A major mystery behind one of the most common autoimmune diseases may finally have an answer.
Researchers from Northwestern Medicine and Brigham and Women’s Hospital say they have discovered an underlying cause of lupus, a disease that affects hundreds of thousands of people in the U.S.
Scientists have long suspected that a person’s genes or hormones may predispose him or her to lupus, and that the disease may be triggered by environmental factors, such as a previous viral infection or exposure to certain chemicals.
A study published Wednesday in the journal Nature outlines a clear progression of the disease, pointing to abnormalities in the immune systems of people with lupus.
“What we found was this fundamental imbalance in the types of T cells that patients with lupus make,” said Dr. Deepak Rao, one of the study authors and a rheumatologist at Brigham and Women’s Hospital in Massachusetts. T cells are white blood cells that play a key role in the body’s immune response.
The study reached its findings by comparing blood samples from 19 people with lupus to blood samples from healthy individuals. The comparison showed that people with lupus have too much of a certain T cell associated with damage to healthy cells and too little of another T cell associated with repair.
At the heart of this imbalance is a protein called interferon, which helps the body defend against pathogens. Scientists have known for years that people with lupus have excessive levels of type I interferon — but the new study links this problem to several negative effects.
First, too much type I interferon can block a protein called the aryl hydrocarbon receptor, which helps regulate the body’s response to bacteria or environmental pollutants.
Blocking this receptor prevents the production of T cells that can help heal wounds in the skin, lung and gut barrier. It also stimulates the production of T cells involved in creating autoantibodies, which attack healthy cells and are a hallmark of lupus.
According to Rao, the theory can explain the vast majority of lupus cases.
“I think this applies to all patients with lupus in principle,” he said.
However, other experts doubt whether there is a single explanation for all cases of lupus.
“It’s very exciting research and very hopeful, but I think it’s probably too early to say that it’s the root cause of the disease,” said Mara Lennard Richard, a scientific program officer for the Lupus Research Alliance. The alliance is a private funder of lupus research and provided grant money for Rao’s study.
Because lupus symptoms are so diverse and the contributing factors are multiple, “it’s very difficult to find a single root cause for the disease,” Lennard Richard said. “If this turns out to be the cause of lupus, that would be great of course and really fantastic for people living with lupus.”
Dr. Jill Buyon, director of the division of rheumatology and the Lupus Center at NYU Langone Health, said the theory needs to be tested on a larger group of people.
“How can we know until they prospectively study 100 patients?” said Buyon, who was not involved in the study.
The Centers for Disease Control and Prevention estimates that more than 200,000 people in the U.S. have lupus, although the Lupus Foundation of America puts the total much higher: about 1.5 million people. About 90 percent of people with lupus are women.
Common symptoms include extreme fatigue, joint pain, or skin rash. In rare cases, the disease can lead to kidney or heart damage, or weaken the immune system so that the body cannot fight infections. These problems can be fatal or life-threatening.
Lupus has historically been difficult to treat. Many current options suppress the immune system, including helpful T cells that fight infection. And for some people with the disease, standard treatments are ineffective.
According to Dr. Jaehyuk Choi, one of the study’s authors and a dermatologist at Northwestern Medicine, the new research points to the possibility of better treatments in the future, such as infusions or pills.
The study found that giving lupus patients anifrolumab, a drug that blocks interferon, prevents the T-cell imbalance that likely leads to the disease.
“We followed patients who received this as part of their clinical care and showed that in patients who received the drug, this cellular imbalance was restored or was on its way to being restored,” Choi said.
In blood samples from people with lupus, the researchers also tested the effects of adding a small molecule that activates the aryl hydrocarbon receptor. They found that it limited the accumulation of disease-promoting T cells.
The biggest challenge in developing a new treatment, Choi says, is finding ways to deliver the treatment without activating aryl hydrocarbon receptors throughout the body, which can lead to more side effects.
Even if such a treatment becomes available, Buyon says it’s unlikely it would work for everyone with lupus.
“We have come to the deep realization that one drug cannot solve everything,” she said.