A very rare and sometimes fatal inflammatory disease called "otulipenia" that mostly affects young children has been discovered by researchers of the National Institutes of Health (NIH) in the United States.
An international network of scientists studying inflammatory diseases identified four children from Pakistani and Turkish families with unexplained skin rashes and inflamed joints. NIH scientists then searched for disease-causing genes using next-generation DNA sequencing that allowed them to sequence DNA quickly and economically.
They've also identified anti-inflammatory treatments that ease some of the patients' symptoms: fever, skin rashes, diarrhea, joint pain and overall failure to grow or thrive.
Otulipenia is caused by the malfunction of Otulin, a single gene on chromosome 5. When functioning properly, Otulin regulates the development of new blood vessels and mobilization of cells and proteins to fight infection.
Otulipenia is one of several inflammatory diseases that occur when the immune system attacks the host's own tissues. Inflammation is the body's natural response to invading bacteria or viruses.
The body releases chemicals that cause blood vessels to leak and tissues to swell in order to isolate a foreign substance from further contact with the body's tissues. Inflammatory diseases affecting the whole body are caused by mutations in genes like Otulin that are part of a person's innate immunity (the cells and proteins present at birth that fight infections).
Researchers determined the children with otulipenia might respond to drugs that turned off tumor necrosis factor, a chemical messenger involved in systemic inflammation. Inflammation subsided in the children treated with anti-tumor necrosis factor drugs (TNF inhibitors). TNF inhibitors are also used to treat chronic inflammatory diseases such as rheumatoid arthritis.
"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."
Cells use biological pathways to send and receive chemical cues in reaction to injury, infection or stress.
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, said the researchers.
NIH researchers published their findings last Aug. 22 in the early edition of the Proceedings of the National Academy of Sciences.
Contributing to the work were researchers from the National Human Genome Research Institute (NHGRI), the National Institute of Allergy and Infectious Diseases, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the National Heart, Lung, and Blood Institute and the NIH Clinical Center, all part of NIH, along with their colleagues in Turkey and the United Kingdom.