“Up until this point, all therapy for lupus is a blunt instrument. It’s broad immunosuppression.” That is how Jaehyuk Choi, a dermatologist at Northwestern Medicine, describes the drugs available today. In July 2024 he and colleagues at Brigham and Women’s in Boston published a study in Nature that points to a different target.
The disease is systemic lupus erythematosus, usually just called lupus. In the U.S. alone it affects over 1.5 million people, and it can cause life-threatening damage to the kidneys, brain and heart. Until this study, its causes were unclear. Current treatments frequently fail to rein it in, the authors said, and they carry a side effect: weaker defences against infection.
An imbalance in the T cells
Deepak Rao, a Brigham and Women’s rheumatologist who also teaches at Harvard Medical School, and Choi were the co-corresponding authors. Their first look at patient immune profiles showed a consistent imbalance. People with lupus had too many B-cell-helper T cells, known as TPH and TFH cells, and a reduced number of IL-22-producing Th22 cells.
The blame falls on a pathway run by the aryl hydrocarbon receptor, or AHR, which regulates how cells respond to environmental pollutants, bacteria and metabolites. In lupus, changes to several molecules in the blood lead to too little activation of AHR. With the brake weak, the disease-promoting T peripheral helper cells multiply, and they encourage the production of the autoantibodies that do the damage. Type I interferon, which the body overproduces in lupus, adds to the problem by suppressing AHR’s effects.
“When we found a molecular switch that controls the generation of disease-promoting B-helper T cells in lupus, we posited that the chemicals that control this switch must be altered in patients,” Choi said. “Indeed, patients with lupus have a deficiency in the AHR signaling pathway.”
Reversing it in blood samples
To test the idea, the team added molecules that switch on AHR back into patients’ blood samples. The disease-causing cells appeared to be reprogrammed into Th22 cells, which may help wound healing after the damage the disease causes. Two routes worked in the lab. One was small-molecule activators of AHR. The other was limiting the excess interferon in the blood. Either way, the number of disease-causing cells fell.
“If these effects are durable, this may be a potential cure,” Choi said. Rao put it more carefully: “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.”
The work was done on cells in the lab, not in patients, and the researchers say more is needed before it reaches the clinic. They are now trying to find ways to deliver the molecules safely and effectively.
Sources
- Scientists Discover a Cause of Lupus and a Possible Way to Reverse It – News Center
- Scientists find potential breakthrough in lupus treatment
- Newly illuminated molecular roots of lupus may lead to treatments with ‘durable benefits’
