Students investigate effect of immune system of Long COVID patients on muscle cell function

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EndME

Senior Member (Voting Rights)
Original title in Dutch: Studenten onderzoeken het effect van immuunsysteem Long-COVID-patiënten op spiercelfunctie

https://www.umcutrecht.nl/nl/over-o...RmxS9TnRhFVjefjg0wrHaSluwSB7J7ihy6pm4DZlj_jis

Translated:

In October 2022, over 400 Medicine and Biomedical Sciences students were challenged with the Long-COVID Challenge. The aim: to take research into the causes of Long-COVID a step further. At the time - and still - there was insufficient biomedical research into the causes of Lung-COVID. The best idea was researched at UMC Utrecht's Bachelor Research Hub for the past 10 weeks. On 30 June, they shared the results.

The students presented their research results to family and friends, scientists from UMC Utrecht, Amsterdam UMC and VU University, representatives of the Long-COVID Foundation and other interested parties.

Autoantibodies affect muscle function in Long-COVID patients
The students focused on the hypothesis that Long-COVID is caused by autoantibodies and immune cells. And that this plays a role in the development of Long-COVID symptoms such as fatigue, muscle pain and reduced muscle strength. The students found specific autoantibodies in Long-COVID patients that can recognise muscle cells. Initial results show, among other things, that the autoantibodies can indeed affect muscle function, both of skeletal muscle cells and cardiac muscle cells. To look at cardiac muscle cells, the students worked with functional human cardiac organoids. In particular, the mitochondria - the batteries and energy suppliers - of muscle cells seem to be affected by specific autoantibodies.

The researchers at the different centres are excited about the results found and are convinced that each new piece of the puzzle brings us one step closer to the solution. They will now continue the research initiated by the students. This follow-up study should reveal whether these tested autoantibodies actually contribute to the pathogenesis of Lung-COVID.

Long-COVID challenge as a first
Never before have so many students at UMC Utrecht participated in innovative interdisciplinary education. In twelve interdisciplinary groups, the students came up with solutions for the treatment of pulmonary CVVID. On 9 November 2022, the most promising idea was announced. Some twenty students researched the unique idea in the Bachelor Research Hub of UMC Utrecht. Here, ten undergraduate students with backgrounds in Medicine, Biomedical Sciences, Veterinary Medicine and Biology collaborated with ten undergraduate students in Biomedical Sciences within the Experimental Translational Medicine elective course as part of their graduation project.

Students conducted their research under the guidance of coordinator Prof Niels Bovenschen, researchers Dr Niels Eijkelkamp (CTI, UMCU), Brent Appelman (Amsterdam UMC) and Dr Jeroen den Dunnen (Amsterdam UMC), their research teams (including Dr Amelie Bos, dr. Hanneke Willemen and Dr Judith Prado Sanchez), the staff members of the Bachelor Research Hub (Dr Toine ten Broeke, Dr Sandra Crnko, Heggert Rebel, Emma Pijnappel and Jan Meeldijk) and student assistants Romee van der Linden and Dani Holla.

Long-COVID Foundation (Stichting Long-COVID)
Annelies Bos worked as a gynaecologist at UMC Utrecht. Long-COVID forced her to stop working there. Together with Ellen Bark, she founded Stichting Long Covid in 2022. The goal: to raise money for biomedical research into the cause and treatment of Lung-COVID. The foundation eventually donated 23,000 euros to make the research possible during the Long-COVID Challenge for students.

My point of view:
There's some pictures in the link above. One for example reads "The antibody mix leads to hyperpolarization and increased mitochondrial ROS production". The research was conducted under the guidance of Jeroen den Dunnen who has apparently found autoantibodies associated to Long-Covid and used these in mice (unpublished work). Given the connection to Rob Wüst's muscle studies the students probably worked on something sensible.

Having said that I find it extremely unlikely, that Bachelor students, who have really only just started their studies, would have really done anything significant. For me the significant part of the project is that medical students investigate Long-Covid under the aspect of it being a physiological illness.
 
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A multi faceted team for a multi faceted illness finds something .
A systems condition requires broad collaboration across disciplines, but research is typically silo- ed
That's the hopeful bit from this .
 
Amw66 said:
A multi faceted team for a multi faceted illness finds something .
A systems condition requires broad collaboration across disciplines, but research is typically silo- ed
That's the hopeful bit from this .
Click to expand...

Second time in two days I read about silo's. Yesterday I read this: https://www.lymedisease.org/new-way-of-thinking-long-haul/. I'm too fogged up to make anything of it, but more collaboration is coming maybe?
 
EndME said:
Annelies Bos worked as a gynaecologist at UMC Utrecht. Long-COVID forced her to stop working there. Together with Ellen Bark, she founded Stichting Long Covid in 2022. The goal: to raise money for biomedical research into the cause and treatment of Lung-COVID. The foundation eventually donated 23,000 euros to make the research possible during the Long-COVID Challenge for students.
Click to expand...
EndME said:
The researchers at the different centres are excited about the results found and are convinced that each new piece of the puzzle brings us one step closer to the solution. They will now continue the research initiated by the students. This follow-up study should reveal whether these tested autoantibodies actually contribute to the pathogenesis of Lung-COVID.
Click to expand...

It's not clear from the article, but it sounds as though the patient organisation influenced the development of the Long-COVID Challenge. It's a smart idea if people have, or can develop, connections with a Medical School. A small amount of funds can get some preliminary research happening, informing the next generation of clinicians and scientists as well as their teachers, and possibly inspiring more experienced researchers to get involved.
 
Hoopoe said:
It would be nice to know the details of these antibodies. What do they bind to? Have they been associated with other diseases?
Click to expand...

Currently no information. Both Rob Wüst and Jeroen den Dunnen are somehow a bit involved in this bachelor student gimmick project. Jeroen den Dunnen has found some kind of autoantibodies associated to Long-Covid and has received a grant to study these in ME/CFS https://projecten.zonmw.nl/nl/project/autonome-autoimmuniteit-als-een-oorzaak-van-mecvs-symptomen. Nothing has been published yet, so I'm still a bit sceptical about someone using mice to inject Long-Covid into them by use of autoantibodies (if it works it would of course be insanely awesome). If one closely looks at some of the slides in the presentations one can see some things, but none of them mean anything to me as a layman.

That being said Jeroen den Dunnen and Rob Wüst are doing good work in the Netherlands without getting much means to do so.
 
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Some additional information on the progress can be found on website of Stichting Long Covid. The translated version reads:

Research on:
The role of autoimmunity in Long COVID

"Unraveling how autoimmunity induces tissue damage in Long COVID"

About this study

There is a large and growing group of people with Long COVID who maintain long-term symptoms after corona infection, with a variety of symptoms such as extreme fatigue after exercise, pain symptoms and brain fog. The cause of all these symptoms is still unclear, hampering the development of diagnostic tests and treatments for Long COVID. One of the theories on the cause of Long COVID is autoimmunity, in which the immune system recognises and attacks not (only) the pathogen, but also its own body. Until now, however, evidence was lacking that autoimmunity plays a causal role in Long COVID symptoms.

Through a collaboration of doctors and researchers from several university medical centres in the Netherlands, we have now been able to show that autoimmunity can directly cause Long COVID symptoms. Autoimmunity is characterised by the presence of antibodies directed against one's own body, so-called autoantibodies. Transferring (auto-)antibodies from Long COVID patients to mice caused similar symptoms, such as fatigue and pain, in the injected mice. Tissue staining of these mice showed that the autoantibodies, among other things, bind to cells in the nervous system. Our further research, by using a very large screening, was able to identify multiple body proteins against which the autoantibodies of Long COVID patients are directed.

The aim of this study is to find out how identified autoantibodies cause Long COVID symptoms. In fact, autoantibodies do not necessarily cause disease. Healthy people also produce antibodies directed against their own bodies. Whether an autoantibody causes disease depends not only on binding to the body's own proteins, but also on the structure of the antibody itself. In particular, sugar structures on the "tail" of an antibody determine how strong the immune response the antibody causes.

In our previous research, we found that during corona infection, some people produce antibodies against the virus with a tail with highly abnormal sugar structures, causing extreme immune responses. Our hypothesis is that in Long COVID patients, the same aberrant sugars are also placed on autoantibodies. To find out, we will first determine the exact sugar structure of the autoantibodies of our cohort of Long COVID patients. We can then determine how this aberrant sugar structure causes disease in different cells and tissues, by first finding out exactly how immune cells are activated, and then determining how the immune cells cause damage to skeletal muscle, platelets and endothelium and the nervous system.

These experiments will help in understanding the underlying mechanisms of Long COVID. Also, the identified autoantibodies, especially in combination with the specific sugar structure, can potentially serve as a bio-marker for the disease, determining both (objective) diagnosis and remission of the disease. This project will also lead to the establishment of in vitro models that can be used in the future to test drug candidates.

Members of research team

Amsterdam UMC

Immunology

Dr Hung-Jen Chen MD - Immunologist and bioinformatician
Dr Jeroen den Dunnen - Immunologist, research antibodies in infection and autoimmunity
Dr Amélie Bos - Immunologist
Drs Ashwin Mak - Immunologist

Antibodies expert
Dr Steven de Taeye - Expert on antibody glycosylation

Long COVID expertise
Prof Michèle van Vugt MD - Internist-infectious diseases
Brent Appelman MD - Physician researcher infectious diseases

LUMC

Antibodies expert
Prof Dr Manfred Wuhrer - Head of the Centre for Proteomics and Metabolomics

Utrecht UMC

Immunology
Dr Niels Eijkelkamp - Neuroimmunologist

Franciscus Gasthuis & Vlietland

Lung COVID expertise
Dr. David Ong MD - Medical microbiologist
Dr Gert-Jan Braunstahl MD - Pulmonologist

Sanquin

Antibodies expert
Prof Gestur Vidarsson - Head of immunoglobulin research

Free University of Amsterdam

Long COVID expertise
Dr Rob Wust - Movement scientist, expert on post-exertional malaise

University of Reading (United Kingdom)

Long COVID expertise
Prof Jonathan Gibbins - Expert on platelets and endothelial cells

UCL Health Informatics (United Kingdom)

Long COVID expertise
Dr Emma Wall - Long-COVID research consortium United Kingdom
 
EndME said:
Some additional information on the progress can be found on website of Stichting Long Covid. The translated version reads:

Research on:
The role of autoimmunity in Long COVID

"Unraveling how autoimmunity induces tissue damage in Long COVID"

About this study

There is a large and growing group of people with Long COVID who maintain long-term symptoms after corona infection, with a variety of symptoms such as extreme fatigue after exercise, pain symptoms and brain fog. The cause of all these symptoms is still unclear, hampering the development of diagnostic tests and treatments for Long COVID. One of the theories on the cause of Long COVID is autoimmunity, in which the immune system recognises and attacks not (only) the pathogen, but also its own body. Until now, however, evidence was lacking that autoimmunity plays a causal role in Long COVID symptoms.

Through a collaboration of doctors and researchers from several university medical centres in the Netherlands, we have now been able to show that autoimmunity can directly cause Long COVID symptoms. Autoimmunity is characterised by the presence of antibodies directed against one's own body, so-called autoantibodies. Transferring (auto-)antibodies from Long COVID patients to mice caused similar symptoms, such as fatigue and pain, in the injected mice. Tissue staining of these mice showed that the autoantibodies, among other things, bind to cells in the nervous system. Our further research, by using a very large screening, was able to identify multiple body proteins against which the autoantibodies of Long COVID patients are directed.

The aim of this study is to find out how identified autoantibodies cause Long COVID symptoms. In fact, autoantibodies do not necessarily cause disease. Healthy people also produce antibodies directed against their own bodies. Whether an autoantibody causes disease depends not only on binding to the body's own proteins, but also on the structure of the antibody itself. In particular, sugar structures on the "tail" of an antibody determine how strong the immune response the antibody causes.

In our previous research, we found that during corona infection, some people produce antibodies against the virus with a tail with highly abnormal sugar structures, causing extreme immune responses. Our hypothesis is that in Long COVID patients, the same aberrant sugars are also placed on autoantibodies. To find out, we will first determine the exact sugar structure of the autoantibodies of our cohort of Long COVID patients. We can then determine how this aberrant sugar structure causes disease in different cells and tissues, by first finding out exactly how immune cells are activated, and then determining how the immune cells cause damage to skeletal muscle, platelets and endothelium and the nervous system.

These experiments will help in understanding the underlying mechanisms of Long COVID. Also, the identified autoantibodies, especially in combination with the specific sugar structure, can potentially serve as a bio-marker for the disease, determining both (objective) diagnosis and remission of the disease. This project will also lead to the establishment of in vitro models that can be used in the future to test drug candidates.

Members of research team

Amsterdam UMC

Immunology

Dr Hung-Jen Chen MD - Immunologist and bioinformatician
Dr Jeroen den Dunnen - Immunologist, research antibodies in infection and autoimmunity
Dr Amélie Bos - Immunologist
Drs Ashwin Mak - Immunologist

Antibodies expert
Dr Steven de Taeye - Expert on antibody glycosylation

Long COVID expertise
Prof Michèle van Vugt MD - Internist-infectious diseases
Brent Appelman MD - Physician researcher infectious diseases

LUMC

Antibodies expert
Prof Dr Manfred Wuhrer - Head of the Centre for Proteomics and Metabolomics

Utrecht UMC

Immunology
Dr Niels Eijkelkamp - Neuroimmunologist

Franciscus Gasthuis & Vlietland

Lung COVID expertise
Dr. David Ong MD - Medical microbiologist
Dr Gert-Jan Braunstahl MD - Pulmonologist

Sanquin

Antibodies expert
Prof Gestur Vidarsson - Head of immunoglobulin research

Free University of Amsterdam

Long COVID expertise
Dr Rob Wust - Movement scientist, expert on post-exertional malaise

University of Reading (United Kingdom)

Long COVID expertise
Prof Jonathan Gibbins - Expert on platelets and endothelial cells

UCL Health Informatics (United Kingdom)

Long COVID expertise
Dr Emma Wall - Long-COVID research consortium United Kingdom
Click to expand...

Sounds like the antibodies they discovered in acute Covid (discussed here and here) were anti-spike IgG with some specific tail and now they are looking at antibodies with similar tails directed against endothelial cells in Long Covid. Whilst it sounds like they identified the proteins against which the antibodies were directed it doesn't necessarily sound like they were able to pin down the antibodies and as such it call all just be a consequence of injecting mice with IgG rather than anything else.
 
EndME said:
Whilst it sounds like they identified the proteins against which the antibodies were directed it doesn't necessarily sound like they were able to pin down the antibodies and as such it call all just be a consequence of injecting mice with IgG rather than anything else.
Click to expand...
The same thought crossed my mind. But surely they would also inject mice with IgG from healthy people as controls?
 
Hutan said:
The same thought crossed my mind. But surely they would also inject mice with IgG from healthy people as controls?
Click to expand...

Yes they definitely did. I think the problem is that they most likely looked at many different outcomes in the mice and only a few of those outcomes showed differences and then they decide to go with those and from there onwards anything might still be a result of different sampling techniques, who runs the mouse model or other ways to introduce noise even when you have good controls.

One might argue that one then just has to look at the differences between IgG in controls and LC patients but since it sounds like they couldn't determine anything causal, I'm guessing that the results simply aren't robust enough to do that.
 
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