A recent paper from Emory pathologist Cheryl Maier and colleagues provides more evidence for autoantibodies in critically ill COVID-19 patients. Autoantibodies are signs that the immune system attacking the body itself, and are features of diseases such as lupus and rheumatoid arthritis. They have been proposed as an explanation for the severity of some acute COVID-19 cases, as well as continued symptoms in long COVID.
Generally, antibodies are a good thing, and a major goal of COVID-19 vaccination is to drive the immune system to generate protective antibodies against the coronavirus. With autoantibodies and COVID, the idea is that intense inflammation coming from viral infection is causing immune cells to become confused. Not every COVID-19 patient’s immune system goes off the rails, but the train wreck seems to happen more often in COVID-19.
Last year, immunologist Ignacio Sanz’s lab at Emory demonstrated that patients with severe COVID-19 display signs of immune dysregulation similar to those seen in lupus. A follow-up preprint found the suspected autoantibodies, and several other labs have observed autoantibodies in COVID-19 that may be sabotaging antiviral responses or perturbing blood clotting. Now, an active topic of investigation is whether the autoantibodies last longer or don’t diminish as quickly in long COVID. Stay tuned.
However, in the current paper in Cell Reports Medicine, autoantibodies were also found in most control samples from intensive care unit patients with pneumonia or sepsis, who are experiencing a state of systemic inflammation comparable to severe COVID-19.
“It’s a reminder that autoantibodies are not necessarily unique to COVID,” Maier says. “They may be more dramatic in COVID, but we see autoantibodies associated with other severe diseases too.”
Maier is medical director for Emory’s Special Coagulation Laboratory, and her team came to the autoimmunity question from a side angle. They were investigating blood clots and hyperviscosity in COVID-19 patients, and wanted to check whether high concentrations of antibodies might be an explanation. Antibodies are proteins, after all, and if someone’s blood is full of them, they thicken it.
The Emory investigators obtained samples from 64 hospitalized COVID-19 patients, with 55 in the ICU, and compared them against 13 non-COVID ICU patients as well as 13 healthy controls and 9 people with hypergammaglobulinemia (meaning lots of antibody).
The researchers used a panel of epithelial and endothelial cells, which represent the tissues in lungs and blood vessels that are damaged in COVID-19, and tested whether antibody samples reacted against them. In the COVID-19 ICU patients, 93 percent had IgM antibodies that reacted against human cells, while 85 percent of non-COVID ICU patients also had auto-reactive IgM. In contrast, auto-reactive IgM was seen in 25 percent of healthy controls.
IgM is the first type of antibody that appears in an immune response against something new – later, immune cells switch to making other types such as IgG and IgA. Intriguingly, the presence of auto-reactive IgA was actually the best discriminator of COVID-19 vs other conditions in ICU patients (51 percent versus 15 percent). IgA is the predominant antibody isotype in the lungs. In a few patients, the researchers took a more detailed look at what proteins the auto-reactive antibodies were targeting, and saw that the patterns were broad and did not overlap much.
Autoimmunity provides several handles for intervention. The authors propose that going after the antibodies themselves directly via plasma exchange — sifting them out of the blood, essentially — may be one tactic. Interfering with the complement system, which is a support crew for antibodies’ attack, may be another. To be sure, other effective COVID-19 treatments, ranging from corticosteroids (dexamethasone) and other anti-inflammatories (baricitinib), may be working by tamping down inflammation and reducing autoantibody levels.
The first author of the Cell Reports Medicine paper was postdoc Andrew Kam Ho Wong.