Primary Immune Deficiency Disease

Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease, September 24, 2009 News Release – National Institutes of Health (…
http://www.nih.gov/news/health/sep2009/niaid-24.htm[9/24/2009 2:15:35 PM]
National Institute of Allergy and
Infectious Diseases (NIAID)
For Immediate Release
Thursday, September 24, 2009
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Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency
Disease
Researchers at the National Institutes of Health have identified a genetic mutation that accounts for a
perplexing condition found in people with an inherited immunodeficiency. The disorder, called combined
immunodeficiency, is characterized by a constellation of severe health problems, including persistent
bacterial and viral skin infections, severe eczema, acute allergies and asthma, and cancer.
The team that made the discovery was led by Helen Su, M.D., Ph.D., at the National Institute of Allergy
and Infectious Diseases (NIAID), and included collaborators from NIAID and the National Cancer
Institute (NCI). The research is reported in this week’s New England Journal of Medicine.
“NIH clinicians have cared for people with unusual and difficult-to-treat immune disorders for decades,”
says NIAID Director Anthony S. Fauci, M.D. “This study exemplifies their commitment to improving the
lives of people with these diseases by trying to uncover the causes of these disorders and thereby better
understanding how to treat them.”
Combined immunodeficiency is a type of primary immune deficiency disease (PIDD) in which several
parts of the immune system are affected. This inherited disorder is characterized by increased
susceptibility to bacterial, viral and fungal infections of various organs of the body. In some cases,
susceptibility to cancers also may be seen.
There are 150 known PIDDs. Approximately 500,000 people in the United States have been diagnosed
with a PIDD, while many more remain undiagnosed.
The NIAID and NCI investigators recognized that certain patients with an undefined form of combined
immunodeficiency shared enough clinical features to make it likely that the cause might be a common
genetic mutation. Originally, these individuals were thought to have a variant form of hyperimmunoglobulinema
E syndrome (HIES), a disorder characterized by increased levels of a class of
antibodies known as immunoglobulin E, superficial and systemic bacterial and fungal infections, and
atopic dermatitis, also known as eczema.
This newly described group, however, had far more severe eczema than is typical in people with variant
HIES. They also had extensive and difficult-to-manage viral infections of the skin, such as warts,
molluscum contagiosum — a type of poxvirus that only infects the skin — and herpes simplex. Some in
this group also developed skin cancers, as well as lymphoma of the skin.
“Even though these individuals were diagnosed with a more uncommon form of HIES, they were still
Scientists Identify Genetic Cause of Previously Undefined Primary Immune Deficiency Disease, September 24, 2009 News Release – National Institutes of Health (…
http://www.nih.gov/news/health/sep2009/niaid-24.htm[9/24/2009 2:15:35 PM]
considered to have a mystery disease, because they had severe allergies and had developed cancers,” says
Dr. Su.
Using a technique called comparative genomic hybridization, a process by which large amounts of DNA
are fixed to a computer chip and analyzed for changes in the genes, scientists examined the genes in the
tissue samples from five different groups: the 11 individuals with the unknown immunodeficiencies,
people with the variant form of HIES, people with classic HIES, those with other immunological diseases,
and healthy individuals.
The researchers discovered that people with the unique form of HIES had mutations in a gene called
DOCK8 that led to deletions in parts of the gene. The normal function of DOCK8 is currently unknown.
When compared with healthy individuals, the people with DOCK 8 mutations had fewer CD8 positive T
cells, immune cells needed to fight viral infections; fewer antibody-producing B cells; and increased
numbers of eosinophils — immune cells associated with allergy.
According to Dr. Su, these findings indicate that DOCK8 is essential for defense against viral infections
and for preventing the development of cancer and allergies.
Although further study is required to determine if DOCK8 mutations occur in other people with similar
disease symptoms, DOCK8 immunodeficiency syndrome may be a new PIDD. These findings mean that
individuals with this rare disease will be able to receive a more accurate diagnosis. Identifying a genetic
cause for the disease provided comfort to some of those diagnosed who had battled an unknown immune
disease for years, according to Dr. Su.
“The study of inherited disorders and the genetic alterations that are responsible for their complex array of
disease symptoms has often resulted in the discovery of causative genes that play a role in cancer
initiation,” said NCI Director John E. Niederhuber, M.D. “The disease mutations found in this study in the
DOCK8 gene exemplify that kind of important finding. As with any discovery of a genetic defect, the
challenge going forward is to develop a complete knowledge of the cascading pathways of biological
function for which DOCK8 is responsible.”
NIAID conducts and supports research — at NIH, throughout the United States, and worldwide — to
study the causes of infectious and immune-mediated diseases, and to develop better means of preventing,
diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at http://www.niaid.nih.gov.
NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer
and improve the lives of cancer patients and their families, through research into prevention and cancer
biology, the development of new interventions, and the training and mentoring of new researchers. For
more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI’s
Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
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 www.nih.gov.
Reference: Zhang et al. DOCK8 mutations underlie a new form of combined immunodeficiency with
allergy, hyper-immunoglobulinemia E, lymphocyte dysfunction, viral infections, and cancer. New England
Journal of Medicine DOI: 10.1056/NEJMoa0905506 (2009)