NIH Press Release
National Institute of
Allergy and Infectious Diseases

Thursday, July 8, 1999
Ramie Leibnitz, Ph.D.
(301) 402-1663

Alteration in Cell Death Pathway Sheds Light on Autoimmune Disease

A cell's ability to commit suicide, a process scientists call "apoptosis," is an important feature the body uses to prevent overgrowth of cells and to get rid of cells it no longer needs. Now, in a paper to be published July 9th in the journal Cell, National Institute of Allergy and Infectious Diseases (NIAID) researchers and their colleagues describe a mutation in immune cells in patients with autoimmune lymphoproliferative syndrome, or ALPS, that interferes with cell death and results in the condition's hallmark uncontrolled cell growth. The study also defines a new role for a branch of the immune system previously thought to be uninvolved in the body's ability to distinguish itself from foreign invaders. While discovery of the mutation in these ALPS patients paves the way for better treatment, understanding the new-found interplay between components of the immune system will lead to new ways to investigate autoimmune disease.

"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 disease.

"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 Dr. Lenardo.

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.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at

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.

Reference: J Wang, et al. Inherited human caspase-10 mutations underlie defective lymphocyte and dendritic cell apoptosis in autoimmune lymphoproliferative syndrome, type II. Cell 98(1):47-58 (1999).