Inhibiting Protein to Prevent Immune Reaction May Help Harness Lupus

Blocking a protein that controls the immune system’s reaction to a virus may also be used to prevent autoimmune reactions in diseases such as systemic lupus erythematosus, research indicates.

Although the PLSCR1 protein was discovered in the brain, researchers are exploring its role in inflammatory diseases throughout the body.

An important finding was that the reduction in inflammatory activity that researchers achieved by inhibiting the protein lasted at least six months.

The study, “Phosphatidylserine exposure controls viral innate immune responses by microglia,” was published in the journal Neuron.

Researchers at the Salk Institute for Biological Studies were seeking to understand immune reactions to viruses used to deliver gene therapies. Although such modified viruses are unable to spread and cause disease, their presence may trigger an immune reaction that is harmful, particularly if the virus is delivered to the brain.

“Normally, the immune system will quickly recognize and act upon potential threats such as virally infected cells,” Axel Nimmerjahn, an assistant professor in Salk’s Waitt Advanced Biophotonics Center and senior author of the paper, said in a press release. “But in targeting PLSCR1, we’ve effectively shielded infected cells from immune attack and increased gene expression from an engineered virus from a few days or weeks to at least six months, creating the potential for much longer-lasting therapies.”

Researchers injected a modified virus — of a type often used to deliver treatments — into the brains of mice. The team noticed that the brain cells used a molecular flag to signal the virus’ presence.

This signal attracted microglia cells to the site. They are the brain’s main immune fighters, and have the capacity to kill virus-infected cells. But when they reach the site of an infection, the cells first assess the situation to decide on a response. And the decision is a fine line to walk.

Destroying the infected cells can cause irreparable damage, particularly in the brain. Leaving them may allow the infection to spread, damaging other areas as well.

To understand the microglia’s decisions, researchers removed and boosted levels of various proteins involved in cellular communication. When they removed PLSCR1 — short for phospholipid scramblase 1 — they got a surprise.

Without the factor, microglia left the cells alone. This led to the production of considerably less inflammatory molecules, such as cytokines.

“When we saw how much inhibiting PLSCR1 reduced the inflammatory response, we immediately wondered if this mechanism could apply more broadly, not just to virus infection of the brain, but to other types of infections or even autoimmune diseases,” said Yusuf Tufail, a former Salk postdoctoral fellow and first author of the paper.

Since PLSCR1 is present throughout the body, the researchers believe their discovery may have far-reaching consequences for inflammatory conditions in general. They noted, for example, that a study has shown that PLSCR1 is higher in lupus patients.

None of the other factors that the team investigated had as powerful and lengthy an effect on the immune response as PLSCR1.

“Given how complex the immune response is, and how many genes are regulated up or down in response to infection, it was amazing to find a single protein that controls so many pathways,” Nimmerjahn said. “Imagine a small molecule inhibitor that a patient could take to curb excessive inflammation. This could have a hugely beneficial effect on many disease outcomes.”