Genetics of Apoptosis

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apoptosis. Defects of the CD95-CD95L system also result in similar immune
disorders in humans (Fisher et al., 1995; Rieux-Laucat et al., 1995; Nagata, 1998).
Children with type Ia autoimmune lymphoproliferative syndrome (ALPS; Canale
Smith syndrome) frequently have mutations in the DD of CD95 and exhibit
lymphadenopathy, aberrant accumulation of T cells, and autoimmunity. While type
Ib ALPS is associated with defects in CD95L, type II ALPS involves defects in CD95
signaling, such as mutations in caspase-10 (Wang, H.G. et al., 1999).


Augmentation of death receptor-induced apoptosis in AIDS

Acquired immunodeficiency syndrome (AIDS) is characterized by an excessive
depletion of CD4+ T helper cells via apoptosis. Several different mechanisms underlie
the increased apoptosis of CD4+ T cells in response to infection with the human
immunodeficiency virus (HIV). HIV-encoded gene products (such as HIV-1 Tat)
increase expression of CD95L, which promotes TCR-induced CD95-mediated
apoptosis as well as fratricidal deletion of uninfected T cells (Debatin et al., 1994;
Finkel et al., 1995; Li, C.J. et al., 1995; Westendorp et al., 1995). T cells from HIV-
infected individuals also show increased sensitivity to Apo2L/TRAIL (Jeremias et al.,
1998). In addition to CD95L- and Apo2L/TRAIL-induced apoptosis, HIV-binding
of CD4 and the chemokine receptor CXCR4 also contributes to the rapid depletion
of CD4+ T cells in AIDS (Gougeon and Montagnier, 1999).


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Role of death receptor-induced apoptosis in development

Physiologic cell death is essential for animal development, maintenance of adult tissue
homeostasis, tissue remodeling and regeneration, and elimination of cells with genetic
or stochastic developmental errors (Meier et al., 2000). The apoptotic culling of
overproduced, unnecessary, misplaced, or damaged cells occurs via different
mechanisms. Such cell death may occur autonomously via withdrawal of the
appropriate trophic survival signals or transcriptional induction of genes that promote
apoptosis (Raff, 1992). The survival of different cell types depends on specific survival
signals within their specialized microenvironments. These survival signals include
cytokines, hormones, interactions with neighboring cells, and the extracellular matrix,
as well as more specialized signals such as neuronal synaptic connections or productive
assembly of an appropriate immune receptor. Withdrawal of such survival signals
results in cell death by default or neglect. Interference with the autonomous deletion
of cells is manifested by not only developmental abnormalities, but also a wide variety
of adult pathologies, such as neoplastic disorders. Spontaneous or induced mutations
in the mitochondrial cell death machinery manifest as phenotypic defects that are
especially evident in the immune and nervous systems. Mice lacking caspase-9,
Apaf-1, or caspase-3 exhibit gross neuronal hyperproliferation and abnormalities in
brain development (Kuida et al., 1996; Cecconi et al., 1998; Hakem et al., 1998;
Kuida et al., 1998; Yoshida et al., 1998). Transgenic mice with tissue-specific


DEATH RECEPTORS IN APOPTOSIS 25
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