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BROADMINDED BLOG

Blog / 04.23.15

Fanning the flames of lupus

By Paul Goldsmith
What: A team of researchers from the Massachusetts General Hospital, Broad Institute of MIT and Harvard, and the University of North Carolina has identified an inflammatory molecule that may play an essential role in the development of lupus—a chronic, painful autoimmune disease affecting more than...

What: A team of researchers from the Massachusetts General Hospital, Broad Institute of MIT and Harvard, and the University of North Carolina has identified an inflammatory molecule that may play an essential role in the development of lupus—a chronic, painful autoimmune disease affecting more than 1.5 million Americans.

In a study published this week in Nature Immunology, the MGH/Broad team, led by Terry Means, revealed that a molecule, known as TREML4, amplifies a key signaling pathway in the immune system. TLR7 is one member of a family of proteins known as toll-like receptors (TLRs) that help the immune system recognize pathogens and initiate the release of inflammatory molecules to protect against infection. Research has indicated that over-activity in the TLR7 pathway is a key initiator of autoimmune disease.

“TLR7 is clearly a driver of autoimmunity, so we set out to find its targetable parts,” said contributing author and Broad Institute Member Nir Hacohen.

With generous support from the Lupus Research Institute and the Alliance for Lupus Research, the team screened more than 8,000 genes to find out what triggered TLR7 activation. Results revealed that TREML4 intensified immune response in cells activated by TLR7. Loss or suppression of TREML4 reduced the production of inflammatory immune cells related to the development of lupus.

Although the exact mechanism that triggers TREML4 remains to be determined, the team is optimistic about its potential.

“For Dr. Means and myself, an exciting part is the mystery that is now opened up,” said Hacohen. “Along with being an important protein and a potential therapeutic target, TREML4 points us to a new step in the whole process of viral and bacterial recognition. We don’t know what the mechanism is. What signal tells TREML4 to do this? Those are great open questions, and the answers will help us understand the underlying biology of the system.”

Why: 16,000 new cases of lupus are diagnosed each year, and yet only one new therapy has emerged to treat the disease in the last 50 years. Because it is a surface protein—meaning it is embedded in the cell membrane, and therefore easier to target with antibodies—TREML4 has therapeutic potential. Understanding the role TREML4 plays in lupus could open the door to new forms of therapy.

Who: The multidisciplinary team was led by Terry Means, and included members from the Center for Immunology and Inflammatory Diseases and the Division of Rheumatology, Allergy, and Immunology at Massachusetts General Hospital, the Division of Infectious Disease at Massachusetts General Hospital, and the University of North Carolina Kidney Center. Along with Hacohen, Glenn Cowley and David Root from the Broad’s Genetic Perturbation Platform also contributed to this study.

Where to find it: The paper was published online at Nature Immunology.