Transfer of IgG from Long COVID patients induces symptomology in mice

[junkcrap50]

https://www.biorxiv.org/content/10.1101/2024.05.30.596590v1

Transfer of IgG from Long COVID patients induces symptomology in mice​

View ORCID ProfileHung-Jen Chen, View ORCID ProfileBrent Appelman, View ORCID ProfileHanneke Willemen, Amelie Bos, Judith Prado, Chiara E. Geyer, View ORCID ProfilePatricia Silva Santos Ribeiro, Sabine Versteeg, View ORCID ProfileMads Delbo Larsen, Eline Schuchner, Marije M.K. Bomers, Ayesha H.A. Lavell, Amsterdam UMC COVID-19 biobank, Braeden Charlton, View ORCID ProfileRob Wust, View ORCID ProfileW. Joost Wiersinga, Michele van Vugt, View ORCID ProfileGestur Vidarsson, View ORCID ProfileNiels Eijkelkamp, View ORCID ProfileJeroen den Dunnen
doi: https://doi.org/10.1101/2024.05.30.

Abstract​

SARS-CoV-2 infections worldwide led to a surge in cases of Long COVID, a post-infectious syndrome. It has been hypothesized that autoantibodies play a crucial role in the development of Long COVID and other syndromes, such as fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this study, we tested this hypothesis by passively transferring total IgG from Long COVID patients to mice. Using Glial Fibrillary Acidic Protein (GFAP) and type-I interferon expression, we stratified patients into three Long COVID subgroups, each with unique plasma proteome signatures. Remarkably, IgG transfer from the two subgroups, which are characterized by higher plasma levels of neuronal proteins and leukocyte activation markers, induced pronounced and persistent sensory hypersensitivity with distinct kinetics. Conversely, IgG transfer from the third subgroup, which are characterized by enriched skeletal and cardiac muscle proteome profiles, reduced locomotor activity in mice without affecting their motor coordination. These findings demonstrate that transfer of IgG from Long COVID patients to mice replicates disease symptoms, underscoring IgG's causative role in Long COVID pathogenesis. This work proposes a murine model that mirrors Long COVID's pathophysiological mechanisms, which may be used as a tool for screening and developing targeted therapeutics.

Twitter thread about/explaining the paper from the head researcher:
https://x.com/DrDenDunnen/status/1796901736151392282

They identified subgroups in their LC patients and those subgroups' IgG induced different symptoms in mice.

Seems to be independently validated by Putrino:

10 minute presentation of this work, from Dec. 2023:

Putrino Video Presentation, from May 2024:

 

[junkcrap50]

They propose doing this for use as a mouse model. Similar experiment and results gave IgG from fibromyalgia patients to mice/rats giving them fibro symptoms. So... why hasn't anyone done this with IgG or serum with ME/CFS? We knew serum induces ME/CFS in cells for some time. And why hadn't anyone thought of doing this to make a mouse model for CFS? Seems sort of like a dropped ball.

 

[Treeman]

They propose doing this for use as a mouse model. Similar experiment and results gave IgG from fibromyalgia patients to mice/rats giving them fibro symptoms. So... why hasn't anyone done this with IgG or serum with ME/CFS? We knew serum induces ME/CFS in cells for some time. And why hadn't anyone thought of doing this to make a mouse model for CFS? Seems sort of like a dropped ball.

Didn't Prusty do it?

 

[smtl]

Don't you think it means efgartigimod should lessen the symptoms?

 

[junkcrap50]

Didn't Prusty do it?I

No. Not exactly. He used serum and IgG from ME/CFS patients, but placed them in cell cultures, not full mice to see if they develop the disease. That's still good as it validates other "something in the blood" experiments which expose cell cultures to ME/CFS serum.

Don't you think it means efgartigimod should lessen the symptoms?

I don't know anything about efgartigimod, but heard it's currently in a trial for LC. And looking up it's mechanism on wikipedia - it prevents IgG from being reused/recycled - it sounds like yes, it possibly could help. I hope it does.

 

[Hip]

I wonder if these researchers only transferred the IgG component of long COVID patients' blood to mice, or whether they may have also transferred some other unknown factors in the blood of these LC patients that might be responsible for creating the symptomology in the mice?

As we know, several ME/CFS research groups have previously found that there is "something in the serum" of ME/CFS patients which in vitro causes healthy cells to develop a dysfunctional energy metabolism (see this post).

 

[Treeman]

I wonder if these researchers only transferred the IgG component of long COVID patients' blood to mice, or whether they may have also transferred some other unknown factors in the blood of these LC patients that might be responsible for creating the symptomology in the mice?

As I understand it, IgG is treated for between 9-12 months to remove everything but the IgG for those who have primary immune diseases. It's not clear to me if the IgG taken underwent this treatment before being placed in the mice from the abstract, I don't have the energy to read the full paper, this may provide the answer.

 

[junkcrap50]

As I understand it, IgG is treated for between 9-12 months to remove everything but the IgG for those who have primary immune diseases. It's not clear to me if the IgG taken underwent this treatment before being placed in the mice from the abstract, I don't have the energy to read the full paper, this may provide the answer.

Everything was removed. It was pure IgG, no serum. From their methods:

Human IgG purification​

IgG was purified from 800 μl of patient serum or healthy donor EDTA plasma using Protein G-conjugated beads (Cytiva cat# 17061801). The beads were added to 1-ml gravity flow columns (Thermo Scientific, 89896) and washed with PBS. Serum/plasma was diluted 1:1 with PBS (pH = 7) and added to the washed column. The flow through was collected and reapplied to the column five times to increase recovery rate. After washing, bound IgG was eluted with elution buffer (0.1 M glycine buffer pH = 2.7) and immediately neutralized with neutralization buffer (1 M Tris buffer pH = 9). Protein concentration was determined by nanodrop measurement. Salt content was removed with Slide-A-Lyzer MINI Dialysis Device (Thermo Scientific). Purity of the eluted fractions was determined via SDS page and WB. Prior to injection, the samples were concentrated in saline buffer using Vivaspin to achieve a final concentration of 13 mg/ml.

 

[percyval577]

They propose doing this for use as a mouse model. Similar experiment and results gave IgG from fibromyalgia patients to mice/rats giving them fibro symptoms. So... why hasn't anyone done this with IgG or serum with ME/CFS? We knew serum induces ME/CFS in cells for some time. And why hadn't anyone thought of doing this to make a mouse model for CFS? Seems sort of like a dropped ball.

Long ago something like this had been done twice, with whole blood to apes. I think it was in the 50's.

In the first experiment the apes showed signs of neuro inflammation, post mortem.

In a second trial the finding was not reprocuced.

But this was actually the reason for classyfing ME/CFS as a neurological disease.

 

[Treeman]

Everything was removed. It was pure IgG, no serum. From their methods:

So it could be considered that the IgG is being corrupted, possibly by a virus. Any comments? Thanks.

 

[junkcrap50]

So it could be considered that the IgG is being corrupted, possibly by a virus. Any comments? Thanks.

I don't think anyone knows really why. But rather the virus acting on the IgG and corrupting it, I would view it more as the virus malfunctions the immune system, which then possibly creates corrupted IgG or does something else. The same thing happens in fibromyalgia, when giving mice IgG from fibromyalgia patients.

 

[Treeman]

Everything was removed. It was pure IgG, no serum. From their methods:

I don't think anyone knows really why. But rather the virus acting on the IgG and corrupting it, I would view it more as the virus malfunctions the immune system, which then possibly creates corrupted IgG or does something else. The same thing happens in fibromyalgia, when giving mice IgG from fibromyalgia patients.

In purification of IgG everything except the IgG is removed, therefore an expectation that anything including viruses can no longer be negatively impacting on it should be expected, I assume.

Unless the interruption is permanent wether the virus etc. is still present or not.