Researchers Discover an Immune Defect in Lupus and a Possible Way To Reverse It

The autoimmune disease systemic lupus erythematosus — known as lupus — affects more than 1.5 million people in the U.S. It can result in life-threatening damage to multiple organs including the kidneys, brain and heart. The causes of this disease have long been unclear. Existing treatments often fail to control the disease, the study authors said, and have unintended side effects of reducing the immune system’s ability to fight infections.

But now, Northwestern Medicine and Brigham and Women’s Hospital scientists have discovered a molecular defect that promotes the pathologic immune response in lupus and show that reversing this defect may potentially reverse the disease.

“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression,” said co-corresponding author Dr. Jaehyuk Choi, associate professor of dermatology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine dermatologist. “By identifying a cause for this disease, we have found a potential cure that will not have the side effects of current therapies.”

“We’ve identified a fundamental imbalance in the immune responses that patients with lupus make, and we’ve defined specific mediators that can correct this imbalance to dampen the pathologic autoimmune response,” said co-corresponding author Dr. Deepak Rao, an assistant professor of medicine at Harvard Medical School and a rheumatologist at Brigham and Women’s Hospital and co-director of its Center for Cellular Profiling.

In a study published in Nature on July 10, the scientists report a new pathway that drives disease in lupus. There are disease-associated changes in multiple molecules in the blood of patients with lupus. Ultimately, these changes lead to insufficient activation of a pathway controlled by the aryl hydrocarbon receptor (AHR), which regulates cells’ response to environmental pollutants, bacteria or metabolites, a substance created when the body breaks down food, drugs, chemicals or its own tissue. Insufficient activation of AHR results in too many immune cells that promote the production of disease-causing autoantibodies.

To show this discovery can be leveraged for treatments, the investigators returned the AHR-activating molecules to blood samples from lupus patients. This seemed to reprogram these lupus-causing cells into a type of cell that may promote wound healing from the damage caused by this autoimmune disease.

“We found that if we either activate the AHR pathway with small molecule activators or limit the pathologically excessive interferon in the blood, we can reduce the number of these disease-causing cells,” said Choi, also the Jack W. Graffin Professor at Feinberg. “If these effects are durable, this may be a potential cure.”

Choi, Rao and colleagues next want to expand their efforts into developing novel treatments for lupus patients. They are now working to find ways to deliver these molecules safely and effectively to people.

Reference: Law C, Wacleche VS, Cao Y, et al. Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus. Nature. 2024. doi: 10.1038/s41586-024-07627-2

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