Some People Are Immune to a Deadly Disease – Scientists Finally Know Why

A rare genetic disease that ravages some but spares others has baffled researchers — until now.

Researchers found that a genetic variant, HAQ-STING, acts as a shield against COPA Syndrome, a discovery that could lead to life-changing gene therapies. For families long plagued by the disease, the revelation was both an explanation and a beacon of hope.

A Breakthrough in Understanding COPA Syndrome

For over 15 years, Dr. Anthony Shum, a pulmonologist at the University of California, San Francisco, has been investigating a rare genetic disorder that affects families in unpredictable ways. Some people with the mutation develop severe lung hemorrhaging in childhood, while others remain completely unaffected.

A Genetic Shield Against Disease

Now, Shum and his team have identified a separate genetic variation that can prevent the disease, known as COPA Syndrome. This breakthrough could pave the way for a new gene therapy to treat a condition that currently requires intensive medical care and immunosuppressant drugs.

Researchers discovered that some relatives of COPA Syndrome patients stayed healthy despite carrying the disease-causing COPA mutation. The reason? They also had a protective variant of another gene, HAQ-STING. When scientists introduced this protective variant into diseased COPA lung cells, the cells improved.

“We really think HAQ-STING could be a gene therapy tool and a clear step toward a cure,” said Shum, the senior author of the paper, which was published today (February 27) in the Journal of Experimental Medicine.

Families and Clinicians Connect the Dots

In 2011, Shum was called in to help stabilize a patient in the emergency room at the UCSF Helen Diller Medical Center. The patient, a young woman named Letasha, had severe bleeding in the lungs. It wasn’t clear what was causing Letasha’s condition. But Shum began to suspect it had a genetic cause when the woman’s mother, Betty Towe, told him her other daughter, Kristina, had nearly identical symptoms.

Since early childhood, both Letasha and Kristina had routinely visited UCSF to be treated for their unusual combination of life-threatening bleeding in the lungs and rheumatoid arthritis. Betty always accompanied her daughters on the four-hour trip from Oakdale, California to UCSF.

Shum began helping them navigate care at UCSF while investigating how far these symptoms extended through their family tree. He soon became their primary pulmonologist.

“My mom’s cousin mentioned that we had distant relatives in Texas, third cousins, who had a young daughter with lung problems and arthritis, and other relatives in Oakland with similar problems,” said Letasha, who is now 43. “Dr. Shum took blood samples from all of us and started to connect the dots.”

In 2015, Shum, along with colleagues from Baylor College of Medicine and Texas Children’s Hospital, announced that they had found a common factor behind these symptoms in five families: a mutation in a gene called COPA. While 30 individuals across these families had the mutation, only 21 of them were stricken by the disease, which they dubbed COPA syndrome.

The Domino Effect of the COPA Mutation

COPA syndrome is rare, perhaps affecting a few thousand individuals in the U.S., many of whom are not diagnosed. The discovery of the COPA mutation sparked efforts worldwide to raise awareness of the disease, understand it, and work toward a cure.

In 2020, while experimenting with the COPA gene in the lab, Shum discovered a second gene of interest called STING. When COPA was mutated, as is the case in people with COPA syndrome, STING went awry.

“Everybody needs STING to fight off occasional infections and get rid of viruses, but in patients with COPA syndrome, STING is on all the time,” Shum said. “This causes a lot of inflammation, and for reasons that aren’t totally clear, it damages the lungs, kidneys, and joints.”

The Protective Power of HAQ-STING

However, the researchers knew that STING had a variant, called HAQ-STING, that appeared in over a third of the population. They wondered if it might be able to neutralize the effects of the COPA mutation and explain its inconsistent effects on families. To test their hypothesis, they’d need the cooperation of dozens of patients – and their healthy family members.

Letasha, Kristina, and Betty immediately stepped up.

“Whenever Dr. Shum has asked us to help with his research, I was so happy to do all of it – donating, working with them, taking any tests,” Letasha said. “I knew he would figure it out.”

Shum joined forces with another Baylor College of Medicine pediatrician, Tiphanie Vogel, MD, PhD, and others to assemble health records and DNA samples from 26 patients with COPA syndrome from around the world.

They also put nine healthy relatives with the COPA mutation through several rounds of testing, including CT scans and blood tests for inflammation, to make sure they did not have any symptoms of the disease. Then, the team sequenced the STING gene in every patient and relative.

“All the healthy relatives had HAQ-STING, while none of the COPA syndrome patients had it,” said Noa Simchoni, MD, PhD, a pulmonologist at UCSF who is the first author of the paper. “It’s the first report of a common allele providing total protection from a severe genetic disorder.”

HAQ-STING Clears a Path to a Cure

Simchoni and Shum saw a clear opportunity to test whether HAQ-STING could be used therapeutically. They took lung cells from a patient with COPA syndrome and treated them with HAQ-STING, akin to gene therapy in a petri dish. Even though these cells already had other forms of STING, the addition of HAQ-STING brought their immune signals back into balance.

Shum sees several promising paths for turning the HAQ-STING discovery into relief for COPA syndrome patients.

“Maybe if a baby is diagnosed prenatally with the COPA mutation, but lacks HAQ-STING, we could do prenatal gene therapy,” Shum mused, noting how UCSF’s Tippi MacKenzie, MD, has already demonstrated how this can work. “Or in adults, we could deliver HAQ-STING in an aerosol directly to their airways and protect their lungs.”

Discovery Brings Understanding and Hope

A few weeks before the discovery was to be published, Shum gave Betty a call to share the news. He explained that she had remained healthy through her 60-plus years because HAQ-STING had protected her. Then Shum called Letasha and Kristina.

Soon the three women were calling each other, crying tears of joy all afternoon. The mystery of their family’s health had been solved. Maybe, in the future, others would also be spared from the suffering the had endured.

“We’ve always believed Dr. Shum would get to the bottom of it,” Letasha said. “I hope he understands the amazing thing he’s doing. It’s going to change people’s lives.”

Reference: “The common HAQ STING allele prevents clinical penetrance of COPA syndrome” by Noa Simchoni, Shogo Koide, Maryel Likhite, Yoshihiko Kuchitsu, Senkottuvelan Kadirvel, Christopher S. Law, Brett M. Elicker, Santosh Kurra, Margaret Mei-Kay Wong, Bo Yuan, Alice Grossi, Ronald M. Laxer, Stefano Volpi, Dilan Dissanayake, Tomohiko Taguchi, David B. Beck, Tiphanie P. Vogel and Anthony K. Shum27 February 2025, Journal of Experimental Medicine.

Other authors are Christopher S. Law, Brett Elicker, MD, and Santosh Kurra, PhD (UCSF); Senkottuvelan Kadirvel, PhD, Bo Yuan, PhD (Baylor College of Medicine); Shogo Koide, Yoshihiko Kuchitsu, PhD, Tomohiko Taguchi, PhD, (Tohoku University in Japan); Maryel Likhite, Margaret Mei-Kay Wong, MS, David B. Beck, MD (NYU); Alice Grossi, PhD, Stefano Volpi, MD, PhD (Gaslini Institute in Italy); Ronald M. Laxer, MD, Dilan Dissanayake, MD, PhD (Hospital for Sick Children in Canada).

This work was supported by the National Institutes of Health (R21AI160107, R01AI168299, T32AR007304, F32HL172586), the American Thoracic Society, and the Children’s Interstitial Lung Disease Foundation.