New Autoinflammatory Disease Discovered

Researchers at the National Institutes of Health this week announced the discovery of otulipenia — a condition that primarily affects young children.

Otulipenia is caused by the malfunction of OTULIN, a single gene on chromosome 5. When it’s functioning properly, this gene regulates the development of new blood vessels, as well as the mobilization of cells and proteins to fight infection. But when it malfunctions — it turns the immune system on itself. Symptoms range from unexplained fevers and skin rashes, to diarrhea, joint pain, and overall failure to grow or thrive.

“This discovery suggests a direction for development of new therapies for patients with a wide range of inflammatory diseases,” said one researcher.

Working alongside colleagues from Turkey and the United Kingdom, NIH researchers identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. Using DNA-sequencing technology, they were able to quickly realize that the OTULIN gene was abnormal and study the immune pathway to figure out why.

They discovered a problem in the processing of a small protein, ubiquitin. The protein is “critical to the regulation of many other proteins in the body, including immune molecules. In the affected children, the inability to remove the ubiquitin proteins from various molecules resulted in an increased production of chemical messengers that lead to inflammation,” according to the study.

The researchers then determined that the children with otulipenia might respond to drugs that turned off tumor necrosis factor, a chemical messenger involved in systemic inflammation. It worked.

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Inflammation subsided in the children who had been treated with anti-tumor necrosis factor drugs (TNF inhibitors). TNF inhibitors are also used to treat chronic inflammatory diseases like rheumatoid arthritis.

[lz_bulleted_list title=”Autoinflammatory Diseases” source=”http://www.niams.nih.gov”]The relatively new category of diseases are characterized by intense episodes of inflammation that result in fever, rash, or joint swelling. These diseases also carry the risk of amyloidosis, a potentially fatal buildup of a blood protein in vital organs.[/lz_bulleted_list]

“The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” said Ivona Aksentijevich, M.D., a staff scientist in National Human Genome Research Institute’s (NHGRI) Medical Genetics Branch and the study’s co-author, in a statement. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”

“The results have been amazing and life-changing for these children and their families,” said Daniel Kastner, M.D., Ph.D., co-author and NHGRI scientific director and head of its inflammatory disease section. “We have achieved the important goal of helping these young patients and made progress in understanding biological pathways and proteins.”

This study, along with the identification of haploinsufficiency of A20 (HA20) earlier this year, suggests a new category of human inflammatory diseases caused by impaired ubiquitination, according to the researchers. The team’s findings are published this week in the early edition of the Proceedings of the National Academy of Sciences.

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