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

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 and Michael J. Lenardo ()
Additional contact information
Hyung J. Chun: National Institutes of Health
Lixin Zheng: National Institutes of Health
Manzoor Ahmad: National Institutes of Health
Jin Wang: National Institutes of Health
Christina K. Speirs: National Institutes of Health
Richard M. Siegel: National Institutes of Health
Janet K. Dale: National Institutes of Health
Jennifer Puck: National Institutes of Health
Joie Davis: National Institutes of Health
Craig G. Hall: University of Alabama at Birmingham School of Medicine
Suzanne Skoda-Smith: University of Alabama at Birmingham School of Medicine
T. Prescott Atkinson: University of Alabama at Birmingham School of Medicine
Stephen E. Straus: National Institutes of Health
Michael J. Lenardo: National Institutes of Health

Nature, 2002, vol. 419, issue 6905, 395-399

Abstract: 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 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.

Date: 2002
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DOI: 10.1038/nature01063

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