The rare immunodeficiency disorder known as Job’s syndrome is caused by a specific genetic mutation that both overstimulates and understimulates the human immune system, leading to harmful bacterial and fungal infections and the physical features characteristic of the syndrome, according to two independent groups of scientists, one from the National Institutes of Health (NIH) and the other from the Tokyo Medical and Dental University.

The NIH team’s report will be available the evening of September 19 online in The New England Journal of Medicine. The Tokyo group published its findings in Nature last month.

“Understanding the genetic cause of this rare immunological disorder is a signal accomplishment, revealing information that has been sought for decades,” says Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), a component of NIH. "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.”

Only about 250 cases of Job’s syndrome (pronounced like “robe,” and technically known as hyperimmunoglobulin E syndrome, or HIES) have been reported since it was first discovered in 1966. While individuals with Job’s syndrome often live long lives, life-threatening complications from basic infections are a constant concern. Identifying the specific gene implicated in the disease could benefit scientific study of several diseases that afflict people with Job’s syndrome, including infections caused by Aspergillus, Candida and Staphylococcus.

Job’s syndrome makes the immune system extremely sensitive to invading microbes. People with the syndrome often have multiple, recurring ailments, such as skin infections that cause lesions and boils, and lung infections that cause pneumonia. They also are at high risk of breaking bones, having a curved spine, and experiencing facial and dental developmental difficulties. There is no cure for Job’s syndrome, although antibiotics and antifungals are used to prevent and treat the infections associated with the disorder.

Steven M. Holland, M.D., chief of the NIAID Laboratory of Clinical Infectious Diseases, led the research team that over several years assembled the patient group that helped unravel the 41-year-old mystery. A key finding involved work with proteins that alert the body to increase production of white blood cells, increase immune-enhancing chemicals, and increase their killing of invaders. These signal transducer and activator of transcription (STAT) proteins help alert and direct immune system responses to stop invading pathogens. In 48 Job’s syndrome patients, Dr. Holland’s team sequenced the gene that makes STAT3 protein and discovered that mutations in the gene causes Job’s syndrome.

The team became interested in the role of the STAT3 gene after observing increased levels of some immune system responses in Job’s patients, but inadequate levels of response to others, indicating a defect in immune system signaling. Researchers found mutations in the STAT3 gene in 48 patients with Job’s, but not in 48 unaffected relatives or 158 unaffected people in a control group.

“We found that Job’s is associated with excessive immune reaction, not deficient immune reaction as many people suspected,” says Dr. Holland. “STAT3 is the key, and it can become a really powerful tool to dissect other aspects of immunity at a molecular and functional level.”  For example, in studies done in mice, other investigators have demonstrated specific roles for STAT3 in bone and organ development, preservation and inflammation.