How Viruses Cause Autoimmunity

Pyrrhus

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:monocle: I thought I would start a thread to summarize discussions about the research on how viruses can cause autoimmunity. :monocle:

We already have two good discussions about papers which describe the ways in which viral infections, or chronic inflammation, can cause autoimmunity:


How pandemics strengthen links between viruses and autoimmunity (King, 2021)
https://forums.phoenixrising.me/thr...toimmunity-journal-article-from-nature.85019/
A rather good article. It mentions three ways that viruses can cause autoimmunity:
  • Molecular mimicry, where an immune response generated against a pathogen happens to cross-react against normal human tissue.
  • Epitope spreading, where immune cells mistake human tissue that is near a pathogen as part of the infection, generating an autoimmune response against that human tissue. Often, the human tissue is an intracellular remnant from a cell destroyed in the infection.
  • Failure of Regulatory T cells, where the regulatory T cells (Treg) that normally suppress autoimmune cells fail to activate during inflammation.


The role of infections in autoimmune disease (Ercolini and Miller, 2009)
https://forums.phoenixrising.me/threads/the-role-of-infections-in-autoimmune-disease.31721/
A paper that describes molecular mimicry and epitope spreading, as well as bystander activation and cryptic antigens.
ABSTRACT
Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.
[...]
Mechanisms by which pathogens may cause autoimmunity.
  • (a) Molecular mimicry occurs when pathogen-derived epitopes are cross-reactive with self-derived epitopes. Pathogen-derived epitopes are taken up by antigen-presenting cells (APCs) and presented to cytolytic T cells (Tc) via major histocompatibility complex (MHC) class I or to helper T cells (Th) via MHC class II. T cells activated by pathogenic epitopes that are cross-reactive with self-epitopes can then damage self-tissue via lysis (Tc) or release of cytokines (Th). Cytokines released by activated Th cells can activate macrophages (Mφ) or provide help to B cells. Pathogen-derived surface antigens are recognized by a B cell's B cell receptor (BCR), which triggers the secretion of antibodies. These antibodies can cause damage by binding to cross-reactive epitopes on the surface of tissues and disrupting tissue function, or the Fc portion of the antibody can bind simultaneously to the Fc receptor (FcR) on Mφ; this will trigger the Mφ to produce tissue-damaging cytokines. Damaged tissue will release more cross-reactive antigens, which will be taken up by APCs, propagating further damage.

  • (b) In epitope spreading, the immune response to a persisting pathogen, or direct lysis of self-tissue by the persisting pathogen, causes damage to self-tissue. Antigens released from damaged tissue are taken up by APCs, and this initiates an immune response directed towards self-antigens.

  • (c) In bystander activation, the various parts of the immune system respond to the invading pathogens. The inflammatory environment triggered by this response damages self-tissue in an antigen non-specific manner, and in addition triggers non-specific activation of immune cells.

  • (d) In contrast to dominant antigenic determinants, subdominant cryptic antigens are normally invisible to the immune system. The inflammatory environment that arises after infection can induce increased protease production and differential processing of released self-epitopes by APCs.

MOLECULAR MIMICRY and EPITOPE SPREADING:
1641410339291.png



BYSTANDER ACTIVATION and CRYPTIC ANTIGENS:
1641410364370.png
 
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Pyrrhus

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Another good paper, which notes how in some cases, autoimmunity seems to develop only after a long period of chronic inflammation, similar to what has been observed in multiple sclerosis. (Where studies suggest that the disease process in multiple sclerosis begins many years before any autoimmunity might be detected.)


Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and Autoimmune Disease (Fujinami et al., 2006)
https://doi.org/10.1128/CMR.19.1.80-94.2006
ABSTRACT
Virus infections and autoimmune disease have long been linked. These infections often precede the occurrence of inflammation in the target organ. Several mechanisms often used to explain the association of autoimmunity and virus infection are molecular mimicry, bystander activation (with or without epitope spreading), and viral persistence. These mechanisms have been used separately or in various combinations to account for the immunopathology observed at the site of infection and/or sites of autoimmune disease, such as the brain, heart, and pancreas. These mechanisms are discussed in the context of multiple sclerosis, myocarditis, and diabetes, three immune-medicated diseases often linked with virus infections.
[...]
Persistent Virus Infections
Persistent viral infections can lead to immune-mediated injury due to the constant presence of viral antigen driving the immune response. Many of these aspects will be discussed in the myocarditis section. One example of a persistent CNS infection is Theiler's murine encephalomyelitis virus infection of susceptible mice. Following infection, an acute disease develops where neurons are infected and an encephalitis ensues. Most mice recover from this acute disease phase and develop a persistent infection. In the CNS Theiler's murine encephalomyocarditis virus is able to persist in glial cells, particularly astrocytes, microglial cells, and oligodendrocytes, and macrophages (137). Infectious virus, viral proteins, and the viral genome can be detected for the life of the animal. Much of the demyelinating disease is driven by the presence of virus and viral antigens in oligodendrocytes or associated glial cells. T-cell responses against virus-infected cells lead to inflammation and demyelination. Antiviral antibodies can also play a role in immune-mediated disease. Antiviral immune responses initiate disease (34). However, later during the chronic phase, immune reactivity to CNS myelin antigen can be detected and is thought to enhance the extent of demyelination (139).
(emphasis added)
 
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Pyrrhus

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Another good paper, which notes that perhaps too much emphasis has been placed on "genetic influences" when discussing the causes of autoimmunity:


Virus infection, antiviral immunity, and autoimmunity (Getts et al., 2013)
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC3971377/pdf/nihms565378.pdf
Summary
As a group of disorders, autoimmunity ranks as the third most prevalent cause of morbidity and mortality in the Western World. However, the etiology of most autoimmune diseases remains unknown. Although genetic linkage studies support a critical underlying role for genetics, the geographic distribution of these disorders as well as the low concordance rates in monozygotic twins suggest that a combination of other factors including environmental ones are involved.

Virus infection is a primary factor that has been implicated in the initiation of autoimmune disease. Infection triggers a robust and usually well-coordinated immune response that is critical for viral clearance. However, in some instances, immune regulatory mechanisms may falter, culminating in the breakdown of self-tolerance, resulting in immune-mediated attack directed against both viral and self-antigens. Traditionally, cross-reactive T-cell recognition, known as molecular mimicry, as well as bystander T-cell activation, culminating in epitope spreading, have been the predominant mechanisms elucidated through which infection may culminate in an T-cell-mediated autoimmune response. However, other hypotheses including virus-induced decoy of the immune system also warrant discussion in regard to their potential for triggering autoimmunity. In this review, we discuss the mechanisms by which virus infection and antiviral immunity contribute to the development of autoimmunity.
 

Pyrrhus

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Another related publication, which questions whether immunosuppressive treatments are really the correct way to treat autoimmune disease in the long-term.

This may be a particularly relevant question, since billions of dollars have been poured into approving various immunosuppressive treatments for autoimmune diseases, despite the fact that these immunosuppressive treatments have a somewhat questionable record of efficacy.

Some have noted that the FDA only requires proof that such treatments work in the short-term, up to 18 months. Sometimes the FDA asks the manufacturer to perform long-term follow-up studies, but these studies are not always performed within the time frame of the drug patent.


Re-framing the Theory of Autoimmunity in the Era of the Microbiome: Persistent Pathogens, Autoantibodies, and Molecular Mimicry (Proal and Marshall, 2018)
https://forums.phoenixrising.me/threads/why-autoimmunity-probably-doesnt-exist.75795/


Excerpt:
The theory of autoimmunity was developed at a time when the human body was regarded as largely sterile. Antibodies in patients with chronic inflammatory disease could consequently not be tied to persistent human pathogens. The concept of the "autoantibody" was created to reconcile this phenomenon.

Today, however, the discovery of the human microbiome has revolutionized our understanding of human biology. Humans are superorganisms that harbor trillions of persistent microbial cells. Indeed, vast human microbiomes have been detected in human tissue and blood. These microbial ecosystems harbor thousands of newly identified bacteria, viruses, and other microorganisms -- most of which can act as pathogens under conditions of immunosuppression.

The theory of autoimmunity must be revised to account for the human microbiome. Here, we propose a model in which "autoantibodies" are created in response to chronic, persistent microbiome pathogens. The structural homology (molecular mimicry) between pathogen and host proteins can result in "collateral damage" to surrounding human tissue.

This calls for a paradigm shift in autoimmune disease treatment. Immunosuppressive medications palliate inflammatory symptoms at the expense of microbiome health and balance. In contrast, treatments that support the immune system in autoimmune disease could allow patients to target pathogens at the root of the disease process.
(bolding added for emphasis and spacing added for readability)
 
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Thank you for both of those. Sometimes I think they want to discourage .... uh ..... the more casual, non-professional readers ..... and by casual, I mean non-pharma or medically connected ....
As a former (and potentially future if I get cured somehow.!) postdoc in medical research, I can quite confidently say that this is not the case. Scientific language is just more complete, accurate and expressive, particularly when it comes to the specific topics and sub topics.

We would often have to write a "plain English summary" for grants and some papers. This is very difficult to compile, and you lose a lot of the nuance.

Overall, papers are written with the understanding that the primary (if not only) audience is other scientists, and not only scientists, but ones from your specific field. I don't believe anyone outside of my field would have read any of my papers. We just happen to get into the weeds here because mainstream medicine has failed us so we have to assume the role of self-tinkerer.
 

godlovesatrier

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I do wonder whether some of the things on joshuas protocol actually make inflammation worse. Specifically oat bran and liposomal glutathione. The first one can make you feel a bit agitated which could also be linked to inflammation, the latter seems to give me terrible pain in my upper back so I take it sparingly. I might be wrong though, oddly enough all the women in my mums family inc her and some of the men have auto immune diseases, so maybe inflammation runs high in them. Whereas my father never had any of that and whereas my mother has all sorts if issues her energy levels remain constant, steady and very decent and she's in her mid sixties.

I just figure in my case maybe that inflammation is lower as I don't have any of those issues, but I do have ME.
 
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Second star to the right ...
Scientific language is just more complete, accurate and expressive, particularly when it comes to the specific topics and sub topics.
If conforming to 'plain English' loses nuance, then the translation effort is at fault, not the stated intent of more mainstream-accessible clarity.
We would often have to write a "plain English summary" for grants and some papers. This is very difficult to compile, and you lose a lot of the nuance.
I'm not talking about using 'plain English' to describe issues, protocols, research, research parameters, participating test subjects in terms of number, age, prior medical conditions, etc, along with any efforts taken to level that field, and other issues critical to establishing a credible basis for your research efforts, or in describing the conclusions reached by the researchers.


And I'm not dense. I fully understand the need for medical-ese and science-ese and can navigate that adequately.... what I'm talking about is the obliqueness of some of the approaches taken to expressing the knowledge contained in the study, much of which would be confusing even to medical professionals, and the lack of any effort at clarity, like a glossary of the terms used in that specific research paper which are not industry-standard, but seem to have been particular to that research and paper. Also irritating are the failures to observe basic rules of grammar, like paragraphs and simple punctuation, and the failure to use basic communications civility in the incredibly tight line-spacing that makes it difficult to read, absorb, and fully process the content if, like many of us here, you have to take a time-out for a 30-60 second break to rest your eyes and brain before forging ahead, and then try to find your place again on a chaotic, crowded page.

I find this particularly true in the more predatory journals, tho it's been creeping into some of the respected journals as well.

While I respect the medical research credentials you state, I stand by my statement, however tongue-in-cheek it might have been.