Antibodies generated by the SARS-COV-2 virus can be early harbingers of full-blown autoimmune disease, warn experts.

At least one in every five hospitalized COVID-19 patients generates new antibodies that attack their own tissue within a week of hospitalization.

According to a new study, hospitalised COVID-19 patients are much more likely to have autoantibodies — antibodies directed at their own tissues or chemicals secreted into the blood by their immune cells — than persons who do not have COVID-19.

“If you get sick enough from COVID-19 to end up in the hospital, you may not be out of the woods even after you recover,” said PJ Utz, MD, professor of immunology and rheumatology at Stanford Medicine.

The researchers examined for autoantibodies in blood samples collected from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California in March and April of 2020. As controls, blood samples collected from other donors before the COVID-19 pandemic were used.

The researchers detected and quantified virus-specific antibodies, autoantibodies, and antibodies directed against cytokines, substances secreted by immune cells to interact with one another and coordinate their overall strategy.

The researchers discovered that anti-cytokine antibodies were present in up to 60 percent of all hospitalized COVID-19 patients, compared to roughly 15 percent of healthy controls. This could be the outcome of immune-system overload caused by a persistent, virulent infection. The number of cytokines in the fog of war may cause the erroneous development of antibodies targeting them, according to the authors.

If any of these antibodies prevent a cytokine from binding to its proper receptor, the intended recipient immune cell may not be triggered. This, in turn, may give the virus more time to reproduce, resulting in a far worse consequence.

Tracking down autoantibodies

For about 50 patients, blood samples drawn on different days, including the day they were first admitted, were available. This enabled the researchers to track the development of the autoantibodies.

 “Within a week after checking in at the hospital, about 20% of these patients had developed new antibodies to their own tissues that weren’t there the day they were admitted,” Utz said.

“In many cases, these autoantibody levels were similar to what you’d see in a diagnosed autoimmune disease.”

In some cases, the presence of those newly detected autoantibodies may reflect an increase, driven by the immune response, of antibodies that had been flying under the radar at low levels, Utz said. It could be that inflammatory shock to the systems of patients with severe COVID-19 caused a jump in previously undetectable, and perhaps harmless, levels of autoantibodies these individuals may have been carrying prior to infection.

In other cases, autoantibody generation could result from exposure to viral materials that resemble our own proteins, Utz said. 

“It’s possible that, in the course of a poorly controlled SARS-CoV-2 infection — in which the virus hangs around for too long while an intensifying immune response continues to break viral particles into pieces — the immune system sees bits and pieces of the virus that it hadn’t previously seen,” he said.

“If any of these viral pieces too closely resemble one of our own proteins, this could trigger autoantibody production.”

The finding bolsters the argument for vaccination, he added. Vaccines for COVID-19 contain only a single protein — SARS-CoV-2’s so-called spike protein — or the genetic instructions for producing it. With vaccination, the immune system is never exposed to — and potentially confused by — the numerous other novel viral proteins generated during infection.

In addition, vaccination is less intensely inflammatory than an actual infection, Utz said, so there’s less likelihood that the immune system would be confused into generating antibodies to its own signaling proteins or to the body’s own tissues.

“Patients who, in response to vaccination, quickly mount appropriate antibody responses to the viral spike protein should be less likely to develop autoantibodies,” he said.

Identifying autoantibody triggers

Indeed, a recent study in Nature to which Utz contributed showed that, unlike SARS-CoV-2 infection, the COVID-19 vaccine produced by Pfizer doesn’t trigger any detectable generation of autoantibodies among recipients.

“If you haven’t been vaccinated and are telling yourself, ‘Most people who get COVID get over it and are OK,’ remember that you can’t know in advance that when you get COVID-19 it will be a mild case,” Utz said.

“If you do get a bad case, you could be setting yourself up for a lifetime of trouble because the virus may trip off autoimmunity. We can’t say yet that you’ll definitely get an autoimmune disease — we haven’t studied any patients long enough to know whether these autoantibodies are still there a year or two later, although we hope to study this — but you certainly might. I wouldn’t want to take that chance.”

Utz intends to study blood samples from SARS-CoV-2-infected people who are asymptomatic or who’ve had mild COVID-19 symptoms. That could help determine whether the massive hyperactivation of the immune system, which doesn’t occur in mildly symptomatic or asymptomatic people, is what causes trouble, or whether the mere molecular resemblance of SARS-CoV-2 proteins is enough to trigger autoantibody generation.

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