Discovery of Immune System Brake Could Lead to Lupus Treatments

The discovery of a factor that acts as a brake on the immune system’s first line of defense may lead to new strategies for fighting autoimmune diseases such as systemic lupus erythematosus, a study reports.

The factor could also impact research into antiviral therapies, vaccine adjuvants, and cancer immunotherapies. An adjuvant is a substance that helps accelerate, prolong, or enhance a vaccine response.

Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) identified the factor, known as an immune checkpoint. The braking device makes sure the immune system’s response toward invading microbes is not too aggressive, since an overly harsh response can do more harm than good. Among other things, a hyped response can cause autoimmune reactions.

“We discovered that a protein called K-homology splicing regulatory protein (KHSRP) weakens the immune response to viral RNA,” Sumit Chanda, PhD, the senior author of the study, said in a press release. Chandra is director of the Immunity and Pathogenesis Program at SBP.

“Depleting KHSRP improved immune signaling and reduced viral replication in cell culture and in vivo [ in a living organism] , suggesting that drugs inhibiting the protein may have therapeutic value.”

Reseachers found that KHSRP interacts with another immune factor, RIG-I, to check immune response. Screening for molecules that impact RIG-I’s activity led to the team identifying the immune checkpoint.

The study, “Systems-based analysis of RIG-I-dependent signalling identifies KHSRP as an inhibitor of RIG-I receptor activation,” was published in the journal Nature Microbiology.

“We identified KHSRP by systematically testing every human protein to identify those that impact RIG-I signaling,” said Stephen Soonthornvacharin, a recent PhD graduate on the research team. “We found about 240 proteins, but we focused on KHSRP because it was the only one of the 240 that was found to inhibit the very early steps of RIG-I signaling.”

The remaining 239 proteins may also prove useful, however. Since 125 of them activate RIG-I, searching for drugs that prevent their activation may lead to new treatments for autoimmune diseases.

“Finding drugs that inhibit these proteins may be a way to treat autoimmune conditions involving too much interferon, like type 1 diabetes or lupus. Figuring out which ones are promising requires further investigation,” Soonthornvacharin said.

“We think KHSRP protects against autoimmunity,” Chanda said. “RIG-I normally recognizes RNA molecules that arise during viral infections, but it can also mistakenly sense RNA present in normal cells. Without KHSRP, the innate immune response could be erroneously turned on when there’s no virus. Increasing the activity of KHSRP might, therefore, be a way to treat autoimmunity.”

The research team plans to examine the interaction between KHSRP and RIG-I in greater detail. A better understanding of how RIG-I is controlled could help them develop treatments for lupus and other conditions.