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Healthcare:

Is Long COVID an Autoimmune Disease?

Is SARS-CoV-2 an Autoimmune Virus?

Carolyn Serraino March 26, 2021

A comparative look at the overlap between COVID-19 infection and autoimmunity, and the science behind it

A lack of diagnosing and misdiagnosing makes it nearly impossible to calculate a true estimate for how many people live with an autoimmune disease (AD). As AD cases continue to be on the rise, there is an even more apparent need to promote research and awareness on behalf of this sizable population (1). The recent influx of scientific evidence around COVID-19 is showing a more direct correlation between the two.

As the similarities between the symptoms and mechanisms of long-term SARS-CoV-2 infection (or long covid) and autoimmune disease became more apparent, researchers started calling the COVID-19-causing virus the “autoimmune virus.” This article breaks down some of the groundbreaking research corroborating this discovery into the following categories:

  •   Presence of autoantibodies
  •   Hyperferritinemia and cytokine storms
  •   Molecular mimicry
  •   HLA gene polymorphism

While the following information is by no means exhaustive, it can serve as a summary of key developments around the SARS-CoV-2 virus, long COVID, and autoimmune disease. For the most up-to-date information regarding COVID research and news as it pertains to autoimmune disease, check out our timeline.

Autoantibodies Activating Autoimmunity

The current understanding surrounding autoantibodies is that they play a role in activating the immune response and induce cellular damage and inflammation (2). However, these findings have not been studied in all autoimmune diseases. The pathogenicity (ability to be disease-causing) of autoantibodies in mouse models with a lupus-like disease is the most thoroughly studied as of now (3).

Autoantibodies in AD and COVID-19

Comparing the presence of autoantibodies in autoimmune disease and COVID-19 infection.

Sources for graphic: (4, 5)

Hyperferritinemia & Cytokine Storms

Hyperferritinemia is when there are unusually large amounts of ferritin in the blood. Ferritin is a protein that’s primary function appears to be the storage of iron and the concentrating of cellular iron to protect cells from its toxic effects (6). It has recently emerged as an important molecule in the immune system response and, when present at normal levels, helps to coordinate the battle against hyper-inflammation.

At higher levels, hyperferritinemia has been shown to lead to disease states by “mechanisms of inflammation, infection, injury, and repair” (7). The production of ferritin is regulated by cytokines. Cytokines respond to infection in part by expressing ferritin genes and when cytokines are being overproduced by macrophages (“cytokine storm) it has been shown to enhance the inflammatory process and trigger an unusually large amount of ferritin in the blood (8). It is suspected that the active ferritin production by macrophages and cytokines following COVID-19 infection might promote the production of several pro-inflammatory and anti-inflammatory cytokines (9).

Hyperferritinemia and Cytokine Storms

Comparing hyperferritinemia and cytokine storms in autoimmune disease and COVID-19 infection.

Sources for graphic: (5, 7, 10, 11, 12, 13, 14, 15, 16)

Malicious Molecular Mimicry

Molecular Mimicry has been drawing extra attention lately, as it is thought to be a possible mechanism of the autoimmune phenomena in COVID-19. Studies have shown that there is a homology (state of having the same or similar relation, relative position, or structure) of primary sequence between humans and components of SARS-CoV-2 (17). This is interesting in that the same structural similarity is not found in mammals unaffected by the virus, indicating that the virus is specifically adapting to imitate human biology.

Comparing molecular mimicry in autoimmune disease and COVID-19 infection.

Comparing molecular mimicry in autoimmune disease and COVID-19 infection.

Sources for graphic: (18 , 19 , 20 , 21)

Polymorphisms Predicting Pathogenicity

It should come as no surprise that there are significant genetic sequence variations when comparing individuals’ DNA. These differences in the DNA sequence are called polymorphisms when they occur in ≥1% of the population. These polymorphisms can present silently (meaning they have not been found to alter the function or expression of a gene) or visibly.

Polymorphisms can occur in any region of the genome, but the genes coding for the major histocompatibility complex (MHC), which in turn code the human leukocyte antigens (HLA) genes, have been found to contain the most polymorphic genes. This is relevant for the study of autoimmunity because these MHC molecules are involved in the immune system and interact with T-cells. (22)

What do these polymorphisms have to do with COVID-19? Well, one of the biggest questions remaining is why some people have severe and potentially life-threatening responses to SARS-CoV-2 infection while others experience little to none. Another aspect of that question is why some individuals are developing autoimmune disease-related issues long after they’ve tested negative for COVID-19 and others are not. These differences have been found between individual patients as well as different populations. This discovery has led to the hypothesis that the differences in HLA genes might be influencing this variation through gene polymorphisms which involve one of two or more variants of a particular DNA sequence.

Comparing HLA gene polymorphism in autoimmune disease and COVID-19 infection.

Comparing HLA gene polymorphism in autoimmune disease and COVID-19 infection.

Sources for graphic: (23 , 24 , 25 , 26)

Further Associations between COVID-19 and Autoimmunity

The loss of smell has been a prevalent symptom experienced with COVID-19 infection. Olfactory dysfunction has been linked to several autoimmune diseases as well, including multiple sclerosis, lupus, and myasthenia gravis (28). While experts are not surprised by this connection, more research is required to bolster associations such as this one. The development of autoimmune diseases secondary to COVID-19 infection (2935), bystander immunity activation (14), and neutrophil extracellular traps (NET) activation and release (36), are some examples of more associations that, with stronger data and research, would show more robust connection to shed light on both autoimmune disease and COVID-19.

Sources

  1. Article Sources and Footnotes
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