June 8, 2009

Scientists Discover New Genetic Immune Disorder in Children

Image of red and white blood cells Scanning electron micrograph of white and red blood cells.David Gregory and Debbie Marshall. All rights reserved by Wellcome Images.

Researchers have identified a rare but devastating genetic condition that affects children around the time of birth. Most of the children responded quickly to a synthetic form of the protein that's abnormal or missing in the condition.

A research team led by Dr. Raphaela Goldbach-Mansky of NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) spotted a disorder in children by a set of symptoms that were distinct from other recognized diseases. Children with the disorder display serious and potentially fatal symptoms that include swelling of bone tissue; bone pain and deformity; inflammation of bone tissue and the periosteum (a layer of connective tissue around bone); and a rash that can span from small individual pustules to extensive pustulosis that covers most of the patient's body. Many of the children begin to have symptoms from birth to 2 weeks of age.

The researchers suspected that they were dealing with a previously unrecognized autoinflammatory syndrome. In autoinflammatory diseases, the immune system, which normally protects against invading microbes, instead goes awry, can not be shut down and can attack the body’s own tissues. This misdirected attack causes unprovoked and dangerous inflammation and tissue destruction.

The team's further investigations were supported by NIAMS and other several other sources. The results appeared in the June 4, 2009, issue of the New England Journal of Medicine.

The scientists treated 1 patient with anakinra, a drug normally used for the autoimmune disease rheumatoid arthritis, and saw prompt and impressive clinical improvement. That clinical response prompted them to look for variations in genes that regulate interleukin-1, a protein known to play a key role in inflammation.

They found a mutation in IL1RN, a gene that encodes a protein known as interleukin-1 receptor antagonist (IL-1Ra). IL-1Ra binds to the same cell receptors as interleukin-1. Essentially, it acts as a brake on the inflammatory protein. Without IL-1Ra, the body can't control the systemic inflammation caused by interleukin-1.

Ultimately, a genetic team led by Dr. Ivona Aksentijevich at NIAMS identified IL1RN abnormalities in a number of other cases, with 9 patients from 6 families in the Canadian province of Newfoundland, the Netherlands, Lebanon and Puerto Rico. The scientists call the new autoinflammatory syndrome DIRA (deficiency of the interleukin-1 receptor antagonist).

The children who were alive at the time of diagnosis — 6 in all — were treated with anakinra, which is the synthetic form of human IL-1Ra. Although the patients were resistant to other medications such as steroids, most responded successfully and immediately to anakinra.

"Our first patient had been unresponsive to several treatments, and his health care team had almost given up," Goldbach-Mansky said. "But with anakinra, he was out of the intensive care unit in 10 days and his symptoms resolved."

Although DIRA is rare, this discovery may shed light on the role of interleukin-1 in more common autoimmune disorders, such as certain forms of psoriasis, that share some of the symptoms of DIRA.

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