"Our study," says Michael Lenardo, Ph.D., senior author and NIAID
scientist, "has led to the recognition of a new regulatory pathway in the
immune system that prevents it from attacking one's own body. It may be
likely that other more common autoimmune diseases such as diabetes,
arthritis, multiple sclerosis, systemic lupus erthematosus may also involve
similar types of changes".
After protecting the body from invaders such as bacteria and
viruses, cells of the immune system turn off a response by committing
suicide. In ALPS patients, immune cells called lymphocytes do not die;
instead, they remain activated, proliferate continuously, and attack the
body. Excess lymphocytes account for the enlargement of spleen, liver, and
lymph nodes in children with this inherited condition. However, lymphocytes
initially rely on other cells of the immune system to become activated. The
current study found that dendritic cells, a rare type of cell in charge of
stimulating the lymphocytes, also survive past the point of usefulness.
Persistence of these dendritic cells prolongs lymphocyte stimulation.
Abnormalities in both these interacting cell types leads to dysregulation of
the immune response.
Dr. Lenardo was among the team of scientists at the National
Institutes of Health who first characterized the disease and gave it the
name ALPS in 1995. Now more than 60 families have been identified from all
parts of the United States as well as from around the world with members who
have mutations in genes directing the suicide pathway. Most people with
ALPS lack the ability to start the elaborate cascade that leads to cell
death. In other patients, the process begins normally, but breaks down
somewhere further down the cascade. In the current study, lead author
Jin Wang, Ph.D., and colleagues at the National Cancer Institute (NCI) and
the National Human Genome Research Institute (NHGRI) studied each step in
the process in cells from two patients with this second type of ALPS known
as Type II. Eventually, they discovered a mutation in a gene encoding a
protein called caspase 10, which has not been previously linked to a human
"Although caspases carry out cell death in all types of mammalian
cells, we have found the first examples of caspase deficiency in humans,"
reports Dr. Wang. "These mutations result in apoptosis defects not only in
lymphocytes, but also in dendritic cells."
Studies in the worm, C. elegans, demonstrated that a key "death
protein," CED3, functioned as an enzyme to activate other proteins. The
similarity of caspase 10 with the worm's CED3 made it a target for
investigation in this study. "It's terrific that the discovery of the
molecular basis of a previously unexplained disease in these children came
from fundamental research studies of programmed death in worms," comments
Both patients in this study had different mutations in their caspase
10 genes. One patient possessed two copies of the altered gene, one from
each parent, and was unable to produce a normally functioning caspase 10
protein. Lack of a working protein prevented the suicide signal from
reaching the cell nucleus, and cells continued to grow out of control. The
other patient inherited only one altered gene, but that mutation disrupted
the functioning of the normal gene. The parent who had passed on the mutant
gene had impaired apoptosis and a milder form of autoimmunity.
"Although we don't know how frequent such defects are in common
systemic autoimmune diseases," says Dr. Wang, "the clinical implications of
our findings could be very significant."
NIAID, NCI, and NHGRI are components of the National Institutes of
Health (NIH). NIAID conducts and supports research to prevent, diagnose and
treat illnesses such as HIV disease and other sexually transmitted diseases,
tuberculosis, malaria, asthma and allergies. NCI conducts and supports
programs to understand the causes of cancer; prevent, detect, diagnose,
treat, and control cancer; and disseminate information to the practitioner,
patient, and public. NHGRI supports the NIH component of the Human Genome
Project, a worldwide research effort designed to analyze the structure of
human DNA and determine the location of the estimated 100,000 human genes.
The NHGRI Intramural Research Program develops and implements technology for
understanding, diagnosing, and treating genetic diseases. NIH is an agency
of the U.S. Department of Health and Human Services.
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on the NIAID Web site at http://www.niaid.nih.gov.
The National Institute of Allergy and Infectious Diseases is a component of the
National Institutes of Health, U.S. Department of Health and Human Services.