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Nature 419, 395-399 (26 September 2002) | doi:10.1038/nature01063; Received 24 June 2002; Accepted 31 July 2002

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

Hyung J. Chun1,2, Lixin Zheng1,2, Manzoor Ahmad1,2, Jin Wang1,3, Christina K. Speirs1, Richard M. Siegel1,3, Janet K. Dale4, Jennifer Puck5, Joie Davis5, Craig G. Hall6, Suzanne Skoda-Smith6, T. Prescott Atkinson6, Stephen E. Straus4 & Michael J. Lenardo1

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
  2. Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
  3. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
  4. University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294, USA
  5. These authors contributed equally to this work
  6. Present addresses: Baylor College School of Medicine, Houston, Texas, USA (J.W.); Immunoregulation Unit, Autoimmune Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA (R.M.S.).

Correspondence to: Michael J. Lenardo1 Correspondence and requests for materials should be addressed to M.J.L. (e-mail: Email: lenardo@nih.gov).

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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 autoimmunity1, 2. 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 complex3, 4. 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 autoimmunity5, 6, 7, 8, 9, 10, 11, 12, 13, 14. 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.