Scientists Identify Cause of Job’s Syndrome
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.