Abstract |
Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.
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Authors | Hyung J Chun, Lixin Zheng, Manzoor Ahmad, Jin Wang, Christina K Speirs, Richard M Siegel, Janet K Dale, Jennifer Puck, Joie Davis, Craig G Hall, Suzanne Skoda-Smith, T Prescott Atkinson, Stephen E Straus, Michael J Lenardo |
Journal | Nature
(Nature)
Vol. 419
Issue 6905
Pg. 395-9
(Sep 26 2002)
ISSN: 0028-0836 [Print] England |
PMID | 12353035
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- CD28 Antigens
- CD3 Complex
- Cytokines
- CASP8 protein, human
- CASP9 protein, human
- Caspase 8
- Caspase 9
- Caspases
- Calcium
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Topics |
- Apoptosis
- B-Lymphocytes
(immunology, pathology)
- CD28 Antigens
(immunology)
- CD3 Complex
(immunology)
- Calcium
(metabolism)
- Caspase 8
- Caspase 9
- Caspases
(genetics)
- Cell Division
- Cytokines
(analysis)
- Female
- Homozygote
- Humans
- Immunologic Deficiency Syndromes
(enzymology, genetics, immunology, pathology)
- Killer Cells, Natural
(immunology, pathology)
- Lymphocyte Activation
- Lymphocytes
(immunology, pathology)
- Male
- Mutation
(genetics)
- Pedigree
- Phenotype
- T-Lymphocytes
(immunology, pathology)
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