Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency
| Autor: | Richard M. Siegel, Hyung J. Chun, Craig G Hall, Jin Wang, Michael J. Lenardo, T. Prescott Atkinson, Janet K. Dale, Christina K. Speirs, Sharon E. Straus, Suzanne Skoda-Smith, Jennifer M. Puck, Manzoor Ahmad, Joie Davis, Lixin Zheng |
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| Rok vydání: | 2002 |
| Předmět: |
Male
Programmed cell death CD3 Complex Lymphocyte T-Lymphocytes Apoptosis Caspase 8 Lymphocyte Activation CD28 Antigens medicine Humans FADD Lymphocytes Immunodeficiency B-Lymphocytes Multidisciplinary biology Homozygote Immunologic Deficiency Syndromes medicine.disease Fas receptor Caspase 9 Pedigree Killer Cells Natural medicine.anatomical_structure Phenotype Autoimmune lymphoproliferative syndrome Caspases Immunology Mutation biology.protein Cytokines Calcium Female Cell Division |
| Zdroj: | Nature. 419(6905) |
| ISSN: | 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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