Newly found ‘molecular switch’ in lupus could help treatment

Lupus, in superhero terms, tells a devastating story. A loyal hero turns villain and tries to destroy his own people. But new research asks the question: What if immune cells could be turned back into good guys and actually help save tissue damaged by autoimmune diseases?

Lupus is complicated because it turns the body’s own defense mechanisms against itself, causing an ongoing immune misfire. B cells and T cells are the white blood cells that identify and destroy pathogens in the body. They work together: T cells make a protein called CXCL13 that calls B cells to sites of inflammation. In a disease like cancer, more CXCL is beneficial because it brings B cells to the site of the malignancy and enhances the immune system’s response. In the case of lupus, B cells are recruited to places where they shouldn’t be, such as the skin, lungs and kidneys.

More than 200,000 adults in the US are believed to have the most common form of lupus: systemic lupus erythematosus. Because the immune system attacks healthy tissues, lupus can lead to organ damage and joint pain, as well as fatigue, rashes, and other symptoms. For decades, scientists have been trying to tease apart the factors that lead to the condition, which mainly affects women and girls.

Many lupus patients also have other imbalances, according to the data. Compared to people without autoimmunity, people with lupus have fewer T cells that produce a protein called interleukin-22, which can help with inflammation and wound healing. It’s a double whammy: fewer helpful cells and more damage-promoting cells, says Jaehyuk Choi, associate professor of dermatology, biochemistry and molecular genetics at Northwestern University’s Feinberg School of Medicine.

“We wondered if there was a molecular switch that determined how these cells could switch between the two,” said Choi, senior author of the study. published Wednesday in Nature. With a team of researchers and co-senior author Deepak Rao, associate professor of medicine at Harvard Medical School, Choi found the switch.

Cells can switch between the two phenotypes (helpful IL-22 makers, harmful B helpers) with a “naturally occurring see-saw,” he told STAT. And scientists may be able to tilt the plank toward beneficial T cells as a way to treat the disease.

Choi and Rao’s research points to the aryl hydrocarbon receptor, or AHR, as a regulator of the cellular seesaw, and therefore a cause of lupus.

AHR activates genes that are important for the birth of IL-22-producing T cells (the good guys in this video). It also helps keep CXCL13 – the protein that calls many B cells – under control. Their research found that suppressing AHR caused the population of harmful cells to proliferate, while stimulating AHR with an agonist increased the presence of wound-healing T cells. (When they studied synovial fluid from people with rheumatoid arthritis, they found that a similar ordeal occurred with CXCL13 and AHR, suggesting that the problem could extend beyond lupus and other autoimmune diseases.)

The researchers performed numerous tests, including using CRISPR to remove AHR and seeing what happened, performing single-cell analysis, RNA sequencing, and studying patients receiving lupus therapy. These experiments were “quite extensive” and provided a “huge amount of data,” says Marta Alarcón-Riquelme, professor and scientist at the Center for Genomics and Oncological Research: Pfizer and the University of Granada in Spain. The end result is a study that unifies many of the abnormalities and imbalances that lupus researchers have been reporting for decades — and offers an idea of ​​the mechanism by which this happens, she said. (Alarcón-Riquelme was not involved in the research.)

The study also suggests that interferons, molecules that activate the immune system, actively promote the imbalance by counteracting AHR. This then leads to more inflammation and fewer useful cells. “We have known for years that patients with lupus have too much interferon production, but how interferon contributes to the disease is less clear,” Rao said.

Certain lupus medications, such as anifrolumab (AstraZeneca’s Saphnelo), target the problem by blocking interferon. But addressing AHR itself may allow for a more “surgical” approach to treatment, Choi said. For a long time, lupus medications have largely suppressed the immune system, which can be effective but can also cause unwanted side effects and health risks.

Clearer understanding of the cause of lupus could help drug developers take a more limited approach. Rao and Choi’s research “nominates a new strategy” aimed at activating AHR.

More research is needed to find out whether IL-22 T cells are truly beneficial and wound-healing for everyone with lupus, and whether this approach can be turned into a viable treatment for lupus or other autoimmune diseases.

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