Since its initial description cell death has appeared as a
basic biological phenomenon
development and regulation of tissue homeostasis
whose alteration has important implications in
pathology . Indeed cell death contributes to tissue
homeostasis by balancing mitosis and pathology can
derive from both its increase or decrease. Since the
initial description of cell death in the 1960s a number of
different death mechanisms have been described and
have been classified both on morphological and
biochemical criteria. A recent paper published in CDD
 by a large number of experts in the field has
suggested a classification of the different types and is a
good reference for the subject. This review will mostly
focus on the role in different human diseases of caspase
dependent apoptosis Table 1).
Caspase dependent apoptosis (Figure 1) is characterized
by the activation of pathways leading to the activation
of a family of proteases: caspases resulting in an
ordered disruption of the cell without leakage of cellular
components and induction of inflammation. Apoptosis
occurs following the activation of specific pathways
that result in a series of well defined morphological
events. The dying cell initially shows nuclear and
cytoplasmic condensation, followed by blebbing of the
plasma membrane that results in release of small
components known as apoptotic bodies. These are
rapidly identified by neighbouring cells or professional
phagocytes and disposed generally without induction of
inflammation or tissue scarring . Apoptosis depends
on activation of caspases that will then cleave a number
of substrates  resulting in the biochemical and
morphological changes typical of this form of death. All
caspases are synthesized as inactive zymogens that need
activation to exert their function. Full activation is
achieved through cleavage of a pro-domain generally by
other caspases. From a functional point of view we can
distinguish two types of caspases: up-stream and down-
stream caspases. Up–stream caspases are activated
when more enzyme molecules are brought in close
proximity and undergo conformational changes upon
binding to activation complexes, this results in their
cleavage and full activation [5, 6]. Once activated they
will activate additional molecules of the same enzyme
as well as down stream caspases. Down stream caspases
on the other hand can only be activated by cleavage of
the pro-domain by up-stream caspase. Two main
molecular pathways lead to caspase activation and
therefore to apoptosis the so-called extrinsic and
www.impactaging.com AGING, May 2012, Vol. 4, No 5
Role of Apoptosis in disease
B. Favaloro 1,2, N. Allocati 1 , V. Graziano 1,2, C. Di Ilio 1, 2 and V. De Laurenzi 1,2,3
1 Dipartimento di Scienze Biomediche, Universita' "G. d'Annunzio" Chieti‐Pescara, 66100, Chieti, Italy
2 Fondazione “G. d’Annunzio”, Centro Studi sull’Invecchiamento, Ce.S.I., 66100, Chieti, Italy
3 BIOUNIVERSA srl, University of Salerno, Fisciano (SA), Italy
Key words: cell death, caspases, apoptosis, cancer, aging, diseases
Received: 5/15/12; Accepted: 5/30/12; Published: 5/31/12
Correspondence to: Vincenzo De Laurenzi, PhD; E‐mail: email@example.com
Copyright: © Favaloro al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Abstract: Since the initial description of apoptosis, a number of different forms of cell death have been described. In this
review we will focus on classic caspase‐dependent apoptosis and its variations that contribute to diseases. Over fifty years
of research have clarified molecular mechanisms involved in apoptotic signaling as well and shown that alterations of these
pathways lead to human diseases. Indeed both reduced and increased apoptosis can result in pathology. More recently
these findings have led to the development of therapeutic approaches based on regulation of apoptosis, some of which are
in clinical trials or have entered medical practice.
www.impactaging.com 330 AGING, May 2012, Vol.4 No.5
Extrinsic apoptosis indicates a form of death induced by
extracellular signals that result in the binding of ligands
to specific trans-membrane receptors, collectively
known as death receptors (DR) belonging to the
TNF/NGF family. All death receptors function in a
similar way: upon ligand binding several receptor
molecules are brought
conformational changes allowing the assembly of a
large multi-protein complex known as Death Initiation
Signalling Complex (DISC) that leads to activation of
the caspase cascade. In the FAS/CD95 signalling
complex, that can be used as a prototype of this form of
death, upon ligand binding FAS recruits, through a
highly conserved 80 amino acid domain, known as
death domain (DD), an adaptor molecule: Fas-
associated protein with a DD (FADD). FADD contains
another conserved protein interaction domain known as
Death Effector Domain (DED) that binds to an
homologous domain in caspase 8 leading to its
activation. Active caspase 8 will activate additional
together and undergo
caspase 8 molecules as well as downstream caspases
such as caspase 3 .
The intrinsic pathway is activated in response to a
number of stressing conditions including DNA damage,
oxidative stress and many others. In all cases this
multiple forms of stress converge on the mitochondria
and determine mitochondrial
permeabilization (MOMP) this in turn results in
dissipation of the mitochondrial membrane potential
and therefore in cessation of ATP production as well as
release of a number of proteins that contribute to
caspase activation. At least two molecular mechanisms
(not mutually exclusive) have been proposed to explain
how different signals converge at the mitochondria
resulting in MOMP. One involves the pore forming
ability of some of the BCL-2 family proteins in the
outer mitochondrial membrane  and the other is the
result of the opening in the inner membrane of the
permeability transition pore complex (PTPC), that
Table 1. Diseases in which alterations of apoptosis are involved
Ovary and uterus
Head and Neck
Amyotrophic Lateral Sclerosis
Systemic Lupus erythematosus
Autoimmune lymphoproliferative syndrome
[20, 28, 160, 161]
[21, 34, 162]
[13, 23, 25, 163-165]
[24, 30-32, 166]
[33, 35, 168-170]
[63, 184, 185]
[153, 215, 216]
[1, 217, 218]
www.impactaging.com 331 AGING, May 2012, Vol.4 No.5
would require the Adenine Nucleotide Transporter
(ANT) and the Voltage Dependent Anion Channel
(VDAC) [9, 10]. The Bcl-2 family proteins are essential
regulators of this type of apoptosis and are all
characterized by the presence of at least one Bcl-2
Homology (BH) domain. From a functional point of
view they can be classified in anti-apoptotic members
containing three or four BH domains (such as Bcl-2,
Bcl-xl, Bcl-w, Mcl-1) and pro-apoptotic members with
two or three BH domains (such as Bax, Bak, Bcl-xs,
Bok) or with just one (such as Bad, Bik, Bid, Bim,
Noxa, Puma). Pro-apoptotic members of the family
mediate apoptosis by disrupting membrane integrity
either directly forming pores or by binding to
mitochondrial channel proteins such as VDAC or ANT,
while anti-apoptotic members would prevent apoptosis
by interfering with pro-apoptotic member aggregation.
The different apoptotic signals are sensed by BH3 only
proteins that are induced or activated and migrate to the
mitochondria where they bind the pro-survival members
of the family removing their block or to the pro-
apoptotic members promoting their aggregation .
In any case once MOMP occurs a number of proteins are
apoptosome and activation of caspase 9. Caspase 8 and 9 then activate downstream caspases such as caspase
3 resulting in cell death. The two pathways are connected through the cleavage of the BH3 only protein BID.
Cytochrome C (CYTC), apoptosis-inducing factor (AIF),
endonuclease G (endo G), Direct IAP-binding protein
with low PI (DIABLO, also known as SMAC) and
others. Once CYTC is released it binds to APAF-1
inducing the formation of a large complex, known as the
apoptosome, that recruits caspase 9. In the apoptosome,
caspase 9 is activated and cleaved and will activate
additional molecules of caspase 9 as well as down-stream
caspases such as caspase 3. Due to its lethality the system
is subject to a number of controls as an example the cyto-
plasm contains a class of proteins known as Inhibitors of
Apoptosis IAPS that bind and inactivate caspases. Upon
MOMP the mitochondria also releases proteins such as
DIABLO/SMAC that bind to IAPS removing their
inhibition and allowing apoptosis to occur.
The intrinsic and extrinsic pathways are not completely
independent: in some cells in fact activation of caspase
8 results in activation of the mitochondrial pathway. In
this case caspase 8 among other things cleaves a BH3
only protein BID generating a truncated fragment
known as truncated BID (tBID) that can permeabilize
the mitochondrion resulting in MOMP .
from the mitochondria, these include
Figure 1. Schematic representation of the main molecular pathways leading to apoptosis. In the
extrinsic pathway upon ligand binding to specific receptors the DISC complex is formed and caspase 8
activated. In the intrinsic pathway release of cyt c from the mitochondria result in the formation of the
www.impactaging.com 332 AGING, May 2012, Vol.4 No.5
Based on its role in maintaining tissue homeostasis it is
not surprising that alterations of apoptosis play an
important role in cancer development. Moreover defects
in the apoptotic pathways are responsible for resistance
to therapy and new therapeutic approaches attempting
to re-activate these pathways bypassing the block are
currently being studied [13-17]. Alteration of many
proteins involved in both intrinsic and extrinsic
signaling pathways have been described and are in part
summarized below. It is clear that alterations of up-
stream regulators of these pathways are the most
common alterations found in cancer cells, as an
example p53 that can induce cell death in response to a
number of different stress stimuli, is the most frequently
mutated gene in human cancers. A description of these
defects however is beyond the scope of this review.
BCL-2 Family proteins alterations. Bcl-2 was initially
isolated and characterized in a subset of B-cell
lymphomas. These tumours carry a typical translocation
t(14;18) that involves Bcl-2 gene and results in its over-
expression. Thus it appeared that this gene played a role
in cancer even before his function in regulating
apoptosis was clearly defined. Since those early days a
bulk of data have proven the role of Bcl-2 alterations in
development of cancer including a number of animal
models. In fact transgenic mice carrying bcl-2
overexpression are actually susceptible to develop
different forms of lymphoproliferative disorders .
Bcl-2 has been found overexpressed not only in B-cell
lymphomas, but also in a variety of other cancers such
as: Hodgkin lymphoma where it seems to be associated
with worse overall survival ; breast cancer where it
correlates with tumor aggressiveness, reduced survival
and resistance to endocrine therapy ; non-small and
small cell lung carcinoma (moreover squamous) ,
renal cell carcinoma . A novel polymorphism of the
BCL-2 promoter (-938C>A) associates with increased
aggressiveness and worse prognosis in glioblastoma
multiform , chronic lymphocytic leukemia, as well
as with a better survival and outcome in breast and
In the last years a variety of alterations of the different
Bcl-2 family members have been described and have
proven the importance of this group of proteins in
cancer development. Bax and Bak mutations  have
been described in colon and gastric carcinomas.
Unexpectedly however neither BAX single KO or
BAX/BAK double KO show increased tumour
formation suggesting that compensatory mechanisms
can allow apoptosis in these cells. Interestingly however
Bax/pARF double KO mice exhibit an increased variety
of tumours (sarcomas and carcinomas). Furthermore
Bax deletion accelerates growth of brain tumours in a
p53 mutant mice model , and of mammary tumours
in a SV40 large T antigen transgenic mouse model.
Various BH3 protein alterations have also been
implicated in cancer development, as an example Bid-
deficient mice are prone to develop a form of chronic
myelomonocytic leukemia , as well as diffuse large
The possibility to target Bcl-2 family members proteins
to induce apoptosis in cancer cells has been studied for
many years now and particular attention has been given
to BH3 only proteins in designing drugs that would
mimic their pro-apoptotic functions. Some of these are
currently being tested in phase I/II clinical trials [27-
29]. Antisense oligonucleotides targeting Bcl-2 have
also been developed and in one case have reached a
phase III clinical trial in patients with chronic
Apoptosome defects. Apaf1 inactivation can substitute
for p53 defects in promoting transformation of myc-
expressing cells, moreover it is frequently silenced or
inactivated in human cancers. Indeed melanomas,
leukemias, glioblastomas, and cervical carcinomas have
been shown to down-regulate Apaf1 by epigenetic
mechanisms. In addition in some cancers a defective
Cyt-C dependent caspase 9 activation in the presence of
normal or elevated Apaf1 levels has been reported but
the underlying molecular mechanism is still elusive and
the existence of an unidentified apoptosome inhibitor
has been suggested. Sequestration of Apaf1 into lipid
rafts has also been demonstrated in Burkitt lymphoma
cells providing another molecular mechanism for
Death receptor pathway defects. Death receptor
pathways alterations have profound implications in
cancer and in particular in the mechanism leading to the
ability of tumours to avoid immune response. In a
simplistic way one can imagine a scenario in which
reduced expression of death receptors protects cells
from the immune system and increased surface (or
soluble form) expression of death ligands allows killing
of reactive cells. Indeed CD95 null mice are prone to
accumulate abnormal T-cells, with splenomegaly and
lymphoadenopathy and CD95 is lost or mutated in
several human cancers. In fact CD95 is lost in
hepatocarcinomas , present in less than 5% of
invasive esophageal cancer cells in 79% of patients 
where it correlates with depth of invasion and nodes
metastasis, mutated in adult T cell leukemia, down-
regulated in colon cancer , ovarian, cervical and
endometrial cancers, melanoma (where lymphocyte
www.impactaging.com 333 AGING, May 2012, Vol.4 No.5
infiltration of the invasive layer correlates with
prognosis)  and in more than 90% of lung cancers
. In support of the above mentioned model, down-
regulation of Fas-L leads to decreased tumor volume
and increased lymphocyte infiltration. Over-expression
of FAS-L has been reported in hepatocarcinomas,
esophageal cancers , breast cancers, melanomas
, astrocytomas , metastatic colon cancers, gastric
cancers and in more than 60% of sarcomas (reaching
95% in metastatic ones). The soluble form of Fas-L
(sFas-L), was also found in peripheral blood of cancer
patients, where it possibly exerts an immunosuppressive
effect [36, 37].
Defects of the CD95 signaling pathway can also be a
consequence of alterations of other components of the
DISC. FADD mutations were reported in non-small-cell
lung cancer  and complete loss was described in a
subset of diffuse large B-cell lymphoma. However
FADD defects have also been shown to have a pro-
oncogenic function, probably due to a role of this
protein different from apoptosis. As an example
correlates with poor survival
overexpression associates with poor prognosis in oral
squamous cell carcinomas.
A number of evidence highlight the importance of the
Trail receptor pathway in tumour onset and
development. The importance of Trail as a tumour
suppressor is supported by a number of results in
different animal models including the onset of
spontaneous haematopoietic malignancies in Trail KO
mice . As described for CD95 also in the case of
Trail, defects mostly allow tumour cells to escape
immune control. Trail receptors 1 and 2 map to
chromosome 8p21-22 frequently lost in tumours and
mutations of trail receptors have been described in up to
20% of various human tumours, including breast
cancer, head and neck cancers, and non-Hodgkin
The possibility to develop cancer therapies based on the
activation of death receptors has been attractive since
their discovery, however toxicity of therapies targeting
TNF and CD95 have greatly reduced the initial
enthusiasm. The finding that recombinant Trail
preferentially induced apoptosis in cancer cells while
sparing normal cells supported by its low or absent
toxicity in vivo [40, 41] have attracted growing
interest on the possibility to exploit this pathway for
cancer therapy. Despite a large investigative effort
however the reason for this selective activity is poorly
, and its
Altered caspase activity. Caspases are the final effectors
of both extrinsic and intrinsic apoptosis, therefore it is
expected that interfering with their function impairs
these pathway leading to a survival advantage for
cancer cells and indeed caspase alterations are not rare
in a variety of tumours. These can be due to mutations,
promoter methylation, alternative splicing, and post-
translational modifications. Some of these defects are
loss of functions, but in other cases mutated caspases
act as dominant negatives preventing activation also of
the wild type protein .
Altered caspase function can also be a consequence of
modified expression of their specific inhibitors, as an
example cFLIPs that competes with caspase 8 for
FADD binding, thus preventing its activation, is often
elevated in tumours, while its down-regulation can
sensitize tumour cells to therapy. Among caspase
inhibitors an important role is played by IAPs. Indeed
alterations of IAPs are found in a variety of human
cancers and are associated with poor prognosis and
resistance to therapy. In some cases however loss of
IAPs correlates with tumour progression complicating
the issue and suggesting that the role of IAPs has to be
carefully evaluated based on cell context. While initially
described as caspase inhibitors now IAPs have been
recognized to regulate a multitude of other cellular
functions including regulation of the immune response
cell migration, mitosis and proliferation . As many
of these processes are often modified in cancer it is
clear how alteration of IAPs can play a role in
tumorigenesis not only as a consequence of altered
apoptosis. In fact probably the most important pathway
regulated by IAPs that contributes to cancer
development is the NF-kB signaling pathway. XIAP,
cIAP1 and cIAP2 have been shown to regulate this
pathway and as a consequence inflammation, immunity
and cell survival. Moreover cIAPs protect from TNF
killing. In addition, recent findings show a role for IAPs
in metastatization as a XIAP/survivin complex would
trigger NF-kB pathway leading to activation of cell
motility kinases . This however is still a
controversial issue and other studies show a suppressive
effect of IAPs on cell mobility.
In any case due to their involvement in cancer
progression and to their ability to suppress apoptosis
IAPs have become an attractive therapeutical target,
leading to the development of IAP inhibitors, some of
which are based on natural inhibitors such as
Smac/DIABLO [43, 44]. These drugs appear to be able
to directly kill cancer cells or at least sensitize them to
other killing agents while sparing normal cells. A
number of these compounds are currently entering
www.impactaging.com 334 AGING, May 2012, Vol.4 No.5
clinical trials and their efficacy will be evaluated in the
next few years.
From a physiological point of view apoptosis plays a
key role in central nervous development [45, 46], while
in adult brain it is involved in the pathogenesis of a
number of diseases including neurodegenerative
diseases and acute injury (i.e. stroke).
Alzheimer's disease (AD) is the seventh leading cause
of all deaths in the United States, it is a progressive
accumulation of amyloid-β β peptides in extracellular
senile plaques intra-cellular neurofibrillary tangles
(NFTs) formation resulting from hyper-phosphorylated
microtubule-associated protein tau resulting in loss of
neurons and consequent progressive dementia [47-49].
Neuronal apoptosis plays an important role in AD
pathogenesis and caspases seem to be involved also in
some of the upstream pathological events. Exposure of
cultured hippocampal neurons to β results in caspase 3
activation and apoptosis . Aβ is generated following
sequential cleavage of the amyloid precursor protein
(APP), and caspase 3 is considered the predominant
caspase involved in APP cleavage [51, 52]. Tau protein
is also a substrate for caspase 3; cleavage of tau at its C-
terminus would promote tau hyper-phosphorylation and
accumulation of NFTs. Moreover, β-induced caspase 3
activation causes abnormal processing of the tau protein
in models of AD . APP is also cleaved by caspase 6
in vivo , moreover the N-terminal APP fragment is
a ligand for death receptor 6 (DR6 also known as
TNFRSF21) activation of which triggers caspase 6
dependent axonal degeneration .
The potential benefit of inhibiting the intrinsic apoptotic
pathway has been suggested through the use of a triple
transgenic AD mouse model wherein overexpression of
the anti-apoptotic Bcl-2 gene blocked activation of
caspases 9 and 3; in these conditions, the degree of
caspase cleavage of tau was limited, the formation of
plaques and tangles was inhibited, and memory
retention was improved [56, 57].
Parkinson's disease (PD) is considered the 2nd most
common chronic neurodegenerative disorder after AD,
it is associated with movement disorders, tremors, and
rigidity and is characterized by a specific loss of
dopaminergic neurons of the substantia nigra. This
degeneration leads to the formation of fibrillar
cytoplasmic inclusions known as Lewy bodies. A
preponderant role of the aberrant activation of intrinsic
and extrinsic apoptotic pathways in PD pathogenesis
has been suggested. The involvement of caspases 1 and
3 in apoptotic cell death has been proved using PD
animal models . PD has been linked to mutations in
several genes such as parkin , DJ-1, and a gene
codifying for a mitochondrial kinase, (PTEN)-induced
kinase 1 (PINK1) . PINK1 function is related to the
inhibition of mitochondria-dependent apoptosis . In
human and mouse neurons deleted for PINK1 Bax
translocation to the mitochondria and cytochrome c
release to the cytoplasm occur earlier than in control
cells. Furthermore loss of PINK1 results in elevated
levels of caspase activation (caspases 3 and 9) .
Gene-expression profiling studies performed on
material from patients affected by PD confirmed down-
regulation of PINK1 as well as other anti-apoptotic
proteins such as Bcl-2 but also found evidence for the
involvement of the extrinsic pathway. Indeed death
receptors such as FAS, TNFRSF10B and TNFRSF21
were up-regulated in PD-affected neurons [62, 63].
Huntington's disease (HD) is a disorder characterized
by a degenerative process, which affects medium spiny
striatal and cortical neurons. HD is an autosomal
dominant disease caused by a mutation in the gene
encoding the huntingtin protein (htt); this mutation is
responsible for abnormal expansion of a trinucleotide
CAG repeat encoding polyglutamine tract expansion in
the N terminus of htt . The expanded polyglutamine
alters protein folding, leading to generation of
aggregates in neurons that seem to be crucial for the
neurodegenerative process [65, 66]. Mutant htt is
cleaved by different proteases including caspases 
and accumulation of caspase cleaved fragments is an
early pathological finding in brains of HD patients .
Moreover transgenic mice models have demonstrated
that caspase 6 cleavage of mutant htt is required for the
development of the characteristic behavioral and neuro-
pathological symptoms. In addition activation of
caspase 6, is observed before the onset of motor
abnormalities in HD brains, suggesting that these
activation could be used as an early marker of the
An additional molecular mechanism involves htt-
interacting protein 1 (HIP-1) that binds a polypeptide
named Hippi (HIP-1 protein interactor) forming a
complex that can activate caspase 8. The free cellular
HIP-1 concentration is increased when htt is mutated
(HD), this would favor the pro-apoptotic Hippi-Hip
complex formation [70, 71].
Amyotrophic lateral sclerosis (ALS) is a progressive
neurodegenerative disease characterized by muscle
www.impactaging.com 335 AGING, May 2012, Vol.4 No.5
atrophy, paralysis, and, death due to progressive loss of
motor neurons . About 10% of cases are familial as
a result of mutations in the copper-zinc superoxide
dismutase (SOD1) gene , whereas the majority of
them are sporadic. SOD1 catalyzes conversion of the
superoxide anion to hydrogen peroxide, however the
mechanism by which SOD1 mutations cause ALS is
still not completely understood. Several alterations have
been identified in ALS and are thought to play a role in
motor neuron death,
abnormalities, aggregate formation, oxidative stress,
and inflammatory processes . Mice overexpressing
a human mutant SOD1 develop neuron degeneration,
and have been used as a model [75, 76]. These mice
show increased p38 activity that determines increased
NO production that in turn results in increased FasL
expression and activation of the extrinsic pathway .
In addition mutated SOD would localize to the
mitochondria and directly trigger CYTC release and
therefore neuronal death .
Motor neurons degeneration in ALS is also accompanied
by inflammation, but the exact mechanism triggering
inflammatory response remains unclear. Meissner et al
have recently reported that mutant SOD1 induces IL-1
beta and promotes caspase 1 activation resulting in
neuro-inflammation that would contribute to the
pathogenesis . Finally caspase 1 would act as a
chronic activator of caspase 3 contributing to neuronal
Acute CNS insults
Stroke is the leading cause of acquired adult disability
in USA . Ischemic injury is caused by the loss of
blood flow to the brain, usually as a consequence of an
embolism. The decrease in perfusion determines both
apoptotic and necrotic neuronal cell death in the
affected region (core) due to energy depletion [82, 83].
Around this area of tissues that is irreversibly lost there
is an area of partially damaged tissue known as
penumbra that triggers local inflammation. Several
evidences suggest that inflammation is a crucial event in
the progression of ischemic
Cyclooxygenase-2 (COX-2) induction and prostaglan-
din E2 elevation have been reported to occur after
cerebral ischemic insult . Takadera et al showed
that prostaglandin E2 directly induced apoptosis in
hippocampal neurons through the activation of caspase
3 , suggesting that a direct effect of prostaglandin
E2 on hippocampal neurons was mediated by activation
of the EP2 receptors. The deletion of EP3 receptors is
known to ameliorate stroke injury in experimental
stroke models , and recently it has been
demonstrated that EP3 receptors are involved in the
enhancement of inflammatory and apoptotic response in
the ischemic cortex .
An important role in ischemic brain damage seems to be
played also by activation of the receptor pathway. TNF
deletion in mice protects the brain from ischemic
damage . Fas and FasL levels seem to be increased
during brain ischemia , and interfering with the Fas
signaling pathway using a blocking anti-FasL antibody
markedly reduces death of neurons and improves
functional recovery in animal models of stroke and
spinal injury. Moreover chronic extrinsic cervical spinal
cord compression leads to Fas-mediated apoptosis of
C-Jun N-terminal protein kinase (JNK) signaling
pathway is known to be activated in response to stress
and ischemia. JNK activation precedes inflammation
and apoptosis in neuronal cells . Indeed, JNK is
involved in the regulation of several pro-apoptotic
proteins such as Bim and inhibition of JNK activity
attenuated Bax translocation in ischemic neurons .
The involvement of caspases in mediating ischemic
neuronal cell death has been also demonstrated using
caspase 1 and 3 KO mice. Cortical neurons from
caspase 3 -/- mice subjected to oxygen-glucose depriva-
tion, were more resistant to cell death , while
caspase 1 deletion in mice led to reduced production of
IL-1 beta . Consistently the reduction of IL-1 beta
function, using specific antagonists, results in
neuroprotective effects in stroke animal models .
Benchoua et al. proposed activation of different and
specific pathways in the core or in the penumbra area of
the brain infarction. In particular, after cerebral
infarction, in neurons of the core area the first apoptotic
events are mediated by ligand binding to specific death
receptors leading to caspase 8 activation. In the
penumbral area, where mitochondria provide residual
energy supply, neuronal death is instead induced
through the mitochondrial pathway .
The reperfusion of ischemic tissue usually improves
clinical outcome of patients, but in others it may
amplify brain damage due to the ischemia-reperfusion
injury. Reactive oxygen species (ROS) levels are
immediately increased after a vessel occlusion is
cleared, and are considered the main mediators of
reperfusion injury  resulting in the release of
cytochrome C .
Adult cardiomyocites are post-mitotic cells, therefore
this tissue has limited response capability to damage. In
www.impactaging.com 336 AGING, May 2012, Vol.4 No.5
general acute damage results in cell death of various
types while chronic stress mainly results in hypertrophy
and myocardial remodelling. Increased evidences
suggest that slow turnover exists in the normal
myocardium sustained by stem cells. In pathological
conditions however death exceeds mitosis resulting in
heart failure. Apoptosis is very rare in normal
myocardium with a reported rate of 0.001-0.002%
however it is increased in both acute and chronic heart
pathologies were it seems to play an important role .
Ischemia reperfusion. Occlusion of coronary arteries
results in myocardial infarction characterized by
massive cell death due to deprivation of oxygen,
nutrients and survival factors. Reperfusion of the
ischemic tissue is the treatment for acute coronary
syndromes and limits the size of the lesion but still
results in damage due to oxidative stress, increased
cytosolic and mitochondrial calcium levels and
inflammation determining what is known as reperfusion
injury. Apoptosis plays an essential role in the
pathogenesis of I/R and in general prolonged ischemia
determines an increase in necrosis while reperfusion
leads to increased apoptosis.
ischemia/reperfusion (I/R) is of different kinds: necrotic
apoptotic and autophagic. Both the intrinsic and
extrinsic apoptotic pathway are involved in I/R. Indeed
lpr mice (FAS deficient) show reduced infarct size
while deletion of both TNFR1 and TNFR2 appears to
have a protective effect. The role of the intrinsic
pathway is demonstrated by reduced apoptosis in
cardiomiocytes over-expressing Bcl-2 or lacking Bax,
both in vitro and in vivo. As explained above the two
pathways are connected through Bid cleavage that is
indeed observed in I/R and Bid KO mice show reduced
infarct size following I/R. Similarly deletion of PUMA
(a BH3 only protein activated by p53) also protects
from apoptosis suggesting the involvement of the p53
pathway . A number of studies have shown that
inhibitors of caspases can protect cardiomyocites
reducing the infarct size. Interestingly over-expression
of constitutively active Akt or pharmacological
sustained activation, shows significant protection from
apoptosis probably by inactivating a number of pro-
apoptotic proteins .
Ischemia damages several mitochondrial components
including proteins of the oxidative phosphorylation
complexes and membranes and predisposes them to
ROS generation . Indeed it is well known that the
production of ROS is greatly increased during the
reperfusion phase when oxygen becomes available and
the mitochondrial respiratory chain is impaired.
Furthermore this is exacerbated by reduced antioxidant
Chronic Heart Failure. Heart failure is a complex
syndrome where the heart is incapable of o meeting the
metabolic requirement of the body, it can be the result
of a number of other heart diseases such as myocardial
infarction, cardio-myopathies and hypertension. In all
cases it is characterized by left ventricular remodeling
with chamber enlargement and wall thinning. During
heart failure cardiomiocytes show a modest increase in
apoptosis, that however seems to play an important role
in the pathogenesis . The estimated rate of apoptosis
in cardiomiocytes in
cardiomyopathy is between 0.08% and 0.25% and
increasing apoptosis by only 0.023% in cardiomyocites
by over-expression of caspase 8 in mice results in
dilated cardiomyopathy after 2-6 months, that is
reduced by treatment with caspase inhibitors .
Multiple stress stimuli have been implicated in
activating apoptosis in cardiomyocites eventually
leading to heart failure, these include: excessive
mechanical stress, ROS, β1 adrenergic receptor
agonists, angiotensin II, cytokines. The ASK 1-JNK
pathway seems to play an important role in mediating
ROS dependent apoptosis in these cells (in part trough
inactivation of Bcl-2) and regulating left ventricular
remodeling. Indeed it has been proposed that inhibition
of Ask-1 can attenuate heart failure . Another
important pathway seems to involve Gαq, that
transduces the signal of a number of receptors including
angiotensin II receptor and α1-adrenergic receptor.
Over-expression of Gαq in mice heart results in heart
failure, this is accompanied by over expression of
Nix/Bnip3L, a BH3 like protein, that can induce
cardiomiocyte apoptosis .
Pathogenic microorganisms, once inside a host must
avoid detection and destruction for as long as possible.
Several pathogens are able to trigger or inhibit apoptosis
in eukaryotic host cells thus escaping the immune
system. On the other hand the host can use apoptosis in
an attempt to defend himself from pathogens. Thus,
apoptosis has a fundamental role in cellular host-
pathogen interactions that depends on the nature of the
pathogen, the cell type and the intensity of the infection.
Although it is outside the scope of this review, it is
worth mentioning a physiological role for apoptosis in
bacteria . While initially counterintuitive, several
studies have underlined how this process may be
fundamental to bacterial physiology. As an example,
autolysis, the most common known form of apoptosis in
bacterial cells, is used by Bacillus subtilis during
patients with dilated
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sporulation to eliminate a barrier, the cell wall that
could interfere with spore germination. Also, when
exposed to harmful conditions as antimicrobial agents,
to eliminate defective cells, damaged bacteria self-
digest the cell wall by peptidoglycan hydrolases.
Moreover, bacterial apoptosis maintains biofilm
homeostasis by balancing cell death and viability. The
increasing knowledge of ancestral forms of apoptosis in
bacteria will possibly shed light on the evolution and
molecular mechanisms of apoptosis in eukaryotic cells.
More relevantly to the subject of this review it is well
known that bacteria can modulate apoptosis in the host
favoring their survival and propagation. Several
apoptogenic molecules have been identified in bacteria
including common structural
lipopolysaccharide in Gram-negatives , lipotechoic
acid the major constituent of the cell wall of Gram-
positives and lipoarabinomannan in Mycobacteria
 as well as virulence factors such as exotoxins
, cytolysins  and hemolysins . Through
all these different molecules, bacteria are able to trigger
both intrinsic and extrinsic apoptotic pathways, here we
report some examples in different types of both endo-
cellular and extracellular bacteria.
Mycobacterium tuberculosis continues to be a major
cause of pulmonary infection in the world. It is an
intracellular parasite capable of establishing a long-term
infection. It lacks toxins and exerts its virulence through
its cell wall components . The initial infection
typically occurs in the alveolar spaces of the lung where
bacteria are phagocytized by macrophages. In the
alveolar macrophages, bacteria can survive and replicate
by preventing fusion of phagosomes with lysosomes
and thus their cellular lysis . The apoptotic
response to intracellular pathogens may favour both
host and parasite in several ways. The host responds to
the presence of intracellular M. tuberculosis triggering a
TNF-α-mediated apoptotic pathway. On the contrary,
bacteria block the TNF-α signalling by up-regulating
the anti-apoptotic protein Mcl-1 . Recently it has
been reported that mycobacteria may trigger a non-
classical type of apoptosis to exit host cells . Cell
death is induced when a threshold of about 20 bacteria
per macrophage is reached and begins with some typical
features of apoptosis followed by secondary necrosis
and release of bacteria. To indicate this non-classical
mode of apoptosis, Lee and colleagues coined the
expression “high-MOI apoptosis” . In addition
Mycobacteria secrete a 19kDa lipoprotein that binds the
TLR2 receptor that signals
differentiation factor 88 (MyD88) activating apoptosis
in macrophages .
multidrug resistant bacterium that often causes severe
nosocomial infections such as urinary tract infections,
pneumonia and bacteremia . P. aeruginosa is also
responsible for pulmonary infection of patients with
cystic fibrosis . Although considered as an
extracellular pathogen, P. aeruginosa can invade and
survive within different types of cells, in particular
epithelial respiratory cells. P. aeruginosa triggers cell
death of lung epithelial cells through the CD95 pathway
. In vivo experiments have demonstrated that, in
this case, apoptosis plays a role in the host defence
against the bacterial infection . Usually, P.
aeruginosa is aspired into the lower respiratory tract
after colonizing the oral cavity where oral bacteria may
facilitate the adhesion and invasion of P. aeruginosa
into respiratory epithelial cells followed by cytokine
release and apoptosis . Indeed co-incubation with
oral bacteria resulted in increased induction of apoptosis
in host cells .
Chlamydiae are obligate intracellular bacteria that have
adapted to endo-cellular life to the extent of no longer
being able to replicate outside the host. Chlamydia
trachomatis is a common sexually transmitted human
pathogen that causes
conjunctivitis and trachoma, while Chlamydophila
pneumoniae is commonly associated with upper
respiratory tract infections and can give rise to
community-acquired pneumonia . Apoptosis-
inhibiting mechanism have been shown in both and
appear to be similar . During persistent infection,
Chlamidiae inhibit the release of cytochrome c thus
blocking apoptosis . The underlying molecular
mechanism seems to be the proteolytic degradation of
BH3-only proteins by a chlamydial protease-like
activity factor (CPAF) .
Enteric pathogens producing Shiga toxins Shiga toxins
(Stxs) consist of a family of related cytotoxic proteins
expressed by the enteric pathogen Shigella dysenteriae
serotype 1 and by
Enterohaemorrhagic Escherichia coli (EHEC; Shiga
toxin-producing E. coli, STEC), Shigellae are
endocellular human-adapted pathogens transmitted by
the fecal-oral route. STEC are frequently associated
with severe disease, while not invasive they are able to
adhere to the intestinal epithelium, causing severe cell
alterations. Stxs inhibit protein synthesis by inactivation
of eukaryotic ribosomes , they have an AB5
structure consisting of an enzymatically active A-
subunit and a pentameric B-subunit that bind the toxin
receptor globotriaosylceramide (Gb3), a neutral
glycolipid of the globo-series. Stxs are transported in a
aeruginosa is an opportunistic,
several serotypes of
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retrograde manner, through the Golgi, to the
endoplasmic reticulum allowing the transfer of the A-
subunit into the cytosol where it inhibits protein
Shigellae and EHEC can survive phagocytosis by
inducing apoptosis through activation of the MAPK
pathway [107, 122]. Moreover through the prolonged
activation of the ribotoxic and endoplasmic reticulum
stress responses, they may initiate apoptosis with the
rapid activation of caspase 8 and activation of both
intrinsic and extrinsic pathways .
Interestingly it has also been demonstrated that Stxs
induce apoptosis in cancer cells and therefore could be
used as potential anticancer agents . However, an
obstacle is constituted by the possible toxicity since
they can also inhibit protein synthesis and trigger
apoptosis in normal cells.
Helicobacter pylori is
gastroduodenal diseases including peptic ulcer disease,
gastric lymphoma and gastric adenocarcinoma .
Vacuolating cytotoxin (VacA) is one of several
virulence factors identified in H. pylori . In
addition to cell vacuolation, VacA has other effects on
different cell types, including membrane channel
formation, inhibition of
proliferation as well as apoptosis. It has been
documented that VacA induces apoptosis through the
mitochondrial-dependent pathway in gastric epithelial
cells . The toxin binds to the RPTPβ (receptor-like
protein tyrosine phosphatase) receptor and activates the
pro-apoptotic Bcl-2 family proteins, Bax and Bak. In
addition, VacA causes down-regulation of JAK-STAT3
signaling pathway resulting in reduced expression of the
anti-apoptotic Bcl-2 family proteins, Bcl-2 and Bcl-XL.
Staphylococcus aureus is an ubiquitous bacterium and
is a part of the human skin and mucosal flora, it can
engender a variety of diseases and it is one of the most
common causes of hospital infections. It secretes
several virulence factors, exotoxins and enzymes,
involved in the pathogenic mechanisms of the
bacterium. Two virulence factors have mainly been
involved in induction of cell death. Superantigen
enterotoxin B directly binds to both MCH class II
molecules and to the variable regions of the T-cell
receptor beta chain (TCRVbeta), cross-linking them in a
non-specific way, resulting in polyclonal T-cell
activation which can be followed by cell death .
Enterotoxin B causes activation-induced cell death of T
lymphocytes, a process involving TCR binding,
activation, cell expansion, FAS expression and finally
PCD. Staphylococcal α-toxin is an hemolysin that
the major cause of
T-cell activation and
causes pore formation in the host cell membranes, and
the consequent disruption of the Na+/K+ balance appears
to trigger apoptosis through regulation of Bcl-2 and
Streptococcus pneumoniae is part of the human
respiratory tract normal flora and is the common cause
of community-acquired pneumonia, bacterial meningitis
and bacteremia. Although the virulence of this pathogen
is in large part determined by its capsular
polysaccharide, it produces several additional virulence
factors involved in the infection mechanisms.
Pneumolysin, like α-toxin as an example, is a pore
forming exotoxin that can trigger cell death in
macrophages and other cell types. In human
macrophages it permeabilizes mitochondrial membranes
causing cytochrome c release .
Bacillus anthracis is the causative agent of anthrax a
well known zoonotic disease. Three different primary
forms of the disease are recognized, the cutaneous, the
inhalation and the gastrointestinal form. The bacterium
has two major virulence factors, the poly-D-glutamate
capsular filaments that plays a major role as an
invasiveness factor and a toxin complex . The
toxin complex is a tripartite exotoxin that consists of
three polypeptide subunits: the protective antigen, the
edema factor and the lethal factor. The protective
antigen binds to cellular receptors and mediates the
entry into the cytosol of the other two factors. The lethal
factor is a Zn+ metalloprotease that inhibits the MAPK
pathway causing cell death, while the edema factor is an
adenylate cyclase that converts ATP to cyclic AMP and
promotes lethal tissue edema . Both lethal factor
and edema factor inhibit acquired and innate immune
responses, allowing the bacteria to multiply in the host.
Listeria monocytogenes is involved in a foodborne
illness characterized by gastroenteritis, meningitis,
encephalitis and sepsis . It is a facultative endo-
cellular bacterium that grows in macrophages, epithelial
cells and fibroblasts  and can induce apoptosis in
several cell types . In hepatocytes, activation of
apoptosis probably contributes to the resolution of
infection by: (i) elimination of infected cells and
reduction of host cells for bacterial replication and (ii)
allowing access of immune cells to the microorganisms.
On the contrary, Listeriae can induce cell death to
reduce the number of phagocytes, lowering antigen
presentation and breaking efficient adaptative immune
response. The hemolysin listeriolysin O, the most
widely studied virulence factor of L. monocytogenes
promotes apoptosis in host T cells , through a
mechanism that involves loss of mitochondrial
membrane potential .
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Clostridium difficile causes nosocomial diarrhoea in
adults by colonizing the lower intestinal tract .
Two virulence factors, enterotoxins A and B, largely
responsible for pathogenicity, are both inducers of
apoptosis. In intestinal epithelial cells, the toxins
produce a loss of mitochondrial membrane potential
followed by release of cytochrome C . The
decrease of Rho protein activity appears necessary to
trigger apoptosis . These toxins can also trigger the
extrinsic pathway .
Viruses can only replicate inside host cells that in turn
possess several defense mechanisms to limit viral
infection, including cell-mediated immune response,
inflammation and programmed cell death. Viruses have
therefore developed several strategies to inhibit or delay
cell death. On the other hand, some viruses induce
apoptosis to facilitate the viral spreading and/or to kill
uninfected cells of the immune system.
A large number of reports and reviews have been
published on this subject that will provide valuable
insights [133, 134], here we shortly report some of the
newest findings on the topic.
Herpesviridae family comprises double-stranded DNA
viruses that cause common infections in humans.
Herpesviruses may live latently in specific cell types for
years and then be activated and cause disease. Varicella-
Zoster virus (VZV) has a short replication cycle and it is
the etiological agent of chickenpox and after a long
latency period in ganglia along the entire neuraxis,
viruses can reactivate and produce shingles and other
neurological disorders. Despite the bulk of literature on
the subject the molecular mechanism of VZV-induced
cell death is still elusive. A recent study in a melanoma
cell model suggests a potential role for Bcl-2 . The
authors show that Bcl-2 mRNA and protein levels
decrease significantly during progression of the
infection, resulting in the release of cytochrome C.
Cytomegalovirus has a
replication cycle and causes a sub-clinical infection in
immune-competent hosts. Cytomegalovirus ensures its
own survival in the host cells, producing a wide range
of cell death suppressors , among these is a viral
mitochondrion-localized inhibitor of apoptosis (vMIA)
with a wide anti-apoptotic activity against both extrinsic
and intrinsic apoptosis-inducing
functionally and structurally similar to Bcl-xL  and
prevents the release of pro-apoptotic factors from
mitochondria by interaction with the growth arrest and
DNA damage 45α (GADD45α) protein and Bcl-xL
. Additionally, vMIA blocks Bax by binding and
stimuli. It is
Cytomegaloviruses also encode an inhibitor of apoptosis
that suppresses caspase 8 activation. This viral inhibitor
is highly conserved among mammalian betaher-
pesviruses . Finally Human cytomegalovirus
infection is known to cause ER stress , that would
normally result in the unfolded protein response (UPR)
and apoptosis, however cytomegaloviruses encode
UL38 protein that inhibits ER stress dependent
Hepatitis B virus (HBV) is a small hepatotropic virus
with a partially double-stranded circular DNA
molecule. HBV can induce several liver diseases
including asymptomatic infections, acute or fulminant
hepatitis, chronic hepatitis with progression to cirrhosis
and hepatocellular carcinoma. Apoptosis can play an
important role in the progression of HBV infection. To
date, four HBV proteins can triggers apoptosis in
various processes: the large surface protein, a truncated
form of the middle surface protein, the Hbx protein and
HBV codes for three forms of the surface (envelope)
protein, known as large, middle and small surface
proteins . HBV large surface protein induces
apoptosis in cultured hepatoma cells by activating the
ER stress pathway . The protein accumulates
within the ER-Golgi intermediate
(ERGIC) giving rise to membrane-bound vescicles that
cause marked vacuolization of the cytoplasm and
subsequently ER stress .
The HBV surface protein MHBs(t) (C-terminally
truncated middle hepatitis B surface protein) is a potent
regulator of TRAIL-induced apoptosis through a
mechanism that requires activation of ERK2 and
increased cleavage of caspases 3 and 9 .
Hepatitis B X protein (HBx) is a small regulatory
protein involved in the
maintenance of the chronic state of the infection that
can induce apoptosis in several ways . It inhibits c-
FLIP, an inhibitor of the intrinsic apoptotic pathway,
resulting in hyper-activation of caspases 8 and 3 by
death signals . However a more recent study
demonstrates that HBx can be either pro- or anti-
apoptotic in rat hepatocytes , inhibiting apoptosis
by activating NF-κB but stimulating it if NF-κB activity
is inhibited .
HBSP is a splice variant of the HBV DNA polymerase
with a conserved BH3 domain in the N-terminus. It is
expressed during viral replication and can induce
apoptosis functioning as a BH3 only protein .
it at the mitochondrion .
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Hepatitis C virus (HCV) is a small positive single-
strand RNA virus of the Flaviviridae family. HCV
infection is associated with severe liver disease that
frequently evolves into chronic disease, cirrhosis, and
hepatocellular carcinoma. During chronic infection it
was observed an enhanced hepatocyte apoptosis and up-
regulation of the death inducing ligands CD95/Fas,
TRAIL and TNFα . However, despite the
extensive literature the role of apoptosis in chronic
infection remains a matter of debate, and it also
questionable if the virus increases or reduces apoptosis
of infected cells. Moreover the absence of an
appropriate in vitro infection model has rendered the
study of this subject quite difficult and the interpretation
of the data not always univocal. .
Influenza A virus are small viruses of the family
Orthomyxoviridae with a segmented negative-stranded
RNA genome, that affects humans and animals.
Influenza A virus regulates apoptosis in several ways
through multiple viral proteins with both pro- and anti-
apoptotic activity . The flu virus can induce death
through activation of TGF-β, converting it from its
latent form through the viral neuraminidase activity
. It has also been demonstrated that overexpression
of the anti-apoptotic protein Bcl-2 results in impaired
virus production correlating with misglycosylation of
the viral surface protein haemoagglutinin . The
block of apoptosis seems to be crucial for viral
replication, whereas the induction of cell death may be
implicated in evasion of the immune system.
Human immunodeficiency virus (HIV) type 1 and type
2 are the causative agents of AIDS. The majority of
studies have concentrated on the more aggressive HIV-
1. HIV infection is primarily associated with a
progressive decline in CD4+ T lymphocytes number,
susceptibility to opportunistic
malignancies. The main mechanism for CD4+ T cell
depletion is enhanced apoptosis, which can be induced
by HIV through multiple pathways. HIV triggers
apoptosis in both infected and uninfected CD4+ T cells,
and indeed death of uninfected cells seems to be
predominant [149, 150].
HIV enters the cells through the binding of the envelope
glycoprotein gp120 to the CD4 membrane receptors,
along with the chemokine co-receptor CXCR4 that
facilitates membrane fusion between cells to form giant
multinucleated cells (syncytia) that correlate with
increased death. Furthermore, death also occurs by
enhanced membrane permeability due to continuous
budding of virions and Viral Protein U (Vpu). Once
inside the host cell, HIV proteases specifically cleave
and inactivate Bcl-2 and it directly activate procaspase 8
by proteolysis . Finally, other HIV proteins such as
negative regulator factor (Nef), envelope glycoprotein
(Env) and trans-activator of transcription (Tat) are able
to trigger apoptosis in T-cells by a mechanism that
involves the Fas-FasL signaling pathway.
As mentioned above HIV also kills uninfected cells
through several mechanisms, that require the release of
viral proteins such as gp120, Tat and Nef from infected
cells into the extracellular environment. These proteins
in turn trigger apoptosis in bystander cells by different
mechanisms. Soluble and membrane bound gp120 binds
different receptors (CD4, CXCR4 and CCR5) inducing
death both by upregulating Fas and decreasing FLIP and
activating the intrinsic pathway through down-
regulation of Bcl-2 and up-regulation of Bax. Tat is
endocytosed by neighbouring cells and up-regulates
caspase 8 and FasL resulting in death of T helpers and
neurons, while it appears to kill bystander T cells
through up-regulation of TRAIL. Induction of apoptosis
by Nef occurs through unknown mechanisms, however
genes involved both in the intrinsic and extrinsic
pathways have been shown to be regulated by this
protein, in primary human brain microvascular
endothelial cells suggesting that it can potentially
induce death trough different mechanisms.
A common feature of autoimmune diseases is altered
tolerance to self antigens
autoantibodies. Immune homeostasis and maintenance
of immune tolerance are strongly dependent on
apoptosis, moreover defective clearance of dying cells
results in persistence of autoantigens, therefore
autoimmune diseases can arise both from defective
clearance of autoreactive cells or by delayed elimination
of autoantigens. In addition increased apoptosis as a
consequence of viral infections, gamma irradiation or
other stressing conditions may contribute to disease
onset. More recently it has been suggested that upon
apoptosis and/or secondary necrosis autoantigens are
cleaved and modified exposing novel epitopes that are
recognized by the immune system, again altered or
delayed clearance as well as prolonged exposure to
apoptotic inducing stimuli would result in autoimmune
response. Moreover formation of immune complexes
would result in secretion of pro-inflammatory cytokines
such as IL-8, Il-1β, TNFβ and IFN-α resulting in
chronic inflammation and organ damage.
A large number of evidence support the idea that
defective apoptosis of immune cells leads to
autoimmune disease. Lpr and gld mice defective for the
and generation of
www.impactaging.com 341 AGING, May 2012, Vol.4 No.5
Fas signaling pathway develop lymphoadenopathy and
splenomegaly and produce a large number of
autoantibodies developing a disease that resembles
human systemic lupus erythematosus (SLE), clearly
demonstrating an essential role for the extrinsic
apoptotic pathway in controlling autoreactive T and B
cells and the fact that alteration in apoptosis can
strongly contribute to
pathogenesis [152, 153]. In humans defects of the Fas
signaling pathway lead
lymphoproliferative syndrome (ALPS) characterized by
non-malignant lymphoproliferation and autoimmunity
and have increased incidence of malignancies. 70% of
these patients carry germ-line heterozygous FAS
mutations, while the rest have somatic FAS mutations
or mutations of FAS ligand, caspase 10 and caspase 8.
In most cases mutations function as dominant negatives
inhibiting also the function of the wild type protein
While defects in the extrinsic pathway seem to play a
major role in the immune system it is becoming clear
that also the intrinsic pathway participates and its
alterations can contribute to autoimmune disease
pathogenesis . As an example Bim KO mice have
been shown to accumulate lymphoid and myeloid cells
and develop an autoimmune disease, [156, 157]. While
no mutations of the BH3 only proteins have been
described in patients with autoimmune diseases,
reduced levels of Bim were reported in a patient with
ALPS and over-expression of pro-survival members of
the bcl2 family have been reported in SLE .
As mentioned above altered clearance of apoptotic cells
also contributes to autoimmune diseases pathogenesis.
In fact MGF-8 (a protein essential for macrophage
clearance of apoptotic cells) defective mice also
produce a large number of autoantibodies and develop a
SLE-type autoimmune disease . This is probably
due to release of cellular material from apoptotic cells
that have not been cleared by phagocytosis and undergo
secondary necrosis. These cellular antigens would
activate autoimmunity. Along the same line mice
defective for the complement component C1q develop a
clearance of apoptotic cells has been demonstrated in
patients with SLE  and macrophages from at least
50% of these patients show reduced phagocytosis .
Over 50 years of research in the field of cell death have
clarified many aspects of this fundamental process and
brought to the attention of scientist its role in a large
number of different diseases, however exploitation of
to the autoimmune
this knowledge in therapy is only at its early steps. We
expect that in the following years more approaches
based on control of the different forms of cell death will
enter the clinical practice. Many problems need to be
solved, of course, such as activation of alternative death
pathways when one is pharmaceutically blocked, in
diseases where survival of the target cell is the final
goal, as well as unwanted death of “innocent
bystanders”, when attempting to kill pathological cells
such as in anti-tumor therapies.
CONFLICT OF INTERESTS STATEMENT
The authors of this manuscript have no conflict of
interest to declare.
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