Genetics of Apoptosis

caspase-8), the truncated BID generated by granzyme B (gtBID) translocates to the
mitochondrial membrane and promotes the release of mitochondrial death factors
via BAX or BAK (Heibein et al., 2000; Alimonti et al., 2001; Wang, N.S. et al., 2001).
Since granzyme B and CD95L can both activate the BID-BAX/BAK death-signaling
pathway, they provide independent mechanisms of inducing target cell apoptosis.
Accordingly, cells deficient in CD95 or overexpressing c-FLIP remain susceptible to
CTL-induced death (Kataoka et al., 1998). It will be important to determine whether
interruption of a distal step of the death-signaling pathway shared by CD95L and
granzyme B (such as loss of BAX/BAK) reduces CTL-induced death of type II target
cells that require cross-talk between the extrinsic and intrinsic pathways to undergo
apoptosis. Such genetic impediments to CTL-induced death may be an important
mechanism by which tumor cells evade immune surveillance.

Establishment of zones of immune privilege

Immune-privileged sites such as the eye, brain, and the testes may evade damage by
constitutively expressing CD95L to counterattack and eliminate CD95-expressing
infiltrating lymphocytes (Green and Ferguson, 2001). Some reports suggest that
expression of CD95L by certain types of cancer cells may protect such tumors from
immune surveillance. While ectopic expression of FasL by gene transfer can confer
immune privilege on some tissues, it can also induce a granulocytic infiltrate and
increased rejection in tissue transplants. The role of CD95L-CD95 interactions in
the creation of zones of immune privilege in tumors or tissue allografts in vivo remains
debatable (Green and Ferguson, 2001).

5.2

Disorders of the immune system resulting from deregulation of

death receptor-induced apoptosis

The functional importance of the normal physiologic role of death receptors in the
immune system is evident from the occurrence of various disorders resulting from
dysfunctional death receptors/death ligands or their signaling pathways.

Autoimmune disorders from genetic defects in CD95-induced

apoptosis

Mutations that result in defects of the CD95-CD95L system result in immune
disorders that feature lymphadenopathy and autoimmunity. The recessive lpr
(lymphoproliferation) mutation results in a splicing defect that reduces expression of
CD95, while the lprcg is a point mutation in the DD of CD95 that makes it incapable
of transducing a death signal (Nagata, 1997). The gld (generalized
lymphoproliferative disease) mutation in the carboxy domain of CD95L interferes
with its interaction with CD95 (Nagata, 1997). The immune disorders manifest in
mice carrying these mutations result from the loss of CD95-CD95L-induced

24 GENETICS OF APOPTOSIS