In people with severe COVID-19, the immune system goes temporarily berserk and generates a wide variety of autoantibodies: proteins that are tools for defense, but turned against the body’s own tissues.
During acute infection, COVID-19 patients’ immune systems resemble those of people with diseases such as lupus or rheumatoid arthritis. However, after the storm passes, the autoantibodies decay and are mostly removed from the body over time, according to a study of a small number of patients who were hospitalized and then recovered.
In a preprint posted on medRxiv, Emory immunologists provide a view of the spectrum of what COVID-generated autoantibodies react against, both during acute infection and later. Note: the results have not yet been published in a peer-reviewed journal.
The findings on COVID-19-triggered autoimmunity may have implications for both the treatment of acute infection and for long-haulers, in whom autoantibodies are suspected of contributing to persistent symptoms such as fatigue, skin rashes and joint pain.
During acute infection, testing for autoantibodies may enable identification of some patients who need early intervention to head off problems later. In addition, attenuation of autoantibody activity by giving intravenous immunoglobulin (IVIG) – an approach that has been tested on a small scale — may help resolve persistent symptoms, the Emory investigators suggest.
Researchers led by Ignacio Sanz, MD and Frances Eun-Hyung Lee, MD, isolated thousands of antibody-secreting cells from 7 COVID-19 patients who were in ICUs at Emory hospitals. They also looked for markers of autoimmunity in a larger group of 52 COVID-19 ICU patients.
Sanz is head of the division of rheumatology in the Department of Medicine, director of the Lowance Center for Human Immunology, and a Georgia Research Alliance Eminent Scholar. Lee is associate professor of medicine and director of Emory’s Asthma/Allergy Immunology program.
The co-first authors are Matthew Woodruff, PhD, an instructor in Sanz’s lab, and Richard Ramonell, MD, a fellow in pulmonary and critical care medicine at Emory University Hospital. In some of the experiments, Emory researchers collaborated with Exagen, using technology developed by the company to probe clinical autoimmune profiles.
“We were trying to address the question: what is the origin of the autoantibodies?” Sanz says.
That is, are they generated during the course of infection? Or were immune cells capable of making the observed autoantibodies already existing in the body, and let loose by the infection?
“These possibilities are not mutually exclusive, but it appears that new generation of autoreactive clones from naïve cells is a dominant mechanism in acute severe infection,” he says. “What we see is a broad breakdown of tolerance, at least temporarily.”
The researchers characterized the antibodies the cells produced and their DNA, looking for signs of the editing processes the immune system usually applies to ensure antibodies don’t react against the body itself.
The editing processes appeared to have weakened during infection. Germinal centers, the anatomical structures within lymph nodes where antibody-secreting cells mature, can collapse during intense inflammation, Sanz says. As a result, antibody-secreting cells develop in a disorganized, uncontrolled way outside highly regulated germinal centers.
In the hospitalized patients, the majority of their antibody-secreting cells produced antibodies directed against parts of the coronavirus, but some of them were also reactive against different targets in the body. The broad pattern resembled that seen in lupus, but was different in that some types of autoantibodies, such as those against DNA, were not observed. One patient’s immune cells were producing antibodies against glomerular basement membrane, which may contribute to lung and kidney damage.
Six months after acute infection, when some of the patients had survived and recovered, most of the indiscriminately generated antibody-secreting cells had disappeared from their blood. However, the antibodies themselves – what the cells produce – remain in the blood and decay gradually over time. Approaches such as IVIG could encourage recycling of lingering autoantibodies, the authors write.
Sanz says that the question of whether autoantibodies – or perhaps, lingering autoreactive cells — contribute to persistent symptoms needs to be tested in a larger group of COVID-19 patients. His and Lee’s laboratories continue to examine people with severe COVID-19 and those who recovered, as well as outpatients, including those with long haul symptoms. Their expanded study now includes an additional 150 patients, with the aim of correlating clinical features with the presence of autoantibodies.
“This is something we are going to have to follow,” he says. “We also need to compare this to other viral infections that have been associated with autoimmunity.”
The research was supported by the National Cancer Institute (SeroNet, U54CA260563), the National Institute of Allergy and Infectious Diseases (U19AI110483 — Emory Autoimmunity Center of Excellence, P01AI125180, R37AI049660, R01AI121252, U01AI141993), and the National Heart Lung and Blood Institute (T32HL116271).