Overview
A team of NIAMS-funded researchers discovered an imbalance of T cell subtypes in patients with lupus that contributes to ongoing production of disease-causing autoantibodies. Compared to healthy individuals, patients with lupus have more T cells with specialized B cell helper functions and fewer T cells that are important for wound healing and maintaining the epithelial barrier, which acts to protect the body from pathogens and other invaders. The team identified two molecules that control this imbalance, which could be the targets of lupus treatments in the future.
The study was recently published in the journal Nature.
Background
Systemic lupus erythematosus (lupus) is a chronic autoimmune disease that occurs when the immune system attacks tissues in the body, causing inflammation. Patients can experience widespread and varied symptoms in the skin, joints, heart, lungs, kidneys, blood cells, and brain.
One central feature of lupus is the production of autoantibodies, which are antibodies that attack specific tissues in the body. These autoantibodies are made by white blood cells called B cells with the help of another type of white blood cell called T cells. Compared to healthy individuals, patients with lupus have more T cells with specialized B cell helper functions, called T peripheral helper (Tph) and T follicular helper (Tfh) cells. People with lupus also have high levels of interferon in the body, which is a highly inflammatory signaling molecule.
In this study, NIAMS-supported researchers sought to understand the regulation of T cells with B cell helper functions because they play a key role in stimulating the production of disease-causing autoantibodies.
Select Research Highlights
The researchers first performed immune profiling on blood samples from 19 patients with lupus and 19 healthy controls. This technique allows researchers to analyze the number and percent of specific immune cell subtypes present in the blood, which is determined in part by what proteins the cells have on their surface and what signaling molecules they make. The results were similar to previous findings that lupus patients have more Tph and Tfh cells than healthy controls do. The results also showed that lupus patients have fewer T helper 22 (Th22) cells, which produce a specific signaling molecule called IL-22 and have an important role in wound healing and epithelial barrier protection.
Next, the researchers wondered if Tph/Tfh cells and Th22 cells are counterregulated—meaning when the number of one group increases, the other decreases—and what controls this counterregulation. The team studied several molecules with regulatory functions to learn if any are involved in this process. They identified the aryl hydrocarbon receptor (AHR) as a factor that can drive T cells to adopt one subtype over another. When activated, AHR drives T cells to become Th22 cells and prevents them from becoming Tph or Tfh cells. The team then looked at the regulation of AHR. They found that interferon directly inhibits the function of AHR.
In all, the study found that interferon blocks the action of AHR, leading to an overproduction of disease-promoting Tph and Tfh cells and an underproduction of protective Th22 cells, and thus continued autoantibody production and inflammation. The investigators plan to test the extent to which these findings can be applied more widely, considering how different the disease can present among patients.
They also plan to investigate how to apply these findings in the clinic. “As we’re thinking about ways to disrupt the generation or the function of these disease-causing T cells with B cell helper functions, one idea that emerges is that we can turn on the activity of AHR to suppress these cells in patients with lupus,” says Deepak A. Rao, M.D., Ph.D., an immunologist and rheumatologist at Brigham and Women’s Hospital in Boston, Massachusetts, and one of the study’s corresponding authors. The ideal drug candidate, he said, would activate AHR selectively in T cells without activating it throughout the body.
Rao further expressed his support for and gratitude to patients who donate samples for study. “The willingness of patients with lupus to participate in clinical trials is at the heart of continued therapeutic discovery,” he said.
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