How pandemics strengthen links between viruses and autoimmunity

Pandemic insight
The COVID-19 pandemic has pushed the link between viruses and autoimmunity into the spotlight. Over the past year, research suggesting that people with COVID-19 carry numerous autoantibodies in their blood has been widely reported — although the mechanism at play is as yet unclear. Akiko Iwasaki, an immunologist at Yale School of Medicine in New Haven, Connecticut, who was responsible for some of this work6, thinks that this autoantibody effect might partly explain the phenomenon of long COVID, in which people experience symptoms weeks or months after their initial infection. Some people’s symptoms might be due to persistent infection with the virus, but others could be experiencing immune dysregulation that leads to the continued targeting of their own cells.

Viral pandemics can do more than simply draw attention to the problem, however — they could also help to solve it. When a person with symptoms of an autoimmune disease first visits a physician, the acute infection that could have resulted in the disease might be a distant memory. Pandemics, however, are population-wide events that can generate a much clearer signal. “The sample size is very large in a pandemic, and the medical community is vigilant for rare effects,” says Steinman.

https://www.nature.com/articles/d41586-021-01835-w

 

Let me try a slightly different abstract.

Introduction: Viruses might be linked to autoimmunity.

Methods: So we allowed at least 193,668,196 people (so far) to get infected with a virus and waited to see if there was a flush of autoimmune disease.

Results: none seemed to turn up.

Conclusion: seems we were wrong.

We have millions of cases of LongCovid and a few hundred cases of weird syndromes in children and from vaccines but autoimmunity - deathly silence. How can people look out on a Sahara of evidence and cry 'what a lovely forest'?

The pandemic has provided us with a really useful piece of information. Viruses are remarkably good at not causing autoimmunity.

 

I've never suspected an autoimmune disease in my case after a viral infection, but there is a high (?) percentage of pwME who suspect they have an autoimmune disease.

 

I had not actually read the article but it is the tired old old story I was familiar with from my student days which my 1999 article in Immunology with Jo Cambridge should have finally put to bed. There is not a scrap of evidence for it. Rather than being at the cutting edge of immunology people like Altman are just picking up 50 year old fag ends.

What to me has always been so weird is that so many scientists can be so selective inter use of evidence. Maybe they should have become priests.

And of course infection does produce long term immunological disease - but WITHOUT any autoimmunity. The problem is something quite different, todo with non-specific shifts in T cell activation (e.g. psoriasis).

 

Yea because the diagnostic tests are crap* and people haven't picked up a point that @Jonathan Edwards made i.e. if the proposed causal autoantibodies are lowered by rituximab then why didn't people recover when treated with rituximab? OK there could be a few autoimmune cases of ME/CFS i.e. which weren't in the phase 3 rituximab trial.

*there was a paper discussed recently on this forum which uses genetically modified yeast to produce human proteins which are then used to look for autoimmune antibodies - @Jonathan Edwards thought that technology looked promising i.e. to look at ME/CFS.

Hopefully I'm not misquoting Jonathan.

 

I am just curious, but what do you think causes autoimmunity?

 

Read my paper with Jo Cambridge in Immunology 1999!
B cells operate on a basis of random generation of antibody types with a chain reaction positive feedback loop for mass production when needed. To explain autoimmunity you need to find a way to trick the chain reaction into activating for self. The presence of foreign antigens that look like self does not help - the system as we understand it, should make the right choice. If foreign antigen can trick the system then self antigen, which is around all the time, is much more likely to.

The answer we have proposed, and for which the use of rituximab was a real life test, is that the signalling mechanisms for the chain reaction have predictable Achilles heels where self antigens can interact with antibody in a way that does not follow the normal rules. The simplest example is rheumatoid factor - where the antigen and the antibody are the same class of molecule - which it is not too difficult to see is likely to confuse the signalling.

Perhaps the main reason why something like this must be the answer is that autoantibody production is not like the production of antibody to foreign antigens. The normal rules go to pot. You get IgG produced without IgM or you get VH4-34 bearing B cells producing antibodies in bulk when VH4-34 B cells do not normally do that. The epitopes recognised are skewed in strange ways. Autoantibody production is not just producing antibody to the wrong thing it is antibody production that breaks the rules, which happens to include the rule of not recognising self.

The other thing of course is that almost all autoimmunity seems to come out of the blue NOT following an infection. There is no evidence for any consistent trigger for autoimmune diseases with rare exceptions like procainamide induced lupus-like disease. If autoimmunity arises as a random mistake within the regulation B cells that makes sense. The problem is that we instinctively want to find a causal event in the outside world. And another problem is that most immunologists do not seem toothier too much about checking their hand-waving theories would work in terms of physical chemistry!

 

@Jonathan Edwards

Can I ask what your views are on 'autoimmune Lyme"? thank you.

This was published a few weeks ago:

https://www.nature.com/articles/s41584-021-00648-5

 

The quoted abstract illustrates well how poorly immunologists understand their own terminology (and also the pathology of synovium, which at one time was my special expertise).

A dysregulated inflammatory response is not' autoimmune' unless there is actual immune reactivity to self, as there is in RA or lupus but not in Reiter's, psoriasis, ankylosing spondylitis, parvovirus arthropathy or Lyme. IL-10 is one of the main drivers of antibody production so a lack of IL-10 is not going to favour autoimmunity.

One of the misconceptions that underlies a lot of this theorising is that autoimmunity involves autoimmune T cells but nobody has ever found any of those as far as I can see, except in a very rare genetic thyme condition called AIR.

So the suggestion that Lyme provides a model for autoimmunity is just the sort of dumb idea that is the reason why almost no progress has been made in understanding these illnesses in the last 20 years. Before that we made a lot of progress but immunology has been taken over by the same 'fast-followers', who in themselves generate nothing new, as in so many branches of biomedical science.

In other words the same old, old, tired nonsense.

 

I've seen long-covid referred to an estrogen-associated autoimmune disease. It seems autoimmune is the new buzz word for post-covid syndrome too.

 

I get the general impression that autoimmune is mostly used as a proxy for "immune but we don't know what causes it". It's not as if we know much about how any of this works anyway, a mere fraction of the whole puzzle at best and likely missing the key pieces. Probably just something that comes from the endless obsession with dismissing environmental factors as less interesting than Freudian-derived thoughts and beliefs, which would be so easy to fix if any of it were real.

There's a visceral disgust with the possibility that much of human disease could come from something so vast and unpredictable, we have developed nothing to take that into account, haven't even begun actually bothering to keep track of all infectious diseases, instead of just the few that we know are dangerous. The scale ratio between viruses and a human body is as wide as the size ratio between a human body and the whole volume of the Earth, and much of it is beyond the reach of current technology.

Humans love predictable patterns and medicine especially so. The idea that any number of the trillions of pathogens and various toxins could be causes of disease in ways that would simply take too much work to figure out is daunting, especially so as efforts in that direction haven't even begun. The safety of digging under the light is still preferable to going into the uncertainty of the wilderness again. Just looking at how much work it took to stop vaporizing lead in the atmosphere and that's just one factor out of basically trillions.

 

Maybe the following two articles could provide a route? Even in generell?? I though don´t know how T-cells and B-cells are linked to each other -


A manganese-rich enviroment supports superoxide dismutase activity in a Lyme disease pathogen, Borrelia Burgdorferi
Aguirre et al 2013

Discussion, 2nd and 3rd paragraph

From the Results, 5th paragraph

Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses
Wang et al 2018

Introduction (my bold)

 

some further details, if it is worth to have a look.

from the Discussion (my bold)

In the first chapter of the Results they describe how they discovered the Mn-dependency (my bold)

 

While there is no evidence for any sort of generalised increase in autoimmunity risk, you do agree that certain infections can trigger specific acute autoimmune syndromes?

Such as Guillain Barre Syndrome and the various autoimmune throbocytopenia and thrombosis with thrombocytopenia syndromes.

Each can be explained by specific mechanisms of B-cell cocapture of self-foreign antigen complexes.

I also note that while there is strong evidence linking cases of Guillain Barre Syndrome with Campylobacter Jejuni infection, and the most popular mechanism hypothesis is molecular mimicry, it is not the only hypothesis that can explain the phenomena and it also does not explain the association of GBS with other infections where there are no clear mimic sequences of sufficient size. (and I'd expect molecular mimicry to lead to immune tolerance, rather than autoimmunity...)

Also notably, thrombosis with thrombocytopenia syndromes and GBS have also been associated with antibodies targeted towards complexes, such as multiple gangliosides or CXCL4 bound to proteoglycan complexes. All of the known or suspected infectious triggers of GBS all contain antigens that have strong evidence of binding to gangliosides, for example. Given that SARS-CoV-2 spike proteins are known to strongly bind to specific proteoglycans, it doesn't take much imagination to suggest a mechanism for the thrombosis with thrombocytopenia syndrome associated with COVID in patients who haven't received anti-coagulant therapies (or the associated vaccine syndrome).

I wish more researchers would focus on this angle of research in attempting to explain these syndromes, but most research seem to be focused on general/non-specific associations or T-cell BS.