‘What triggers what?’ Much remains unsettled on link between COVID-19, autoimmunity
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Despite massive studies representing millions of participants that demonstrate associations between COVID-19 and autoimmune disease, whether the virus can actually cause autoimmunity remains unsettled.
Among the seemingly ever-growing list of yet unanswered questions in this space is the issue of autoantibody formation during the acute phase of infection. Another concerns whether COVID-19 can cause new-onset or reactivated autoimmune disease. Yet another is whether or not these autoantibodies play a direct pathogenic role in disease manifestation.
Finally answering these questions could mean bettering understanding the nature of long COVID, and thus better prevention and management strategies, according to Leonard H. Calabrese, DO, chief medical editor of Healio Rheumatology, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.
“This relationship between COVID and autoimmunity is at the forefront of understanding post-COVID sequelae, or long COVID, right now,” Calabrese told Healio. “What we have come to understand is that we do not really have a handle on this yet. It is one thing to identify the presence of the footprints of aberrant autoimmunity but another to link them as pathophysiologic drivers of some or all the hundreds of symptoms often ascribed to the long COVID state.”
In terms of incident autoimmunity following COVID-19 illness, the case for autoimmune consequences is growing.
In a paper published in Clinical Rheumatology, Tesch and colleagues investigated 641,704 patients with COVID-19 from a cohort from German routine health care data, totaling more than 38 million individuals. Comparing the COVID-19 group with healthy controls demonstrated that patients who had COVID-19 were 42.63% more likely to acquire autoimmunity than the comparators. Some of the conditions reported included Hashimoto thyroiditis, rheumatoid arthritis, Sjögren’s syndrome and vasculitis.
“This is a huge study, in the millions of patients,” Paul J. Utz, MD, professor of medicine in the division of immunology and rheumatology at Stanford University, and an expert on autoimmunity, told Healio. “It made me believe there is a link.”
This belief is shared by a growing number of physicians and researchers. The argument in favor of that link may begin with autoantibodies.
‘A new way to view pathogenicity of viral infections’
For Jean-Laurent Casanova, MD, PhD, Levy Family Professor at the Rockefeller University in New York, investigator at Howard Hughes Medical Institute in Philadelphia, head of the St. Giles Laboratory of Human Genetics of Infectious Diseases, and senior attending physician at Rockefeller University Hospital, the root of the association may lie in autoantibodies.
“The pathogenesis of critical COVID involves not enough type I interferon in the early stage of infection,” Casanova said. “What we discovered in 2020 is that autoantibodies neutralizing the type I interferon early in critical forms of COVID pneumonia are just like inborn errors of type I interferons.”
Casanova added that autoantibodies to interleukin (IL)-6, IL-17 and others implicated in autoimmunity are also observed in COVID-19, providing further evidence of the association between the virus and autoimmune conditions.
Calabrese said he believes the identification of these anti-cytokine antibodies by Laurent and colleagues, especially those directed against type 1 interferon, has been one of the most significant discoveries of the early phase of the pandemic.
“This discovery has given us a new way to view pathogenicity of viral infections,” Calabrese said. “For rheumatologists, the presence of autoantibodies against type 1 interferon is even more relevant since they have been documented in nearly 10% of patients with systemic lupus erythematous and have implications for both disease severity and infectious complications.”
However, when it comes to the implications of the presence of such autoantibodies in long COVID, there is less certainty, according to Calabrese.
“An association does not equal causality,” he said. “Beyond the production of autoantibodies, on the other side is the perturbation of biology that occurs in the wake of COVID-19. In fact, a recent high impact publication by Akiko Iwasaki, PhD, and colleagues found no difference in the levels of autoantibodies among post COVID subjects with and without symptoms.”
This perturbation includes “low-grade inflammation to the presence of peculiar micro clots that are highly prevalent,” Calabrese added.
“In addition, there are changes in the microbiome and, finally, autoimmunity,” he said. “All of these potential pathogenic mechanisms are swirling on the other end of the recovery phase of COVID-19, but how they connect with the multitudes of seemingly unexplained symptoms in long COVID — such as chronic fatigue, brain fog, somatic pain and sleep disturbances — is unclear. This is the time to sort this out.”
‘Huge activation of the immune system’
According to Utz, among the most critical questions that must be answered, if researchers are to make sense of the increasing body of information on the topic, is this: If a patient has one autoimmune condition, are they more likely to develop a second?
“At the moment, there is some speculation, but we need large epidemiological studies to sort it out,” he said.
Another question Utz raised is whether “truly new” autoimmune conditions can develop in the wake of COVID-19.
Similar to the Tesch data set, a study published in eClinical Medicine by Chang and colleagues included millions of individuals. The researchers studied 888,463 COVID-19 cases and 2,926,016 controls, and ultimately concluded that RA, ankylosing spondylitis and SLE were approximately three times more likely in the COVID-19 group vs. the controls.
Individuals in the COVID-19 group were also between two and four times as likely to develop dermatomyositis, systemic sclerosis, Sjögren’s disease, mixed connective tissue disease, Behçet’s disease, polymyalgia rheumatica, vasculitis, psoriasis, inflammatory bowel disease, celiac disease and type 1 diabetes mellitus. Mortality risk was additionally elevated in patients with COVID-19.
“It is clear from the large studies that there are people who develop these conditions and likely will meet classification criteria,” Utz said.
However, the mechanism by which this occurs remains unclear.
“The idea is that autoantibodies are already percolating,” Utz said. “Then they get the virus, and it pushes the cells that make the autoantibodies over the edge.”
Utz added that similar phenomena have been reported as far back as the 1918 influenza pandemic.
“There have been viruses in the past that were thought to induce autoimmunity,” he said.
The thought process was that there was “molecular mimicry” between self-proteins and viral proteins, according to Utz.
“The other factor, of course, is a huge activation of the immune system,” he said.
When that activation occurs, it may or may not induce an entirely new autoimmune condition. Investigators continue to explore this topic.
Meanwhile, in another paper published in the Journal of Clinical Investigation, Knight and colleagues aimed to answer questions regarding whether established autoimmunity can predispose a patient to severe COVID-19, and whether SARS-CoV-2 infection trigger de novo autoimmunity.
“Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients,” the researchers wrote.
According to Knight and colleagues, previous studies have found functional autoantibodies following COVID-19, including those that enhance thrombosis or antagonize cytokine signaling.
“Unequivocally, there is an autoimmune signature that occurs after COVID-19 that may or may not be accompanied by clinical sequelae,” Calabrese said. “It may be new autoimmunity or activation of something already there or both.”
A closer look at what is happening at the autoantibody level in the early stages of COVID-19 may shed light on what happens after the virus has cleared.
‘What triggers what?’
According to Casanova, multiple research groups around the world have confirmed findings that autoantibodies to type I interferons have been present in patients who were hospitalized with COVID-19 pneumonia. He added that these autoantibodies have been found in other viral illnesses as well, from influenza and West Nile virus to MERS and patients who received the live attenuated yellow fever vaccine.
For Casanova, the question is not whether the autoantibodies are “activated” by COVID-19 infection, but rather whether the autoantibodies are preexisting prior to infection.
“The question is what triggers what,” he said. “Do autoantibodies cause or trigger serious COVID-19 infection, or are the autoantibodies caused or triggered by infection? The question is what precedes what — the chicken or the egg.”
In 2021, Utz’s lab published a paper in Nature Communications authored by Chang and colleagues that investigated antiviral antibody responses in serum from healthy controls and 147 patients who had been hospitalized with COVID-19. Results showed that approximately half of patients in the COVID-19 arm, but just 15% of individuals in the control group, produced autoantibodies similar to those found in myositis, SSc and overlap syndromes.
Although Utz said he continues to hold that there is some correlation between SARS-CoV-2 infection and autoimmunity, he acknowledged that even these findings indicate how “complicated” the association may be.
“The jury is out on which mechanism or mechanisms are involved,” he said. “If you ask five different experts, you would get five different answers.”
Meanwhile, in a paper published in the Journal of Translational Medicine, Rojas and colleagues conducted a clinical and serological assessment of 100 individuals who had COVID-19 and 30 healthy controls. According to the researchers, latent autoimmunity was observed in 83% of patients in the COVID-19 group, while polyautoimmunity was found in 62% of those individuals. “Overt” autoimmune disease was reported in three of those patients, they wrote.
Further data from Rojas and colleagues showed that IgG antibodies against IL-2, CD8B and thyroglobulin were observed in more than 10% of participants in the COVID-19 arm. Anti-interferons and other IgG autoantibodies were also observed in 5% to 10% of the COVID-19 group. In addition, the researchers found anti-SARS-CoV-2 IgG antibodies in more than 85% of patients. These antibodies demonstrated a positive association with autoantibodies, age and BMI. IgG anti-interferon-alpha antibodies carried an association with persistent respiratory symptoms.
According to Utz, it remains unknown whether the presence of various antibodies in the post-COVID setting are “autoimmune in nature or immunologic in nature.”
‘You will soon end up in the ICU’
Both Calabrese and Casanova are interested in the clinical implications of the findings demonstrating the presence of autoantibodies, and the types of autoimmunity, observed in the aftermath of COVID-19 infection.
“There are clearly a host of antibodies created in the wake of COVID-19 and some, such as those directed against type 1 interferon, appear to be associated with important clinical implications, and perhaps there may be an evolving role to detect them clinically,” Calabrese said.
Casanova agreed that knowing a patient’s autoantibody status is critical and could mean the difference between life and death.
“If it is determined that you have certain autoantibodies, you should do your best to avoid COVID,” he said. “If you do get the virus, you will soon end up in the ICU.”
However, there yet is another component to this story, according to Casanova.
“Many of these autoantibodies are found in a small percentage of people under the age of 65,” he said. “But after 65, it goes sky high.”
This could explain the significant increase in severe and fatal COVID-19 cases among older individuals.
According to data from Tesch and colleagues, more severe COVID-19 infection was associated with an increased risk for autoimmune disease.
“The data would suggest that severe disease is much more strongly associated with autoantibody development than mild disease,” Utz said. “But I think the jury is out there, also.”
The possible X-factor is that long COVID has been reported even in patients who had mild COVID-19. Utz stated that autoimmunity may be part of that constellation of sequelae, and stressed the importance of continuing to explore this topic.
“Looking at the pandemic, I think that the mortality numbers have been undercounted,” he said. “There are many people who died of something else but COVID is probably partway to blame. If autoimmunity is part of this equation, we need to understand it.”
References:
Chang R, et al. eClin Med; 2023;doi: 10.1016/j.eclinm.2022.101783.
Chang SE, et al. Nat Comm. 2021;doi:10.1038/s41467-021-25509-3.
Klein J, et al. Nature. 2023;doi:10.1038/s41586-023-06651-y.
Knight JS, et al. J Clin Invest. 2021;doi:10.1172/JCI154886.
Rojas M, et al. J Trans Med. 2022;doi:10.1186/s12967-022-03328-4.
Tesch F, et al. Clin Rheum. 2023; doi: 10.1007/s10067-023-06670-0
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