NIH News Release--Rare Disorder Provides New Insight Into Fighting Infection--09/25/2002

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Rare Disorder Provides New Insight Into Fighting Infection

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 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.

http://www.nih.gov/news/pr/sep2002/niaid-25.htm