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

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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.

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Figure 1: Defective apoptosis and DISC analysis in family 66.
Figure 2: Characterization of an inherited caspase-8 mutation.
Figure 3: Defective immune cell responses in homozygous caspase-8 mutants.
Figure 4: Caspase-8 is required for lymphocyte activation.


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We thank R. Germain, L. Staudt and P. Schwartzberg for critically reading the manuscript; J. Blenis, M. Peter, M. Finer, M. Roberts, D. Chinnasamy and F. Candotti for materials and reagents; D. Stephany, K. Holmes, R. Swofford and S. Tartt for flow cytometry assistance; T. Fleisher for immunophenotyping; R. Fischer for EBV cell lines; W. Strober, F. Dugan and D. Smith for clinical assistance; S. Rajagopalan and E. Long for advice and antibodies; M. Tibbetts and C. Trageser for technical assistance; J. Sung and B. Bierer for assistance with luciferase assays; N. Thekdi for discussions; Amaxa Biosystems for materials and assistance; and Pharmingen-BD Biosciences for donating antibodies for lymphocyte surface markers. H.J.C. is a Howard Hughes Medical Institute-National Institutes of Health Research Scholar.

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Correspondence to Michael J. Lenardo.

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Chun, H., Zheng, L., Ahmad, M. et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature 419, 395–399 (2002) doi:10.1038/nature01063

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