Long COVID: Is autoimmunity to blame?

When our bodies are exposed to a virus — or any infection — it recognizes proteins and other molecules on the invading virus as “not us.” Scientists refer to this as an antigen.

We then ramp up our immune systems to attack that antigen. Therefore, we try to neutralize infectious invaders, such as the SARS-CoV-2 virus.

Once we use our antibodies to attack the invading viral protein, parts of these neutralizing antibody-antigen complexes can also be viewed as “not us” by our bodies. We can also form secondary antibodies, called anti-idiotype antibodies.

What is the purpose of anti-idiotype antibodies? After the initial benefits of first-line immunity, our body has natural processes to try to flatten our response to challenges. These processes are known as downregulation.

Anti-idiotype antibody production is one of our body’s methods of achieving downregulation. However, the presence of anti-idiotype antibodies can have unexpected negative effects.

Firstly, they can neutralize our infection-fighting first-responder antibodies, so they interfere with our body’s ability to fight the infection if it persists.

Secondly, they can mimic the original invading organism and bind to our cells in the same way. This instigates the same symptoms as the infection or causes an immune-cell attack on our healthy cells.

Drs. Murphy and Longo report that this mimicking behavior by anti-idiotype antibodies has been demonstrated already in models, such as viral diarrhea in bovine animals.

For Medical News Today, Dr. Murphy elaborated:

“This concept of anti-idiotype antibodies mediating effects and limiting efficacy could have a profound impact in understanding how to increase effectiveness and duration of protective antibody responses,” he explained. It might also help us “determine if patients are at risk, based on their anti-idiotype responses or allow for therapeutic interventions to be developed.”

The SARS-CoV-2 spike protein on the surface of the virus binds to angiotensin converting enzyme 2 receptors (ACE2) on our cells.

ACE2 receptors are present on many cells throughout the body, including within the lung, heart, kidneys, nerves, and brain. So, any protein, including a virus protein, binding these receptors can profoundly affect our health.

Once bound to the cell, the spike protein allows the virus to enter it. But, the spike proteins’ negative effects do not stop at simply finding a gateway.

By binding the ACE2 receptors, the spike protein can suppress healthy cell function and stimulate the release of inflammatory proteins called cytokines.

Regardless of whether we produce first-line antibodies from the vaccine or a SARS-CoV-2 infection, anti-idiotype antibodies have the potential to produce the same symptoms and side effects as infection with the SARS-CoV-2 infection. They achieve this by binding to the ACE2 receptor.

Dr. Murphy clarified for MNT:

“The vast majority of research on both SARS-CoV-2 infection responses and vaccines solely centers on the protective antibody and T cell responses. There needs to be much more investment in basic research on the immunoregulatory pathways that both can limit responses and duration, but also on their ability to mediate off-target effects.”

“Given the strong dependency on the population for vaccines and the need for boosting, along with the emergence of viral variants, it is imperative that more research be directed to understanding the mechanisms involved using preclinical models, which simply has not been adequately done.”

Dr. Murphy elaborated further: “Despite being put forth by Nobel Laureate Niels Jerne in 1974 as a means for antibody regulation, research in this area of anti-idiotype antibodies has tapered considerably and is not usually in the conversation of antibody responses. This article brings the concept back to the forefront as a possible explanation for the myriad of effects observed with both SARS-CoV-2 infection and vaccine responses.”

Researchers Dr. Claudia Nold-Petry and Prof. Marcel Nold from Monash University in Australia also spoke with MNT. They discussed the potential role of anti-idiotype antibodies in complications associated with both COVID-19 vaccines and the disease:

“Confirmation of the presented hypotheses by basic research (as per the suggestions in the article) would represent a welcome advance in the understanding of the adverse events of vaccines and COVID-19 itself — including of SARS-CoV-2 variants, some of which may induce more and more problematic anti-idiotype antibodies than others!”

Regarding the medical implications of this research, Dr. Nold-Petry and Prof. Nold told MNT:

“Vaccines and antibody-based therapies could be screened for induction of anti-idiotype antibodies in preclinical tests, and modifications could be made to minimize such indications, as required.”

“Patients could be screened for anti-idiotype antibodies following vaccination or administration of antibody-based therapies, and an alternative vaccine could be selected if they were detected.”

Dr. Murphy added that these findings could provide many benefits, particularly “in understanding how to increase effectiveness and duration of protective antibody responses as well as potentially allowing for means to determine if patients are at risk based on their anti-idiotype response or allow for therapeutic interventions to be developed.”

“This article presents a hypothesis on a mechanism that could be at play,” he noted. “The research now needs to be done to ascertain if indeed this is occurring. A recent publication demonstrating the existence of anti-ACE2 anti-idiotypic antibodies in SARS-CoV-2 patients would appear to support this can indeed be a major factor.”