Yes, I believe so. Also the first time in my life I've witnessed an announcement of an announcement of an announcement of an announcement.
Prusty talks about his upcoming research on a podcast
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The Twitter thread to Prusty's talk
. I'm actually very pleasantly surprised by the amount of samples he has.
Judee
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Depletion of natural IgM
So like IgM deficiency?
So like IgM deficiency?
Looks like it. This talks about therapeutic options: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266110/
Interesting that it said something about spleen as I apparently have mild 'splenomegaly' which the doctor believed could be due to viral activity. Early on in the illness as in the first few months, I had a sore pressure sensitive / ache area around the diaphram / middle of the stomach above the belly button, which wasn't explained.
Lipkin analysed serum though, was this what was done here or was it somehow measured more directly in the tissue using other techniques or are these things comparable? In any case, as always for ME/CFS: Small studies and irreproducible results, name a more iconic duo.
Dude
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Maybe this mysterious therapy that has helped some is IVIG. It also contains a small amount of IgM and has already been tried with MECFS. To be fair, with mixed results, but i also know a person that got better with it.
Countrygirl
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Dr Prusty is about to present the contents of his paper here: https://www.tlcsessions.net/episodes/episode-58-breakthrough-biomarker-
junkcrap50
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Yes, perhaps a cocktail of IVIgM could be relatively easily produced and tested in a small scale
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Wouldn't a deficiency of citrate synthase = elevated citrate. I'm not biologically techy but it sounds like citrate synthase utilizes citrate. Therefore if there isn't enough it wouldn't that create a glut of citrate?? IDK.
And maybe I misunderstood what you were saying which is probable.
Citrate synthase is the enzyme that assists in making citrate. So if that enzyme is deficient you would expect citrate levels to be low, but lipkin found the opposite - it was high in blood. You see?
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Judee
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Both you and that summary Osaca posted say that but I've been told there isn't any IgM in IVIG so how would that correct this? (Not trying to contradict anyone, just trying to understand based on what I was told...which could have been wrong info.)
Edit: It sounds like from what Vlad posted in #286 above it would actually have to be enriched with IgM.
??
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junkcrap50
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The link Osaca provided has a text summary of the latest interview. I've copied it below in case anyone did not click through & view the link. Note: I did not write the summary. GimmedatPHDposition from reddit summarized it:
The following is a summary of an interview given by Dr. Bhupesh K Prusty (https://scholar.google.de/citations?hl=en&user=y7cvLpYAAAAJ&view_op=list_works) in TLC Sessions which had previously been announced. Some patients had previously voiced their dissatisfaction with “hyping” up the paper instead of just publishing it or uploading a preprint, whilst others had been eagerly waiting and revisiting the literature and previous papers by Prusty. In either case the reveal of the paper and its possible content have been discussed to a large degree and one can only hope that it meets the expectations that were made in the build up process.
I still want to warn patients not to get their hopes up too much. This is just a singular paper that by no means fully explains or solves ME/CFS or Long-Covid, nor can we currently call the content a tested and verified biomarker. Most importantly though, we haven’t seen the data yet nor has it been peer reviewed. However, it should also be mentioned that Prusty is not a “snake oil salesman” as some people were calling him. He is a well respected scientist amongst his peers, as his track record with many meaningful publications in the ME/CFS field shows.
The full interview can be listed to here: https://www.tlcsessions.net/episodes/episode-58-breakthrough-biomarker- or on Spotify
The interview is a great one and Prusty is very sympathetic in it. There definitely is not any “teasing” or “overpromising”. But it's still early days and we shouldn't jump to conclusions. Reproducibilty and an insight into the actual is key!
Very short summary:
The paper has been submitted to publication (not peer-reviewed yet). After Covid Fibronectin 1 is elevated in the serum but not integrated into the immune complex, where it is low. IgM is statistically low in Long-Covid and ME/CFS patients. This is triggered by the initial acute infection. Some can recover from this, in others it might cause an autoimmune Long-Covid or ME/CFS disease. Other effects are also happening. A treatment that could try to address this, would for example be IVIG. However, it is far too early to say anything yet, this is not medical advice!
TL;DR: No difference in natural IGM levels between severe ME patients & Long Covid patients. 85% similarity between severe ME patients & all Long Covid patients & 81% similarity between all ME patients & all Long Covid patients. Natural IGM differentiates patients from controls
Full summary:
Bhupesh Prusty has recently presented his newer findings at various conferences and has submitted his paper containing the details of this. Prusty has mentioned that he feels uncomfortable about not revealing everything initally, which some believed to be “teasing”. However, this was necessary due to his due diligence process and to verify various cohorts and obtain the bureaucratic means needed within the various cohorts. The paper has been written in collaborations with various world renown researchers at Ohio State university, Carmen Scheibenbogen and Uta Behrends. This allowed him access to large cohorts with different disease severities and subgroups. The Long-Covid cohort have been infected for 6-12 months. He hopes that the biomarker has at least an accuracy rate of 85%.
The research started by looking for signatures of Herpesviruses (EBV, HHV-6, HSV-1, etc.). During this work they came across the work of Maria Ariza of Ohio State university (who had amongst other things previously written this great paper https://insight.jci.org/articles/view/158193) and had previously collaborated with Prusty’s lab. Maria Ariza had been working on dUTPases proteins with Prusty. They found signatures of Herpesviruses. This doesn’t mean that the virus has to be actively reproducing, however it suggests a not too long ago reactivation. In ME/CFS patients the EBV dUTPase are particularly high. In the Long-Covid subgroups this is the case for IgG responses against HSV-1, EBV is also reactivated but the antibody response is not too significant. Interestingly the the antibody response against HHV-6 dUTPase actually goes down in LC patients, which is slightly different from ME/CFS (but there’s also a difference of disease duration)!
The next step was trying to understand what these viral dUTPase proteins could be causing. The found out that these proteins could cause Hypopolarized/Hypofused mitochondria, clumping them together in certain cells. This is typical for neurological diseases. All Herpes dUTPase can change the mitochondrial morphology. Prolonged and leaky Herpesvirus reactivation can can cause autoimmunity. This is the focus of this paper.
In acute Covid we know there’s high levels of autoantibodies. They tried to find specific autoantibodies in Long-Covid and in ME/CFS due to these Herpesviruses. They started off with a small group of ME/CFS patients where they searched for IgG and IgM responses. The IgG response was not sufficient to separate ME/CFS and HC, however the IgM response differed. Out of the 120 autoantibodies that they looked at, the most relevant for differentiation was Fibronectin which was interestingly not higher but lower (other autoantibodies were usually higher similar to autoimmune diseases like Lupus). That is IgM response against Fibronectin goes down in ME/CFS.
A next step was try to understand how the very localised Herpesvirus reactivations could cause the serve symptoms patients are experiencing. They deduced that it had to be that this caused changes in the extracellular fluid, i.e. blood similar to the old saying “there’s something in the blood of ME/CFS patients”.
They looked at 30 ME/CFS patients and 30 ME/CFS patients and looked at their isolated IgG’s. These IgG’s of ME/CFS patients caused changes when applied to healthy endothelial cells causing mitochondrial fragmentation, quantified by low mitofusion 1 levels. There might be further factors that contribute to mitochondrial fragmentation, their focus are IgG’s. Using massspectrometry to try to untangle what’s happening with the blood, they discovered that Fibronectin 1, Transferrin and alpha 2 macroglobulin were decreased within the immune complex of ME/CFS patients vs HC. Since Fibronectin 1 is part of the complement pathway this might mean that ME/CFS patients are more prone to diseases and viral reactivations.
Why are these proteins reduced in the immune complex of ME/CFS patients? They now looked their values in the blood. Interestingly the protein Fibronetin 1 is higher in the serum of ME/CFS patients. That is, the protein is being produced in sufficient amounts but for some still unknown reason its not incorporating into the immune complex. These higher levels can differentiate Fibronectin levels in ME/CFS patients to a decent accuracy. The is also the case for the mild and severe Long-Covid patients. Males have lower amounts of circulating Fibronetin 1 (this might mean that woman are more prone for reaching a threshold).
Next they tried to understand why Fibronectin levels were changed. In the literature they found that it could be because of an infection. To understand autoimmunity better they developed an assay to quantify the IgM and IgG response against Fibronectin. They discovered that they could seperate the severity of ME/CFS patients by levels of IgM response against Fibronectin, that is severe ME/CFS patients have the lowest response. The same holds for Long-Covid. There is a gradual pattern of lower levels, correlating to disease severity.
These results were then discussed with Akiko Iwasaki. In the last month they did some further testing of specific IgM responses she had thought to be useful. They saw that the entire natural IgM population was going down after a Covid infection (independent of some reactivation of Herpesviruses). This was a clear pattern in Covid-19 and they found that the more severe Long-Covid patients did not recover from this. Long-Covid patients have an almost depleted amount of natural IgM. This could be a biomarker, however one would still have to see if it’s really just a cause of acute Covid and that stabilises after sufficient time or whether Long-Covid patients that have been sick for 3+ years still have lower natural IgM levels. Further studies are needed to find out more.
Their hypothesis is that B1-cells aren’t producing sufficient amounts of IgM (possibly because of Herpesvirus reactivations which affect B-cells, but the direct affect of Covid seems the more plausible explanation currently). This requires further work. Tim Henrich et al are currently doing work in this direction. A plausible hypothesis is viral reactivation or viral infection of the bone marrow. This is usually not common and very few studies exist on this.
In any case something is happening in the B1-cells which causes patients to loose amounts of natural IgM. The immune response to this is a IgG response (to do the job IgM usually would), this causes autoimmunity.
In terms of circulating Fibronectin and IgM response against Fibronectin severe Long-Covid and ME/CFS patients look similar. Interestingly woman have more natural IgM than man when healthy, however if both sexes have a Covid infection woman seem to have a lower amount than men. There seems to be a trend which motivates further studies of immunologists into this topic. This IgM response is because of Covid, Herpesviruses might be involved due to their influence on specific localised tissue, however the correlation to Covid is far more obvious. However, if we look at non-Covid induced ME/CFS there seems to be a high degree of similarity and there has to be an explanation for this. Perhaps the exact virus is not relevant. Based on the current data these 2 groups have 2 distinct mechanisms causing the IgM response.
A treatment to address this could possibly be IVIG. Other options could be Immunadsorption or combinations of various therapies including cell transfusions. One might have to reintroduce the natural IgM or start a process which does so naturally. However, it is far too early to call these things treatments. If anything there is still a lot of groundwork to be done to verify the results and further understand them. Research takes time. Reproducibilty is key!
Furthermore all these test can be done by ELISA, which is cost-effective and can be availabe to patients in the future. They are not planning to patent them (yay! Big thumps up Bhupesh). In the future they want to look at animal models to try to understand the above descriped phenomena. There is potential for other autoimmune diseases like MS.
Finally there are other symptoms and aspects of the disease that could be indepent of the above named phenomena.
This is just the beginning (or not).
Someone else also did a TLDR summary of the interview:
And apparently a " bear"
is with them