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

By Hyung J. Chun, Lixin Zheng, Manzoor Ahmad, Jin Wang, C. Speirs, R. Siegel, J. Dale, J. Puck, Joie N. Davis, C. Hall and 4 more. Nature, 2002

742 citations recorded by the source corpus.

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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/74e5f38dcfe4655050c7a8031f351857d528fbe9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Molecular Biology

Citations in the corpus

Caspases in cell death, inflammation and disease (2019, background): “Moreover, patients with ALPS-related syndromes are reported to be deficient for caspases 8 or 10 (Chun et al., 2002; Meynier and Rieux-Laucat, 2019; Wang et al., 1999).”
Caspase function in programmed cell death (2007, background): “Chun et al.85 described a kindred with inherited caspase-8 deficiency.”
30 years of NF-κB: a blossoming of relevance to human pathobiology (2017, positive): “However, rare patients with autosomal recessive disease were found to have homozygous LOF CASP8 mutations (Chun et al., 2002).”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “The absence of either component or point mutation of critical sites involved in enzymatic cleavage not only leads to lethality in mice (Table 1) but also causes immunodeficiencies in humans [113,114].”
Mechanisms of resistance to TRAIL-induced apoptosis in cancer (2005, background): “However, because ZIETD-FMK may also inhibit other caspases, especially at high doses, use of a more specific approach such as small inhibitory RNA should be considered to confirm the specificity of caspase-8 inhibition.(42) Third, caspase-10, although structurally similar to caspase-8 and having a D”
A decade of caspases (2003, background): “Interestingly, caspase-8 deficiency was recently discovered in a human kindred with an immunodeficiency syndrome (Chun et al., 2002).”
Of Mice and Not Men: Differences between Mouse and Human Immunology (2004, background): “Lack of caspase 8 in humans results in immunodeficiency, suggesting a role for this effector in lymphocyte activation as well as death (63).”
Caspases in cell survival, proliferation and differentiation (2007, background): “immune defects observed in patients with defective caspase8 are clearly different from those observed in patients with caspase-10 deficiency, suggesting that these two gene products may also have non-redundant functions in T-cell proliferation.(39,42) Indeed, humans harbouring caspase-10 point mutat”
Caspases in Cell Death, Inflammation, and Gasdermin-Induced Pyroptosis (2020, background): “Loss-of-function genetic mutations in human caspase-8 and caspase-10 are associated with autoimmune lymphoproliferative syndrome (ALPS) due to defective caspase activity and apoptosis (45, 46).”
Caspases in apoptosis and beyond (2008, background): “…not only manifest defective lymphocyte apoptosis, characteristic of ALPS (autoimmune lymphoproliferative syndrome) found in patients with defects in Fas signaling, but also display impaired proliferation of T, B and natural killer cells, which leads to immunodeficiency (Chun et al., 2002).”