Unique immune response in lupus paves the way for new treatments

Immune cells called monocytes produce a key inflammatory protein called interleukin-1 beta (IL-1β) through an unconventional pathway in patients with systemic lupus erythematosus, commonly known as lupus, according to a new study led by Weill Cornell Medicine researchers. .

The results, published in Immunitycould lead to new treatments targeting IL-1β to better manage inflammation in patients who do not respond well to existing therapies.

Lupus is a chronic autoimmune disease in which the body’s immune system attacks its own tissues, leading to widespread inflammation that can affect the skin, joints, kidneys and heart. There are 20 to 150 cases per 100,000 people in the United States, according to medical reference source UptoDate. Although a genetic origin can be identified in a fraction of patients, the exact cause remains unclear in most of them.

However, the disease is known to involve an overproduction of type I interferons (IFN), proteins that help the body fight viruses but can also cause harmful inflammation in autoimmune diseases. Yet some lupus patients do not fully respond to IFN-blocking treatments, prompting investigators to search for another culprit.

“Lupus is considered an ‘interferonopathy’ because almost all patients have elevated interferon activity in their blood and tissues,” said lead author Dr. Virginia Pascual, director of the Gale Institute. and Ira Drukier for children’s health and pediatrics professor Ronay Menschel. “It was surprising to see co-activation of the interferon and IL-1β pathways in lupus monocytes, since these proteins typically downregulate in immune responses.”

The current study builds on previous research from 2021, where first author Simone Caielli, research assistant professor of pediatric immunology at the Drukier Institute, and her team discovered mitochondria-retaining red blood cells in up to 60% of pediatric lupus patients, but not in healthy controls or patients with juvenile dermatomyositis, an autoimmune disease. Mitochondria are normally degraded during red blood cell development and detection of mitochondrial DNA can trigger an immune response characterized by IFN production.

In the new study, Pascual and Caielli found that monocytes produced not only IFN, but also IL-1 β when internalizing lupus red blood cells containing mitochondria. Researchers used in vitro and ex vivo tests on blood samples from lupus patients to identify a surprising mechanism in which IL-1β production ultimately results from interactions between the IFN pathway and inflammasome, a protein complex responsible for the production of IL1b and is normally suppressed by IFN.

Importantly, the study also found that IL-1β secretion occurs without cell death, a process normally required for release of this protein, making it an attractive target for new therapies.

“Without causing cell death, lupus monocytes could potentially travel throughout the body, release IL-1β and survive in inflamed areas, thereby amplifying their harmful effects,” Caielli said. “These cells can also turn into cells that activate other components of the immune system, making inflammation worse.”

Looking ahead, researchers plan to study how these immune pathways behave during lupus flares and remissions, with the goal of refining treatment strategies. They are also developing diagnostic tools to detect monocytes that produce both IFN and IL-1β, which could help identify patients who would benefit from treatments that block both proteins.

The researchers hope that their findings will not only lead to better treatments for lupus patients, but may also be applicable to other autoimmune diseases with similar inflammatory pathways.