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The Making of Medicine

A Surprising Link Between Lupus and Macular Degeneration

Lupus is a potentially debilitating autoimmune disorder. Macular degeneration is a leading cause of vision loss. But the two disparate diseases share an unexpected connection, new research from the School of Medicine reveals.

Our Jayakrishna Ambati, MD, a top expert on macular degeneration, discovered a joint contributor to the harmful inflammation that drives both diseases: an inflammasome called NLRC4-NLRP3.

Inflammasomes play an important role in marshaling the body’s defenses to protect it from invaders such as viruses and bacteria. In lupus and atrophic macular degeneration, however, NLRC4-NLRP3 contributes to damaging inflammation. In lupus, it helps drive the hyperactive immune response that leads to joint pain, rash, fever and other symptoms. And in macular degeneration, NRC4-NLRP3 appears to contribute to inflammation that destroys the vital light-sensing cells in the retina.

NRC4-NLRP3 is sent into action by a special class of genetic material called “short interspersed nuclear element RNAs,” or SINE RNAs, Dr. Ambati found. SINE RNAs make up more than 10% of our genomes, and they activate in response to cell stresses such as infection, genetic damage and aging.

In addition to discovering the role of SINE RNA in the two diseases, Dr. Ambati and his colleagues identified an unknown receptor for the SINE RNAs called DDX17. Scientists have been looking for this receptor for decades, and the new discovery helps them better understand the process that leads to the harmful inflammation.

“These findings indicate that blocking a single inflammasome might not be enough, and that targeting both the NLRC4 and NLRP3 inflammasomes would be a superior strategy,” Dr. Ambati said.

The new findings could lead to better treatments, Dr. Ambati says. He has developed drugs called Kamuvudines to block the dual inflammasome, and he hopes to begin clinical trials next year.

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