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Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency.

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.
AuthorsHyung 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
JournalNature (Nature) Vol. 419 Issue 6905 Pg. 395-9 (Sep 26 2002) ISSN: 0028-0836 [Print] England
PMID12353035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • CD28 Antigens
  • CD3 Complex
  • Cytokines
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases
  • Calcium
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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