November 3, 2025 | By Asher Jones
In 2006, Mark Shlomchik and his colleagues at Yale published a surprising discovery. Two immune receptors, despite supposedly similar signaling pathways, had completely opposite effects on lupus progression. TLR7 drives disease, while TLR9 is protective.
“That paper sparked a 20-year conundrum: Why are TLR7 and TLR9 so different in terms of their regulation of autoimmunity?” said Shlomchik, distinguished professor of immunology in the Pitt School of Medicine. “Both of these receptors sense nucleic acids, they’re both found in endosomes, and, according to the textbooks, they signal by exactly the same means.”
According to a new Journal of Clinical Investigation study led by Shlomchik and his former postdoc Claire Leibler at Pitt, the textbooks may need an update. They found that the signaling domains of TLR7 and TLR9 do, in fact, work differently.
To crack the case, the team engineered chimeric receptors, swapping the TIR signaling domains between TLR7 and TLR9 while keeping their recognition elements intact.
The results were striking: placing TLR9’s signaling domain on TLR7 reduced lupus symptoms in mice, while the reverse swap worsened disease.
“This finding finally explains why TLR7 and TLR9 contribute to lupus in different ways,” said Shlomchik. “It doesn’t have to do with what they’re recognizing; it’s to do with how they’re signaling inside the cell through their TIR domains.”
TLR7 and TLR9 are part of a family called toll-like receptors. Part of the innate immune system, they are found on the membrane of intracellular organelles called endosomes, where their job is recognizing RNA (TLR7) and DNA (TLR9) from viruses and other pathogens. However, they can mistakenly respond to self-RNA or DNA, leading to the production of self-recognizing “anti-nuclear” autoantibodies — a hallmark of lupus.
According to Shlomchik, a lot of genetic variation associated with lupus occurs at the genes encoding proteins involved in TLR signaling pathways, suggesting that the new findings could shed light on why some people get lupus. It also opens the door to new therapeutic approaches.
As a result of Shlomchik’s original study, TLR7-inhibiting drugs are currently being tested for lupus, where they are showing promise. Based on the new findings, it could also be possible to target the disease from the opposite angle by promoting the regulatory mechanisms of TLR9.
Leibler, who is now an assistant professor at the University of Bordeaux in France, is exploring the details of how TLR7 and TLR9 signal differently with the goal of eventually developing novel therapies for lupus and other autoimmune disorders.
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Image 1: Chimeric TLR receptors made of TLR7 recognition elements with TLR9 signaling domains are localized in endosomes, similarly to the native TLR7 molecule. [Credit: Leibler et al. JCI]
Image 2: Mark Shlomchik and Sebastien Gingras, research assistant professor of immunology and coauthor on the study, stand together in the lab. [Credit: Asher Jones]