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


Date:
September 14, 2021
Source:
Stanford Medicine
Summary:
Hospitalized COVID-19 patients are substantially more likely to
harbor autoantibodies --antibodies directed at their own tissues
or at substances their immune cells secrete into the blood --
than people without COVID-19, according to a new study.



FULL STORY ========================================================================== Hospitalized COVID-19 patients are substantially more likely to
harbor autoantibodies -- antibodies directed at their own tissues or
at substances their immune cells secrete into the blood -- than people
without COVID-19, according to a new study.


========================================================================== 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.

========================================================================== Story Source: Materials provided by Stanford_Medicine. Original written
by Bruce Goldman.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sarah Esther Chang, Allan Feng, Wenzhao Meng, Sokratis
A. Apostolidis,
Elisabeth Mack, Maja Artandi, Linda Barman, Kate Bennett, Saborni
Chakraborty, Iris Chang, Peggie Cheung, Sharon Chinthrajah,
Shaurya Dhingra, Evan Do, Amanda Finck, Andrew Gaano, Reinhard
Gessner, Heather M. Giannini, Joyce Gonzalez, Sarah Greib, Margrit
Gu"ndisch, Alex Ren Hsu, Alex Kuo, Monali Manohar, Rong Mao, Indira
Neeli, Andreas Neubauer, Oluwatosin Oniyide, Abigail E. Powell,
Rajan Puri, Harald Renz, Jeffrey Schapiro, Payton A. Weidenbacher,
Richard Wittman, Neera Ahuja, Ho-Ryun Chung, Prasanna Jagannathan,
Judith A. James, Peter S. Kim, Nuala J.

Meyer, Kari C. Nadeau, Marko Radic, William H. Robinson, Upinder
Singh, Taia T. Wang, E. John Wherry, Chrysanthi Skevaki, Eline
T. Luning Prak, Paul J. Utz. New-onset IgG autoantibodies in
hospitalized patients with COVID-19. Nature Communications, 2021;
12 (1) DOI: 10.1038/s41467-021- 25509-3 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210914082653.htm

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