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Rare Disorder Provides New Insight Into Fighting Infection [Chronic Fatigue Syndrome News]

  [ 63 votes ]   [ Discuss This Article ] • September 27, 2002

National Institute of Allergy and Infectious Diseases

Through studying a genetic condition known to exist in only two individuals, scientists at the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues have uncovered new knowledge about the immune system applicable to everyone. The scientists found that an enzyme called caspase-8, known to help trigger apoptosis -- the programmed death of cells -- is also involved in activating many immune system cells to fight off infections. This information, to be published in the September 26 issue of the journal "Nature," potentially could yield a new class of drugs to treat immune system disorders.

"Previously, no one had ever shown that caspase-8 played this other role," says senior study author Michael Lenardo, M.D., of NIAID's Laboratory of Immunology. "Caspase-8 deficiencies might explain why some people don't respond as well as others to vaccines, or why some people's immune systems don't fight off infections as well as others. Caspase-8 may be a useful target for a new class of anti- inflammatory or immunosuppressive therapies."

The NIAID scientists were called on to examine a brother and sister with a puzzling immune system disorder. "These kids were very sick, and their doctors were stymied about the cause of their illness and how to treat it," says Dr. Lenardo. "The doctors referred them to the University of Alabama, and the university in turn referred them to us. We took up the challenge, studied these children for several years, and came up with the answer."

Some of the disorder's symptoms were similar to those of autoimmune lymphoproliferative syndrome (ALPS), which include an overabundance of lymphocytes due to lack of apoptosis, swollen lymph nodes, and an enlarged spleen. ALPS is caused by a defect in the caspase-10 gene. Caspase- 10 is an enzyme that works with caspase-8 to trigger apoptosis. However, genetic tests showed no caspase-10 defects in the siblings.

Instead, the tests revealed a mutation in both copies of the siblings' caspase-8 genes that rendered the caspase-8 enzyme inactive. Furthermore, in addition to their ALPS- like symptoms, the siblings' immune system T cells, B cells, and natural killer cells were not properly activated, causing severe immunodeficiency. The siblings suffered from recurrent viral infections, and they did not respond well to vaccines.

The scientists wondered if all symptoms of this strange disorder -- both the ALPS-like symptoms and the failure of immune system cells to activate -- could be explained by lack of caspase-8. The scientists examined the activity of the caspase-8 enzyme more closely, wondering if this molecule, which had been so firmly established in scientists' minds as a trigger of cell death, could also be instrumental in activating immune system cells to fight off infectious diseases.

Subsequent laboratory tests proved that this is in fact the case. For example, the researchers introduced a functional caspase-8 gene into some of the siblings' lymphocytes and found that the cells recovered their ability to activate in response to stimulation with antigens. Dr. Lenardo and his colleagues plan further study of caspase-8 to determine if deficiencies in this molecule underlie other immune system abnormalities.

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: HJ Chun et al. Pleiotropic lymphocyte activation defects due to caspase-8 mutation cause human immunodeficiency. "Nature" 419: 395-99(2002).

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