September 2010

First Direct Evidence that X-Linked TLR7 Gene Promotes Lupus in Humans

LRI-funded researcher Betty Tsao, PhD, at the University of California Los Angeles has discovered that humans—males in particular—with a variant form of the immune receptor gene “Toll Like Receptor 7 (TLR7)” are at increased risk of developing lupus.

Recently published in the Proceedings of the National Academy of Sciences (PNAS), the powerful finding represents additional strong evidence from human cells—as opposed to mice or other animal cells—that alterations in the TLR7 gene can promote lupus.

It’s a breakthrough that offers renewed hope for developing more targeted treatments.

Validates LRI’s Human Lupus Biology initiative to translate mouse findings to human disease

“This is an extremely important scientific and medical advance,” said Mark Shlomchik, MD, PhD, professor of laboratory medicine and immunobiology at Yale University.

“Before this work, it was known that Toll like receptors 7 and 9 were important in mouse models of lupus, but there was no good evidence for this in people, he said. “We only had some evidence that other genes that may work with TLRs were linked to lupus.”

“Dr. Tsao’s findings demonstrate the power of genetic studies in mouse lupus models to guide the hunt for susceptibility genes in the more complex human disease,” added Michel Nussenzweig, MD, PhD, the Sherman Fairchild Professor and a senior physician at Rockefeller University.

LRI Successfully Pioneers Discovery 

Dr. Tsao built upon a bold and innovative hypothesis that the LRI had supported nearly a decade ago: that a strain of mice prone to lupus carry an extra copy of the TLR7 gene located on the Y-chromosome. Silvia Bolland, PhD, made this major discovery in 2006, soon after she joined the NIH to form her own group. 

The LRI subsequently supported Dr. Tsao’s innovative proposal to translate Dr. Bolland’s discovery in mice to a discovery in humans.

A major finding in male lupus

Dr. Tsao’s discovery that the lupus link to TLR7 is stronger in males supports the idea that there are different genetic pathways to lupus in males and females. Only 10 percent of people with lupus are male, but the disease tends to be particularly severe in this population.

In their research, Dr. Tsao and colleagues noted that men with an extra X (female) chromosome have a higher risk for lupus, and predicted that genes located on the X chromosome would be critical in male lupus.

So they narrowed their search among the approximately 2,000 genes on the X chromosome to genes already implicated in lupus.

After genotyping DNA of blood samples from over 4,000 people with lupus from East Asia, the team discovered a variant form of the TLR7 gene associated with lupus. The link was stronger in men of Chinese and Japanese ethnicity—89% of men with lupus had the risk allele, compared with only 77% of healthy male subjects.

Increases potential for new therapies

“Now that we know the sex-specific genetic contributions to lupus, we can proceed to find more targeted therapies than currently exist,” Dr. Tsao said.

In fact the search for new therapeutics acting on TLR7 is already underway, with candidate drugs in development at several companies.

“This finding strongly confirms the selection of TLR7 as a target for drug therapy,” noted Benjamin Schwartz, MD, PhD, a professor of clinical medicine at the Washington University School of Medicine in St. Louis. “It also further lends credence to the LRI’s support of novel research to help find therapies and cures for lupus.”

The research appears in the Aug. 23 online edition of the journal Proceedings of the National Academy of Sciences (PNAS).

Want to learn more about the LRI’s Human Lupus Biology program? See a full description here.

 

 

 

About the LRI
The nation’s only nonprofit singularly dedicated to novel research in lupus, we champion innovation and scientific risk-taking in the hunt for solutions to this complex and dangerous autoimmune disease.

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