Scientists identify cause of Job's syndrome

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Public release date: 19-Sep-2007

EurekAlert (press release) - Washington,DC*

Contact: Ken Pekoc

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NIH/National Institute of Allergy and Infectious Diseases

http://www.eurekalert.org/pub_releases/2007-09/nioa-sic091807.php

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 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.

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.

###

Contributors to the NIH study came from three NIAID laboratory

groups and three other NIH Institutes—the National Human Genome

Research Institute, the National Cancer Institute and the National

Center for Biotechnology Information—along with the Food and Drug

Administration, the Royal Free Hospital and University College in

London, and the University of California-San Francisco.

NIAID is a component of the NIH. NIAID supports basic and applied

research to prevent, diagnose and treat infectious diseases such as

HIV/AIDS and other sexually transmitted infections, influenza,

tuberculosis, malaria and illness from potential agents of

bioterrorism. NIAID also supports research on basic immunology,

transplantation and immune-related disorders, including autoimmune

diseases, asthma and allergies.

Job's syndrome patient story: To read a story about one of the Job's

syndrome participants in NIH studies, see

http://clinicalresearch.nih.gov/stories_schultz_m.html.

The National Institutes of Health (NIH)—The Nation's Medical

Research Agency—includes 27 Institutes and Centers and is a

component of the U. S. Department of Health and Human Services. It

is the primary federal agency for conducting and supporting basic,

clinical and translational medical research, and it investigates the

causes, treatments and cures for both common and rare diseases. For

more information about NIH and its programs, visit

http://www.nih.gov.

Reference: SM Holland et al. STAT3 Mutations in hyper IgE recurrent

infection syndrome. New England Journal of Medicine DOI:

10.1056/NEJMoa073687 (2007).

Y Minegishi et al. Dominant-negative mutations in the DNA-binding

domain of STAT3 cause hyper-IgE syndrome. Nature DOI:

10.1038/nature06096 (2007).

News releases, fact sheets and other NIAID-related materials are

available on the NIAID Web site at http://www.niaid.nih.gov.