that T-cell exhaustion has been found in ME/CFS, and Selin believes it could be driving the symptoms in ME/CFS.
Conclusion
Numerous immune abnormalities were found in this T-cell/gene expression/antibody/proteome study. One wonders if the exhausted T-cells found in this study might mimic the exhausted T-cells thus far found in ME/CFS (which are the subject of a large NIH-funded study). The idea that reactivation to a herpesvirus might play a major role in long COVID notched up a bit when the study failed to find elevated T-cell responses to the coronavirus.
Several immune subsets appear to be present in long COVID, but the really big news was the disconnect between the T and B-cells. About half of the long-COVID patients who produced a T-cell-specific response to the coronavirus didn’t produce any antibodies to it.
Putting all the pieces together, the authors found a highly inflammatory state, probably driven by immune dysregulation or problems with immune regulation, was present. They concluded that a viral reservoir, reactivation of other viruses, or an autoimmune process could be responsible.
Thanks Cort, very interesting. This aligns with my own long COVID situation. I have T cell exhaustion, EBV reactivation, and no signs of autoimmune response (rheumatologist tested me twice over these three years; unless any autoimmunity with long COVID wouldn’t necessarily show up on the normal rheumatological panels?). She diagnosed me with ME/CFS too, and it’ll be interesting to see studies that include both patient types (long COVID and ME not from COVID).
Nice to see your lab findings track. This study did a much more intense examination of autoimmunity than your lab did. While your lab probably looked for at broad measures of autoimmunity (general antibody tests), this study actually looked for the autoantibodies responsible for driving possible autoimmune response and didn’t find increased levels in the long COVID patients.
That was interesting given that studies have generally found an eruption in autoantibodies during the actual COVID-19 infection. This study suggests they fade away over time and something else is driving the disease.
I don’t think the autoimmune question is over – the authors noted that further studies need to be done – but the result was not heartening for those proposing that autoimmuity is driving this disorder.
I thought the possible EBV reactivation element was fascinating. They’d didn’t pinpoint EBV but they were clearly surprised to not find high levels of coronavirus specific T-cells in the long COVID patients. The immune activation appeared to be focused on something else.
These are the kind of complex studies done at top research institutions that we’ve largely been missing in ME/CFS but are starting to get in long COVID.
Ahh, thank you for clarifying that important piece about the deeper dive they did on autoimmunity than my lab tests would have done. I also tested negative for antibodies, but that was late May of 2020 when the tests were more available and my infection was late March. Who knows if I had any at all.
Did they/why did they not test for other virus-specific T-cells, like EBV specific T-cells? Seems like a no brainer if they think something is driving the immune activation.
Cort, Half of the long Covid patients who produced a coronavirus specific T cell, produced “no antibodies to the virus”? Maybe, I am now too far removed from molecular biology, but that seems like an impossible result. If that were the case, these patients would suffer from all sorts of other immuno-deficiency related diseases. This work came out of UC San Francisco Medical School? One of the best Bio-medical research facilities in this hemisphere. I’m speechless.
Isn’t that crazy! UCSF is one of the best medical schools in the country…The followup studies are going to be fascinating…
Thank you for sharing Cort! For someone who first got Covid, which then reactivated EBV and now suffers from very severe ME/CFS it is nice to see there is some “proper” research also pointing at latent viruses. Due to my brain fog I’m not really able to understand much what is being said here, but I have one question: The study indicates that autoantibodies aren’t playing a role. Does this include the GCPR-autoantibodies studied by Scheibenbogen? And if so how was this determined? Since according to what I’ve heard it doesn’t suffice to compare the levels of the antibodies in sick people with those in healthy people as the autoantibodies aren’t the problem itself but the environment in which they are (ischemia,inflammation,…)?
Great question, I’m also very interested in this, I’ve been watching dr. Scheibenbogens work on autoantibodies for a while now. Same with the BC007 research. My brain fog doesn’t allow me to understand the article fully.
I had the same question. I believe the antibodies they discovered have been associated with POTS, SFN, fatigue, etc.
Don’t worry you three. It’s not “fibro-fog” that is making it difficult to understand the research. Many of us commenting on here were former Bio-scientists. Cort received an extensive Bio-science education in the California State University System. So, he is perfect person to be presenting this complex Immunology, Physiology, and Biochemistry. I still believe that he is angel sent by God to help destroy this disease. Thanks Cort!
Adam and LB, jump ahead to the blog about Amy’s disability. I spent many nights studying Dr. Scheibenbogen’s results that she published in 2020. She has an ELISA assay that with statistical certainty shows that ME/CFS patients have elevated auto-antibody levels of IgG to either Beta-2 receptors (which are norepinephrine receptors in the autonomic N.S), or Muscarinic-4 receptors (which are acetylcholine receptors in the autonomic N.S.). The paper is really well written. Her methodology and stats are top notch. The paper was published in Brain, Behavior, and Immunity in August 2020. This woman and her post-Doc’s/grad students/Lab techs are cooking with gas. There is NO fee to read the journal article!!!!!!
Thanks so much as always for the great article. Thanks especially for ‘the gist.’ I have university degrees and did a lot of research analysis in my past life, but after 48 yrs. with ME, I do not have the brain power to plow through research articles anymore. Your site is a great service!
Glad to hear it! For me – I love plowing through the research 🙂
I used to love it, too. My research analysis professor at post grad level would ask to keep copies of my papers as examples for other students. I was top of maths, too. Now I can’t remember a lot of what I read and I count on my fingers. This is what M.E. can do. You keep up the good work.
Liz, it is incredibly complex. I, too, was a University of California Research scientist for many decades. Remember, there are 5 or 6 publications from outstanding research groups that have, indeed, found auto-antibodies in ME/CFS patients. In particular, antibodies to receptors on blood vessels. Dr. David Systrom at Harvard seems to believe that we may have auto-antibodies to receptors in our parasympathetic nervous system. That would explain the poor blood flow back to the right atrium of the heart. Systrom is a talented researcher. He’s brilliant, and I’m thrilled he is “on board”. He used Pyridostigmine to treat his ME/CFS patients, with great results. He continues to press on. Pyridostigmine is employed to treat another auto-immune disease: myasthenia gravus.
Thank you as always Cort.
My tests normally come back with :
Low CD-8 immune cells.
EBV reactivation.
Low testosterone.
That’s really interesting. Low levels of the T-cells tasked with getting rid of virally infected cells = viral persistence plus T-cell exhaustion (??), plus EBV reactivation, and then there’s low testosterone – a fascinating finding given that Klimas has found that testosterone is protective…..
It seems like you’re right in there! 🙂
If anyone is interested,
I cycle fenugreek (2 weeks on, 1 week off) to boost my testosterone, and I get regular (15minutes) timed sun exposure to keep my EBV under control. I also take lysine for the EBV.
As my testosterone showed up low in a recent test – thanks for mentioning that. 🙂
Happy to help Cort. 🙂
You might find this research paper on EBV quite informative:
https://pubmed.ncbi.nlm.nih.gov/31315893/
how much and how do you take lysine if i may ask? thanks!
I take 2.5grams of Lysine powder in water, on an empty stomach, half an hour before breakfast.
thank you verry much!!!
Pareil, pas assez de cellules tueuses et pas assez performantes.
EBV ancienne ou réactivée
Same, not enough killer cells and not performing enough.
Old or reactivated EBV
Yes – very interesting isn’t it? I wonder what they will find if they start assessing NK cell cytotoxicity (killing effectiveness)?
Exactly. To me studying NK cell effectiveness may be a key finding. I have a high T cell count but they are not working properly. I still show HHV6, C-pneumonia and Epstein Barr virus detected with specialized blood tests. I lost my train of thought. Darn
Wayne, Dr. Lucinda Bateman would probably respond that low testosterone levels are normal in male ME/CFS patients. Our pituitary is part of our autonomic nervous system, which has been “whacked” in ME/CFS.
Thanks a lot for sharing and keeping us up to date Cort, it really means a lot to us! As someone who first got Corona which (re)activated EBV and is now suffering from very severe ME/CFS it’s nice to see some proper research going into the EBV area. Due to my brain fog I’m not able to understand studies or even your detailed summary anymore, as such I have one question. The papers indicate, that the athors looked for autoanibodies and autoimmunity might not be the core problem. Does this include the GCPR-autoantibodies Scheibenbogen focusses on? And if so, how is this determined? As far as I’ve been told it doesn’t suffice to compare the levels of these autoantibodies in controls with those of healthy people as it isn’t the autoantibodies themselves that cause the problems but the environment in which they are (ischemia, inflammation).
That is a great question whichg that I have myself. I don’t know how to compare broad studies like this to studies that focus explicitly on these autoantibodies. Are the studies that specifically focus on these specific autoantibodies like this one – https://pubmed.ncbi.nlm.nih.gov/34441971/ – more accurate with regard to those autoantibodies? I would think so, but I don’t know.
All I’ve heard of is that these GCPR-autoantibodies are notoriously tricky to measure meaningfully. It would be lovely if there was more communication (maybe there is?) between the different research groups across continents. I feel like Europe and the US are very often focussing on completely different explanations for ME/CFS/Long-Covid, which is great for such a complex illness, but I feel like the lack of communication often leads to less meaningful results or simply the reproduction of things that have been expected without adding much more value.
an absolutelly yes, there must be more collaboration worldwide just like for excample breastcancer or so. sometimes i get the feeling , all reaserchers want to find it “alone” as first, the tes(s) and treatment(s) also for ME/cfs, FM, etc
I appreciate “the gist” as being a tool to help share research news with people with me/cfs whose brain fog and cognitive difficulties prevent them from reading or understanding the whole article, however it needs to be a lot more simple and concise. It needs to use shorter and simpler words and sentences. It needs to be straight to the point, less complex, use less words with 3 or more syllables, and it needs to explain any scientific or biological terms in everyday language, as if you were explaining it to a 12 year old. For example, after explaining what t-cells are, “the T-cells found in this study were not made for the Covid virus, they might be made for a reactivated virus, one that hides out in various body tissues, such as a herpesvirus”. No jargon, explained simply, for humans not scientists. I find the current gist just as hard to understand as the original article, only shorter. Please could you make “the gist” basic and simple, as required by its intended audience. Thank you
How could Cort make it even more simple like for excample the word T cells? i forget immediatelly, can often only read a few sentences, must read over and over or just on a little bit better day/moment or not. I clicked and clicked this time, have even forgotten how i did things, saw I guess a video from Mark davis (can not remember anything) except that he is allready working 35 years on T-cells. So if Cort must explain T-cells, i think when a ambitious rearcher studys it for 35 yers, it is just impossible to write it in 3 simple words, I do not understand it also, yes i know something of the immunesystem, but I know they are bussy, I try to find how much money for how long they have, how big the reasearch group is and controls and wich controls, if there is a P value (that is statistic relevance), conclusions (did they find anything, will they do further research, etc). So even if i do not understand it or can read it, I try to find the for me importent stuff. how big is the study, how big and wich controlgroup(s) are there, is there enough money, how long will the study take, the P value, the conclusion and certainly in general is there going to be a test(s) and treatment(s). Only to forge it again, but if there would be tests and treatments, i would not forget. I would print it out. I hope this helps. To not get overwhelmed with things. I am long time verry severelly ill to. but if i try to read, if there is help, i would know. And one day (moment) is better then an other day.
Reading your comment, Konjin, I’m reminded of how much we as a collective group, have learned over the years about medical research.
Still, I think I can do better at explaining 🙂
Hi Cort, you are amazing for someone who is ill himself. you have such a huge brain!!! 🙂 Do not force yourself or go over your bounderys please! if i want to know for excample T cells, i could look at wikipedia or just google it but i would also do not understand it or forget it immediatelly. I am in piece with that. As knowing something of the immunesystem. But if you must call so many things, something of the immunesystem, it would say nothing anymore… NK, T cells, etc. And do not forget, your blog go’s worldwide so my english is also not so good. and what with, is it mRNA or MirNa (allready forgot), SNIPS, etc… it is way to much i think. Just impossible to explain in 3 words. i think you do your job great! And you must rest or do other things to.
I have certainly a billion dollar question about ME/cfs, (the piece about it) when will there be a cure(s) and test(s) 😉 ?
And yes, over decades, when i was still better, I picked some things up. But many things are new and my brain got worse.
thanks for all your effort!!!
Thanks! I have the same billion dollar question – all I can say is that the odds are certainly much better than they were a couple of years ago.
As to finding help with ME/CFS – I would be shocked if several things that provided real help for many people didn’t show up.
you are allways so great in giving hope! 🙂
Thanks for the suggestion Anon. I always want to find ways to communicate better 🙂
I always assumed some of the idea of the gist is to help patients who can’t read a whole article due to brain fog or other issues. Adding in explanations of every technical term would make it substantially longer, making it difficult or impossible for those who rely on it when they are too foggy to read the article. The gist for this particular article is already long enough that it would probably stretch me if it was a bad brain fog day, and it might be prohibitively long (if it’s not already) if definitions were added.
I really appreciate the gist as it is, and I’m sure there are severe patients who rely on it being as short as possible. Just putting this out there as a counterbalance. I’m definitely not opposed to simpler language as long as it can be done without making it long or obscuring important details for patients who can no longer read the whole thing! Just worried about the gist changing so much that it’s unusual for some of us.
Thanks V- an increased length is a potential issue. Anon’s request is a nice reminder to me to try to make the GIST be as effective a communication tool as possible. It should really be a bottom-line thing: what is the bottom-line here?
I actually don’t think this does anything to rule out autoimmunity. If we know that just having COVID increases autoantibodies, then it is probably likely that people who get long COVID have other mechanisms (likely genetic) at play that result in their immune system going on to develop autoimmunity or other immune dysregulation and the people who don’t get long COVID but recover do not. Just because there was no statistical difference when looking at proteomic analysis of autoantibodies between the two groups doesn’t tell us much because as the authors mention this doesn’t take into account conformational factors and that is really important when it comes to antibody binding. Also, I think it is a lot more telling to look at the state of the immune cells as was done. Another thing that should be considered is just take the serum of long COVID patients and put it in mice and see if they develop symptoms – when that was finally done with serum from fibromyalgia patients it finally showed evidence of autoantibodies even though unclear what the autoantibodies were specifically targeting. Much to be done here but definitely seems much more likely to be autoimmune or immune dysregulation mechanism happening in long COVID, especially given the prevalence with which is affects women (who are more prone to autoimmune disease).
Thanks as ever Cort for making sense of this very interesting research, you are truly a hero for us, like others, I am extremely grateful to you!
Very much would second the comment by Emily Mercadante. The work of Goebel et al re fibromyalgia was extremely interesting, and I recall reading that some of the mentioned autoantibodies were binding to the dorsal root ganglia (the ganglia once again in the spotlight!)
Also, what pops into my mind more broadly with long covid and the autoimmune question – the autoimmune disease that seems closest in symptoms to MECFS/long covid, is Sjogren’s disease, with many patients being misdiagnosed with ME and/or fibro for many years (it is also the autoimmune disease with the highest propensity for women with a ratio of 9:1), another commonality with Long covid and ME, although less strongly. This misdiagnosis occurs because Sjogren’s can be seronegative in up to 40% of patients i.e. an ongoing sometimes severe autoimmune/autoinflammatory process going on, with negative autoantibodies (albeit limited to what can currently be tested in commercial labs), and it also tends to be the autoimmune disease with one of the highest predilections for the autonomic nervous system – so causing things like POTs, other autonomic issues, which are often features of long covid. So it’s not unusual to have autoimmunity in the absence of antibodies specifically in the blood (serum).
Would love to see tissue analysis done as a follow up (e.g. from the mucosa). There have been recent studies released indicating that covid can induce Sjogren’s or Sjogren’s like disease: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9628191/
Two really fascinating issues – the Goebel study and the Sjogren’s Syndrome overlap which could be huge…That hasn’t been addressed as much in the ME/CFS community as it has been in the POTS community. Thanks for the link.
Debbie, you are “spot on” about Sjogren’s! Plus, the phrase in Cort’s piece that bothered me was “at least one Covid-19 symptom that was still somewhat bothersome”. Wow, that study was funded, and Ron Davis waited all those years for a “tiny bit” of funding? Additionally, any statisticion would tell you that there were not enough patients in the study. (Yes, I know clinical research is expensive.)
I was first diagnosed with FM & CFIDS in ’98, correct diagnosis was Lyme disease (2010). 4 yrs to get rid of bacteria. Sick 16 yrs. Covid in July 2021, now Long Covid, Lyme symptoms returning. Will get re-tested for Lyme. Never fully recovered from Lyme. Cognitive problems life-changing. Lyme attacked my brain. Have some facility back, but must pace myself. Still unable to work since 1998. Huge social fallout. Insomnia, concentration, neck pain, memory, major problems. I don’t think I will fully recover. 67 now.
Marie, I’m sorry to hear all of that. Hang in there. Your brain can recover at the cellular level. Often times those who test positive for one of the Lyme bacterial strains, also have a tick-borne nematode called “Babesia”. Additionally, Dr. Richie Shoemaker and Dr. Andrew Heyman in Virginia successfully treat many desperate patients for “mold toxicity”, which presents with many of the same symptoms as Lyme or ME/CFS. They call the condition Chronic Inflammatory Response Syndrome.
Very interesting article. I was under Professor John Dwyer immunologist in Sydney Aust in the 1980s. He was the man who gave me the diagnosis of ME. One of his tests was focused on the T cells – I think T3? I had severe EBV earlier and it did not show in blood tests – no antibodies – until I was tested again some years later. A flu virus trigged my ME/CFS about five years after EBV – I had never fully recovered from the EBV.
Professor Dwyer did a trial of gammaglobulin infusions which helped some of his patients. Not me, unfortunately – I developed excema as a result – apparently happened to several others – Prof said he had only seen such a reaction in people with ME.
There you go – a poor antibody response – means you’re missing the part of the immune system that’s supposed to block pathogens from entering the cell. That would put a big load on the T-cells which are supposed to kill the infected cells – of which presumably many more – thus, one would think, possibly resulting in T-cell exhaustion.
He also did a prick test of about eight different substances on my arm – once again very little reaction. I’m not sure what the test was called.
It is a pitfall to convert the results of this small study into conclusions. And certainly to compare it to ME/CFS in general. First, Scheibenbogen found elevated antibodies in more POTS/ME patients. These antibodies are also present in healthy people but in reduced numbers. NK cells in ME patients are actually low in cytotoxicity (Klimas et al.). This is the only consistent finding in ME. In addition, Lipkin found a difference in functioning of the immune system during the first 3 years of the disease compared to a patient group who had been ill for longer.
These patients studied were unvaccinated. It is important in follow-up studies to continue, since many people have now been vaccinated.If you are vaccinated with an mRNA vaccine that has spread through the blood to various organs and can cause chronic inflammation there, the immune differences are no longer comparable to other groups.
Actually I think you can’t speak about long covid after 8 months maybe after 2 or 3 years. Fortunately, people get better within this period.
There are also now several covid variants Wuhan, Delta and Omicron). Perhaps that could also lead to different outcomes.
And what is T cell exhaustion? Can you measure this? Is this a medically accepted term?
Great question about T-cell exhaustion. Lissa Selin has a $2.5 million NIH grant to study it in ME/CFS – so the answer is an emphatic yes- it’s a real thing. Here’s what I found:
In a chronic infection, exhausted T (Tex) precursor cells are not able to fully clear the infection, and with continuous antigen stimulation, differentiate into Tex cells. Tex cells retain some effector and proliferative capacity and so can control infection. The infection remains, however, and Tex cells then enter into a terminal lineage and are eventually deleted.
with high exhaustion, Tmem cells are not created and thus cannot confer future immunity. These characteristics are of great interest to clinical researchers and pharmaceutical companies who are looking to increase the efficacy of checkpoint inhibitors in controlling and clearing tumors.
It’s measured by determining the ability of the cell to kill as well as the increased presence of inhibitory receptors on the cell and a reduction of cytokines that cause the cells to proliferate.
https://cofactorgenomics.com/wk-33-cd8-t-cell-exhaustion/#:~:text=Many%20other%20characteristics%20can%20be%20used%20to%20identify,of%20proliferative%20cytokines%20such%20as%20IL2%20and%20IFNy
Yes T cell exhaustion is a very well accepted medical term, it is highly studied and characterized in the context of cancer (ie, why are CD8 T cells unable to help get rid of cancer cells) and certain viruses. Here is a great free review article also: https://pubmed.ncbi.nlm.nih.gov/31570879/
This research seems like it could be really important ? so both groups still had some of those special CD8 T cells for corona knocking around although the study was done 8 months after ?
” the study did not find elevated T-cell responses to the SARS-CoV-2 coronavirus in the long-COVID patients ”
” They did, however, find evidence of exhausted SARS-CoV-2-specific CD8+ T-cells ”
I’m not sure what that means exactly, was it not elevated compared to the recovered, or elevated compared to normal people who never had coronavirus ?
How do they know whether they are exhausted and how could it be they are exhausted if its not even elevated ? am I right in thinking that the T Cell behaviour was therefore likely identical in the LC and recovered from covid groups during initial infection ?
I wondered about this as well – I suppose it makes sense that the T-cells could be exhausted (there may be receptors on the cells that show they are in an exhausted state (?)) and not elevated – they’ve just been worn out. The comparisons as I remember were between long COVID and recovered COVID-19 patients.
If I remember correctly they looked at the T-cells 4 and 8 months after the infection.
Treatment of coronavirus and other infectious diseases
I have the strongest t-cell immunity. It was proved by 4 immunograms in 3 of them t-cells were exceeded in abs.number/ml. In the first immunogram made in August, lymphocytes at a rate of 800-3600 I have 4108 (52%), t-lymphocytes at a rate of 600-2500 I have 2835, t-helpers at a rate of 450-850 and I have 1808 t-cytotolic at a rate of 270-540 and I have 945. The second time after a rest in a state sanatorium, at the request of an immunologist, he made a result of 3864 (46%) in 20 days. The third time I did it on my own, half a year later, the result was 3936 (48%) the next day after recovering from some kind of cold. With autoimmune diseases, there may be such a condition, the result of the analysis is negative. The AIDS center liked my results so much that they paid for the 2nd and 3rd immunogram, the 1st immunogram was paid for by 33 polyclinics. And in 1 immunogram, the calculation was carried out only as a percentage. I will provide 4 immunograms, if necessary, with an attached file, as well as the result of an analysis for autoimmune diseases, an immunologist’s consultation and 3 invitations to the immunology center in Kazan. The immunogram was made within 5 years.Within 5 years, he made more than 20 general blood tests according to the leukoformula, lymphocytes from 39 to 56%. And during the same time in the private laboratory of Invitro more than a dozen blood tests according to the leukoformula lymphocytes above normal neutrophils below normal. How I achieved such immunity. I eat 5 times a day because my mother is a cook by profession, an old-age pensioner. I eat only healthy food every morning I eat milk porridge every evening I drink kefir. Due to the disease diabetes insipidus (although I take the medicine desmopresin) I drink from 3 to 5 liters of water a day .The nervous system is iron because I don’t work because of disability. I almost don’t do sports because of the disease of olivoponoceribral degeneration with cerebellar atrophy, I only pedal every evening a broken exercise bike Is it possible to make a medicine from my immune cells? I strongly recommend watching the movie virus 2013 Korea.
You don’t want to repeat this scenario only on a global scale
I had a coronavirus in August for 2 days, symptoms of cough, sneezing, runny nose, fever. That it was on August 1 that the deputy heads of the 33 polyclinics could prove that he was ill. I was at his reception, he said that I looked sickly and sent me home. By the evening, these symptoms appeared. The fact that I was sick with coronavirus can prove a PCR test I did it on August 3, whether I am sick or not, the fact that I recovered on August 3 in the evening can be proved by a nurse from the same polyclinic. She came on August 4 in the morning as a coronavirus patient. The second time I was ill, the antibodies spontaneously rose from 201 to 316, the doctors say that I was ill asymptomatically.The day after my recovery, my mother fell ill with the same symptoms but also with a loss of sense of smell. We have a real skunk cat who drinks a lot of water because she eats only dry food and pees into a special plastic trough every day . Her smell is very smelly. So mom didn’t feel this smell for 10 days. And also how my immunity defused the coronavirus vaccination. I vaccinated Sputnik V and after the second injection a week later I tested for antibodies to the coronavirus. The result is 5.5. He was asymptomatically ill with hepatitis B for 2.5 months or less In mid-November, before hospitalization, he was tested for AIDS hepatitis. The result of the analysis was negative. In early February, before being admitted to another hospital, antibodies to hepatitis B were found in the analysis for AIDS hepatitis. And after 20 days, the antibodies disappeared. I did a second analysis, the result is the same.And for insurance in March I did an analysis for AIDS hepatitis, the result was negative. The first two and the final analysis took place at the state clinic AIDS Center and the remaining two analyses at the private clinic Invitro. I had two fatal diseases in a very mild form because I was ill for only 2 days and had hepatitis B in an asymptomatic form for 2.5 months or less. All evidence will be provided if necessary.
One of the two diseases leads to mandatory premature death. I can die at any moment because of the symptoms. My help will be free for Russians and for foreign countries it is also free if one condition is met: the complete cessation of the financing of the war.
I’m a psycho, but I was diagnosed for a similar article, but without proof.
Hi Cort, Do Selin and Gill have a hypothesis about how exhausted cd8 t cells cause post exertional malaise? The link about the grant said they were going to look for mechanisms for ME/CFS pathology, but I was wondering if they published any ideas about how it might work anywhere yet?
FFS this is so insanely disappointing, do they not bother to read the literature of the now well established autoimmune based scientists mainly in germany?
they literally didnt test for GCPR aabs, this is worthless in terms of an actual answer – we knew in 1990 that people with ME had t cell issues, ughhhhh what a damn shame
Siobhan, yes the Germans and the Finns seem to have a much better grip on the Immunology. I’m disappointed that Oncologists Fluge and Mella’s gave up on Rituximab. They found “something” in their cancer patients whose ME/CFS cleared when placed on a B cell depleter like Rituximab.
Medical knowledge has been expanding exponentially. Whereas the doubling time was an estimated 50 years back in 1950, it accelerated to 7 years in 1980, 3.5 years in 2010, and a projected 73 days by 2020, according to a 2011 study in Transactions of the Amercan Clinical and Climatological Association
This, combined with the amount of funding and research targeted at Long CoviD should give us hope.
I’ve been sick for 20 years and I am more hopeful than ever.
First of all – a warm and big thank you Cort. You are indeed a light of hope for all of us. Though, also a big thanks to all of you commenting that all contribute to advices and small pieces of the puzzle. Keep fighting all of you!
Regarding the topic I can conclude that I had moderate ME, went down with Covid and got a severe condition.
Just like many others I got reactivation of CMV, HVS1, HVS2 and likely (test pending VZV). I had good initial success in treating the virus with SOT injections (Supportive Oligonucleotide Therapy). Took down the active CMV to zero and now going after the rest.
How to help and restore the immune system? My (desperate) try is by injections of Thymosin Alpha 1. Currently under treatment and if somebody is interested I can report back in a few months with new lab data.
Best wishes for all of you.
Thanks for the info, Eric, would be great to see your results. Wishing you best of luck.