Job's Syndrome Breakthrough

Genetic Mutation

For three decades, scientists have been studying the rare immunodeficiency disorder known as Job's syndrome. Now, it seems, they've finally caught a break. Job's syndrome is brought on by a genetic mutation that leads to the prevention of appropriate responses by the human immune system to invading pathogens, which in turn brings on harmful bacterial and fungal infections and the physical features specific to the syndrome.

Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), a component of NIH, said, "Understanding the genetic cause of this rare immunological disorder is a signal accomplishment, revealing information that has been sought for decades. The immunological insights from this study not only promise to open new therapeutic doors for Job's syndrome, but also provide new leads for treating other immunodeficiency diseases."

The disease was first reported in 1966 and since then, only 250 cases have been reported. Job's syndrome's technical name is hyperimmunoglobulin E syndrome, or HIES. Individuals with the immune disorder often live normal life spans, though they live under the constant threat of life-threatening complications from very basic infections. The identification of the gene that causes the disease would benefit the scientific study of the many diseases that afflict those with Job's syndrome, including infections caused by Candida, Staphylococcus, and Aspergillus.

Invading Microbes

In Job's syndrome, the immune system becomes extra-sensitive to invading microbes. Those with the disorder tend to have multiple recurrent conditions such as skin infections that lead to lesions and boils, and lung infections that may cause pneumonia. Job's syndrome patients are also at higher risk for bone fractures, curvature of the spine, and trouble with facial and dental development. Though there is no cure for the disorder, antibiotics and antifungals are employed to both prevent and treat the infections that are associated with the syndrome.

The research team was led by Steven M. Holland, M.D., chief of the NIAID Laboratory of Clinical Infectious Diseases and the patient group was assembled over a period of many years in an effort to unravel this 41 year-old mystery illness. One important finding discovered proteins that serve to alert the immune system to increase the production of microbe-killing white blood cells, increase the production of chemicals that enhance the workings of the immune system, and boost the destruction of invading pathogens. The proteins are known as signal transducer and activator of transcription (STAT) proteins. STAT proteins help to warn the immune system and direct its responses to the blockage of harmful invaders.

Dr. Holland's team was able to sequence the gene that produces STAT3 protein in 48 Job's syndrome patients, which led to the discovery of the mutations in this gene that cause the syndrome. The team decided to study the role of the STAT3 gene after they observed increased levels of certain immune system responses in Job's patients, but deficient levels of response in others, which indicated an immune system signaling defect.