Next, the researchers sought to highlight specifically how pDCs promote lupus autoimmunity. For this they used a different mouse gene knockout, based on a mouse strain developed in the TSRI laboratory of Bruce Beutler, a long-time collaborator who has since moved to become the director of the Center for Genetics of Host Defense at the University of Texas Southwestern Medical Center.
Beutler's special mice lack a working gene for a protein called SLC15A4, and as a result of this mutation, the pDCs in these mice develop normally, but are largely unable to produce type I interferons in response to the usual stimuli. Such cells normally produce large amounts of interferons after detecting viral or bacterial genetic material. For this detection, they use a class of internal receptors called TLRs (toll-like receptors). Beutler received the 2011 Nobel Prize in Physiology or Medicine for his work on TLRs. His SLC15A4-mutant mice specifically lack the ability to respond to stimuli that would normally be detected by two of these receptors, TLR7 and TLR9. These same TLRs have been implicated in lupusthey apparently mistake self-nucleic acids for viral nucleic acids.
Working with Beutler, the TSRI team applied the SLC15A4 mutation to a strain of lupus mice to see if it would protect them from autoimmunity. And it did. "The usual lupus-like signs significantly decreased, and survival was extended," said Baccala.
A Potential Target
Baccala and Theofilopoulos now see SLC15A4 as a potential target for a lupus druga drug that, in principle, would prevent flare-ups of autoimmunity without suppressing other parts of the immune system as much as current therapies do. "The SLC15A4-mutant mice seem to be otherwise almost normal immunologically," said Baccala. "They can clear common viral infections, for example."
"We are now trying to find pha
|Contact: Mika Ono|
Scripps Research Institute