A rare and sometimes lethal inflammatory disease that mostly affects young children, called otulipenia, has been discovered by researchers from the National Institutes of Health (NIH), according to findings published in the early edition of the Proceedings of the National Academy of Sciences (Aug. 22, 2016).
What is even more interesting is the fact that the researchers also identified anti-inflammatory treatments that manage some of the symptoms of otulipenia, like joint pain and overall failure to grow or thrive.
Otulipenia is caused by the malfunction of OTULIN, which is a gene located on chromosome 5. The gene’s purpose is to regulate the development of blood vessels and the mobilization of cells and proteins to fight infection.
Children with otulipenia experience inflammation as a result of an autoimmune response that attacks the child’s own tissues, causing blood vessels to leak and tissues to swell, resulting in pain and other complications like the difficulty in fighting infection.
“The results have been amazing and life changing for these children and their families,” said Daniel Kastner, M.D., Ph.D., co-author, NHGRI scientific director and head of NHGRI’s Inflammatory Disease Section. “We have achieved the important goal of helping these young patients and made progress in understanding the biological pathways and proteins that are important for the regulation of the immune system’s responses.”
Once they found that the OTULIN gene was abnormal in the sick children, they studied the immune pathway in order to understand the disease and to figure out what kind of treatment the children needed. They discovered a problem in a small protein called ubiquitin, which is critical to the regulation of many other proteins in the body, including immune molecules.
The researchers found that children with otulipenia might respond to drugs that turned off tumor necrosis factor (TNF), a chemical messenger involved in systemic inflammation. Children taking anti-tumor necrosis factor drugs (TNF inhibitors, like the drugs used to treat other inflammatory disease, such as, rheumatoid arthritis, Crohn’s disease and others) experienced a reduction in overall inflammation.
“The malfunction in this protein has not been previously linked to clinical disorders of the human immune system,” said Ivona Aksentijevich, M.D., staff scientist in NHGRI’s Medical Genetics Branch and study co-author. “This discovery suggests a direction that can be explored for development of new therapies for patients with a wide range of inflammatory diseases.”
This study together with NIH’s 2016 identification of haploinsufficiency of A20 (HA20), suggests a new category of human inflammatory diseases caused by impaired ubiquitination, according to the researchers.