New Study Finds Certain Combinations of Antiviral Proteins Cause Lupus Symptoms

In a new study, scientists from the Johns Hopkins Institute of Medicine say they have uncovered why the symptoms and severity of lupus vary among people with the autoimmune disease, which affects up to 1.5 million Americans. The team says this is an important step forward in understanding the biology of lupus and could lead to changes in the way doctors treat patients with the disease.

The full report, published in Cell Reports Medicine, concludes that specific combinations and elevated levels of immune system proteins known as interferons are associated with certain lupus symptoms, such as such as skin rashes, kidney inflammation and joint pain.

Interferons usually help fight infection or disease, but in lupus they are overactive, causing widespread inflammation and damage. The study also shows that other common lupus symptoms cannot be explained by elevated interferon levels.

"For years, we have been accumulating knowledge that interferons play a role in lupus," said lead study author and rheumatologist Dr. Felipe Andrade, assistant professor of medicine at Johns Hopkins School of Medicine. He explains that this research began with questions about why certain lupus treatments were not effective for some patients.

"We have seen cases where the patient's condition surprisingly did not improve - we wondered whether certain groups of interferons were involved."

Some lupus treatments aim to suppress a specific group of interferons known as interferon I. In clinical trials of these treatments, the team observed that some patients did not improve despite genetic tests showing high levels of interferon I before treatment., or what experts call a high interferon signature. The team hypothesized that two other groups of interferons, interferon II and interferon III, may be responsible for these poor treatment responses.

To get to the bottom of things, the team looked at how different combinations of interferons I, II or III and their overactivity might occur in people with lupus. The researchers took 341 samples from 191 participants to determine the activity of three groups of interferons, and used human cell lines specifically engineered to respond to the presence of each specific group of interferons to analyze the samples.

Through this process, the researchers determined that most participants fell into four categories: those who only had elevated interferon I; those who had a combination of elevated interferons I, II and III; those who had a combination of elevated interferons II and III; or those who had normal interferon levels.

Source: Cell Reports Medicine (2024). DOI: 10.1016/j.xcrm.2024.101569

The researchers were able to use this data to also establish several links between these interferon combinations and lupus symptoms. In those who had elevated interferon I, lupus was primarily associated with symptoms affecting the skin, such as rashes or ulcers. Participants with elevated levels of interferons I, II, and III had the most severe symptoms of lupus, often with significant damage to organs such as the kidneys.

However, not every lupus symptom was associated with elevated interferons. Blood clots and low platelet counts, which also affect clotting, were not associated with elevated levels of interferons I, II, or III.

The researchers believe this indicates that both interferon-dependent and other biological mechanisms are involved in this complex disease. The study also found that genetic testing of the genes associated with these groups of interferons, or interferon signatures, does not always indicate elevated interferon levels. They plan to explore this in future studies.

"Our study shows that these groups of interferons are not isolated; they work as a team in lupus and can give patients different manifestations of the disease," said rheumatologist Dr. Eduardo Gomez-Bañuelos, an assistant professor of medicine at Johns Hopkins and the study's first author. Assessing a patient's elevated interferon combinations provides a better understanding of how they might respond to treatment and allows doctors to group them into clinical subtypes of lupus, Gomez-Bañuelos explains.