Study links severe COVID-19 to increase in self-attacking antibodies

Autoantibodies can be early harbingers of full-blown autoimmune disease.

"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.

Utz shares senior authorship of the study, which will be published Sept. 14 in Nature Communications, with Chrysanthi Skevaki, MD, PhD, instructor of virology and laboratory medicine at Philipps University Marburg in Germany, and Eline Luning Prak, MD, PhD, professor of pathology and laboratory medicine at the University of Pennsylvania. The study's lead authors are Sarah Chang, a former technician in Utz's lab; recent Stanford undergraduate Allen Feng, now a technician in the Utz lab; and senior research investigator Wenshao Meng, PhD, and postdoctoral scholar Sokratis Apostolidis, MD, both at the University of Pennsylvania.

The scientists looked for autoantibodies in blood samples drawn during March and April of 2020 from 147 COVID-19 patients at the three university-affiliated hospitals and from a cohort of 48 patients at Kaiser Permanente in California. Blood samples drawn from other donors prior to the COVID-19 pandemic were used as controls.

The researchers identified and measured levels of antibodies targeting the virus; autoantibodies; and antibodies directed against cytokines, proteins that immune cells secrete to communicate with one another and coordinate their overall strategy.

Upward of 60% of all hospitalized COVID-19 patients, compared with about 15% of healthy controls, carried anti-cytokine antibodies, the scientists found. This could be the result of immune-system overdrive triggered by a virulent, lingering infection. In the fog of war, the abundance of cytokines may trip off the erroneous production of antibodies targeting them, Utz said.

If any of these antibodies block a cytokine's ability to bind to its appropriate receptor, the intended recipient immune cell may not get activated. That, in turn, might buy the virus more time to replicate and lead to a much worse outcome.

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.

Utz is a member of Stanford Bio-X, the Stanford Institute for Immunity, Transplantation and Infectionand the Stanford Maternal and Child Health Research Institute.

Other Stanford study authors are Maja Artandi, MD, clinical associate professor of primary care and population health; Linda Barman, MD, clinical assistant professor of primary care and population health; postdoctoral scholar Saborni Chakraborty, PhD; life science technicians Iris Chang and Evan Do; former senior scientist Peggie Cheung, PhD; Sharon Chinthrajah, MD, associate professor of pulmonary and critical care; former technician Shaurya Dhingra; former undergraduate Alex Ren Hsu; former senior research scientist Alex Kuo, PhD; senior research scientist Monali Manohar, PhD; former research program manager Rong Mao, PhD; former graduate student Abigail Powell, PhD; Rajan Puri, MD, clinical assistant professor of primary care and population health; Rich Wittman, MD, clinical assistant professor of primary care and population health; Neera Ahuja, MD, clinical professor of medicine; Pras Jagannathan, MD, assistant professor of infectious diseases and of microbiology and immunology; Peter Kim, PhD, professor of biochemistry; Kari Nadeau, MD, PhD, professor of pediatrics; William Robinson, MD, PhD, professor of immunology and rheumatology; Upinder Singh, MD, professor of infectious diseases and geographic medicine and of microbiology and immunology; and Taia Wang, MD, PhD, assistant professor of infectious diseases and of microbiology and immunology.

Other researchers at the University of Pennsylvania, Philipps Marburg University, the University of Tennessee, Oklahoma Medical Research Foundation and Kaiser Permanente Northern California contributed to the work.

The study was funded by the National Institutes of Health (grants AI105343, AI112521, AI082630, AI201085, AI123539, AI117950, UC4 DK112217, UM1-AI144288, PA30-CA016520, P30-AI0450080, 5U19AI057229-17, HL137006, HL137915, UM2 AI130836, UM1 AI130839, U19 AI104209, R01 AI139119, U19 AI111825, R01 AI125197-04, U01 AI150741-01S1 and U54 CA260517), the Henry Gustav Floren Trust, the Parker Institute for Cancer Immunotherapy, the Sean N. Parker Center, the Frank Quattrone and Denise Foderaro Family Research Fund, the Chan Zuckerberg Biohub, the Allen Institute for Immunology, the CEND COVID Catalyst Fund, the Chen Family Research Fund, the Carreras Foundation, the Foundation for Pathobiochemistry and Molecular Diagnostics, Universities Giessen and Marburg Lung Center, the German Center for Lung Research and the Deutsche Forschungsgemeinschaft.

Stanford's Department of Medicine also supported the work.