Research Identifies Cause of Lupus and Possible Reversal Technique

Northwestern Medicine and Brigham and Women's Hospital scientists have discovered a molecular defect that promotes the pathologic immune response in systemic lupus erythematosus (known as lupus) and show that reversing this defect may potentially reverse the disease.

The study was published in the journal Nature.

Lupus affects more than 5 million people worldwide. Until now, the causes of this disease were unclear. Lupus can lead to life-threatening damage to multiple organs, including the kidneys, brain, and heart. Existing treatments often fail to control the disease effectively and have unintended side effects, such as reducing the immune system’s ability to fight infections.

In the study, scientists discovered a new pathway that causes lupus. They found changes in multiple molecules in the blood of lupus patients. These changes lead to a lack of activation in a pathway controlled by the aryl hydrocarbon receptor (AHR), which usually helps cells respond to environmental pollutants, bacteria, or metabolites. When AHR is not properly activated, it results in too many immune cells called T peripheral helper cells, which promote the production of harmful autoantibodies that cause the disease.

To explore potential treatments, the researchers added AHR-activating molecules back into blood samples from lupus patients. This reprogrammed the harmful immune cells into Th22 cells, which may help heal the damage caused by lupus.

“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression. 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. 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. If these effects are durable, this may be a potential cure,” said the authors.

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