OTULIN Mutation Identified as Cause of Pediatric-Onset Pyoderma Gangrenosum, TNF Blockade Shows Therapeutic Promise
Key Insights
An international team identified a mutation in the OTULIN (search) gene as the cause of pediatric-onset pyoderma gangrenosum (search), classifying it as a new inborn error of immunity.
The mutation uncouples OTULIN (search)'s enzymatic activity from its interaction with a ubiquitination complex, leading to elevated TNF (search) and IL-1β levels and heightened sensitivity to TNF-dependent cell death.
One patient with treatment-resistant skin sores achieved successful clinical response with TNF (search) blockade therapy.
A mutation in the OTULIN (search) gene has been identified as the cause of pediatric-onset pyoderma gangrenosum (search), an international team of researchers reports in Nature Immunology. The discovery classifies this rare, ulcerating skin condition as a new inborn error of immunity (IEI) — joining a group of more than 500 genetic disorders that impair immune system development or function — and points to TNF (search) blockade as a viable therapeutic strategy.
"The discovery of novel IEIs creates opportunities to dissect the molecular and cellular basis of human immune pathology and can reveal potential therapeutic targets," said Janet Markle, PhD, MPH, Assistant Professor of Pathology, Microbiology and Immunology at Vanderbilt Health (search) in Nashville, TN, and co-corresponding senior author of the study.
Parallel Investigations Converge on OTULIN
Markle's research group at Vanderbilt and a team in the Netherlands led by András Spaan, MD, PhD, Associate Professor of Medical Microbiology at University Medical Center Utrecht, were independently studying patients from different parts of the world with pediatric-onset pyoderma gangrenosum (search). Both groups suspected the condition might represent an unrecognized IEI.
"We were independently investigating whether this condition might represent an unrecognized IEI," Markle said. Using whole exome sequencing, both teams identified the same mutation in OTULIN (search), an enzyme with broad roles regulating inflammation, cell death, and immune responses.
The two groups learned of each other's work through a shared former mentor and decided to join forces. Graduate students Barathram Swaminathan at UMC Utrecht and Hwi Gil at Vanderbilt Health (search) co-led the experimental work using different, complementary approaches.
"The international IEI research community is highly interconnected and collaborative," said Spaan, also co-corresponding senior author of the report. "This study is the product of a highly productive scientific collaboration with a direct clinical impact."
Molecular, Immunological, and Cellular Consequences
To investigate the effect of the OTULIN (search) mutation, the researchers performed functional studies in cell lines and patient-derived samples, examining protein interactions, ubiquitination dynamics — a process with roles in multiple immune signaling pathways regulated by the OTULIN enzyme — and cellular responses.
At the molecular level, the mutation uncouples two important OTULIN (search) functions: its enzymatic activity, which is preserved, and its interaction with a ubiquitination complex, which is impaired.
At the immunological level, patient samples showed high levels of the pro-inflammatory molecules interleukin-1beta (search) and TNF (search) (tumor necrosis factor), along with increased inflammasome activation.
At the cellular level, patient skin cells demonstrated accumulation of linear ubiquitin and heightened sensitivity to TNF (search)-dependent cell death.
Clinical Translation: TNF Blockade
The study pointed to TNF (search) blockade as a potential therapeutic option for patients with OTULIN (search)-related pyoderma gangrenosum (search). The investigators noted that one patient, whose painful skin sores were resistant to years of treatment with nonspecific anti-inflammatory therapy, was successfully treated with TNF blockade.
Pyoderma gangrenosum (search) is poorly understood and currently has no curative treatments. Although familial clustering has been reported, the genetic basis had not been deeply explored prior to this work, according to Markle.
"This study adds to a growing body of work showcasing the critical role of highly regulated linear ubiquitin signaling in human health and highlights the value of studying rare genetic diseases to uncover fundamental immunological mechanisms," Markle said.
Swaminathan, Gil, and Sagar Bhattad, MD, from the Department of Pediatrics at Aster CMI Hospital in Bengaluru, India, are equal contributors and co-first authors of the Nature Immunology report. The research was supported in part by the Dutch Research Council and U.S. National Institutes of Health through grants R35GM155339 and F31AR082264.