Q&A: SARS-CoV-2 can trigger autoantibody reactivity lasting months after infection

SARS-CoV-2 infection, even in asymptomatic cases, can lead to a broad autoantibody response that lasts beyond recovery from infection, according to findings published in the Journal of Translational Medicine.

The breadth and magnitude of autoantibody reactivity was significantly more prominent in women after asymptomatic infection; however, reactivity was more prominent in men after a symptomatic infection, according to Justyna Fert-Bober, PhD, a project scientist in the department of cardiology at the Smidt Heart Institute, and colleagues.

The researchers assessed autoantibody reactivity to 91 autoantigens linked to various autoimmune diseases in 177 health care workers who had confirmed evidence of a SARS-CoV-2 infection prior to the COVID-19 vaccine rollout. These individuals reported the presence or absence of symptoms potentially related to COVID-19 illness during the 6 months preceding a blood test but after their recovery from infection. Fert-Bober and colleagues compared the data with 53 pre-pandemic controls.

“We found signals of autoantibody activity that are usually linked to chronic inflammation and injury involving specific organ systems and tissues such as the joints, skin and nervous system,” Susan Cheng, MD, MPH, MMSc, the director of the Institute for Research on Healthy Aging in the department of cardiology at the Smidt Heart Institute, said in a press release.

Healio spoke with Fert-Bober to learn more about autoimmune responses triggered by SARS-CoV-2.

Healio: Why did you undertake this research?

Fert-Bober: We have been motivated to run a research program focused on trying to understand why the after-effects of COVID-19 infection can sometimes involve persistent symptoms often seen in autoimmune conditions. Other researchers found some evidence of autoantibodies being triggered during or just after severe COVID-19 infections. This has led to the prevailing hypothesis that it is a triggered chronic autoantibody response that may be driving persistent post-infection clinical features seen in people who suffer from long COVID. To better understand if this is indeed the case, we wanted to first start with understanding what the autoantibody response profile looks like in people who had only mildly symptomatic, or even completely asymptomatic, infection and then fully recovered. These individuals made up what we considered to be a COVID-19-recovered, now “back to healthy” referent cohort. We were somewhat surprised to see that in these individuals, there was still quite a significant signal of autoantibody activity.

Healio: Were you surprised by the findings?

Fert-Bober: Yes and no. We were surprised based on the context above. We were also a bit surprised to see, on the one hand, that the autoantibody response was more pronounced in men than in women given that women are much more likely to develop classic autoantibody conditions in general. On the other hand, we were not so surprised to see this apparently paradoxical sex difference given that we know men tend to experience more significant and severe degrees of COVID-19 infection than women for biological reasons that we do not yet fully understand.

Healio: Could you describe the autoantibody response that COVID-19 is creating and how it can impact the body?

Fert-Bober: It is not yet clear. However, we have known for some time that different types of viral infections can trigger autoimmune reactions through molecular mimicry. In other words, the virus causes the B cells that are part of our normal host immune defenses to recognize components of the foreign viral particles. But if these particles happen to look something close to what parts of our own tissues in certain organ systems look like naturally, there can be misrecognition and misdirecting of antibodies created by our B cells towards some of our own tissues.

Healio: How are autoantibodies impacting women and men differently?

Fert-Bober: Interestingly, we found in our study that even though women are more commonly affected by classic autoimmune diseases in general, it is the men in this study who had more pronounced autoantibody response. And so, while paradoxical, this finding is not entirely surprising as it proves our hypothesis that SARS-CoV-2 activates the autoimmune system, and we know that men are more susceptible to the effects of this particular coronavirus than women.

Cellular and humoral immunity are generally stronger in women; women have higher levels of circulating antibodies, more circulating CD4 T cells and more robust cytokine production in response to infection. Many autoimmune diseases show a striking female sex bias, although age is also an important factor. As we published previously, patients treated for COVID-19 in the Cedars Sinai Medical Center were more likely to be male if they required hospitalization, intensive care or intubation for respiratory failure. Women, on the other hand, appear to be somewhat more susceptible to long COVID syndromes.

Healio: For primary care physicians who are trying to treat patients dealing with lingering effects of COVID-19, how should your findings impact clinical practice?

Fert-Bober: Ours and other studies showed that SARS-CoV-2 triggers autoimmune response. We recognized that our study findings need to be validated in more diverse as well as larger study populations. Although we assume that all variants will trigger an autoantibody response to some degree, we need more data to understand how the effects may vary from variant to variant as well as from person to person. We believe that all previously infected persons, even those who have successfully recovered and are “back to health,” should have the chance to be reevaluated at any point in the future for any possible post-infection effects that may or may not develop. As our diagnostic tools and technologies continue to improve, we hope that our ability to predict, identify and manage post-infectious immune-mediated conditions will also improve.

Healio: What should physicians look for among patients to accurately recognize an autoantibody response and immune dysregulation?

Fert-Bobert: In general, doctors often have a hard time diagnosing autoimmune diseases. There's usually not a specific test to show whether you have a certain autoimmune disease. And the symptoms can be confusing. That's because many autoimmune diseases can have similar or overlapping clinical features. We discovered that there is even more diversity in autoantibody response after SARS-CoV-2 infection than previously appreciated. We realize we need even more comprehensive data to generate a clearer picture of what is going on and to increase precision when attempting to make a diagnosis in any given individual patient. This is all quite frustrating for many long COVID patients, we do understand that. We are doing our best to support what are now global efforts to understand the pathological mechanisms underlying the long-term effects of SARS-CoV-2 infection.

Healio: Are there ways of bringing the body out of this autoantibody response?

Fert-Bober: We don’t know yet which already existing or potentially completely novel therapeutics could be helpful. We hope to have a clearer picture of which specific parts of the broad autoantibody response profile might be most important to target for potential interventions.

Healio: Can getting vaccinated possibly prevent developing this lingering autoantibody response?

Fert-Bober: It seems reasonable as the vaccination is required to protect our body and enhance and potentially sharpen the adaptive immune response. The antibody response produced against the virus after vaccination should ideally be targeting only the virus when it enters the body, and not the host proteins that are incidentally similar in shape or form to the virus. We know that this process may not happen perfectly in every person.

References:

COVID-19 can trigger self-attacking antibodies. https://www.cedars-sinai.org/newsroom/covid-19-can-trigger-self-attacking-antibodies/. Published Jan. 3, 2022. Accessed Jan. 10, 2022.

Liu Y, et al. J Transl Med. 2022;doi:10.1186/s12967-021-03184-8.