Download Apoptosis and the immune system

Apoptosis and the immune system
Paul G Ekert and David LVaux
The Walter and Eliza Hall Institute for Medical Research, Melbourne, Victoria, Australia
Apoptosis is a physiological process of cell death that occurs as part of normal
development and in response to a variety of physiological and pathophysiological
stimuli.The effector mechanisms which carry out the death program are well
preserved across species and evolution. Apoptosis is important in the immune
system, and plays significant roles in the control of the immune response, the
deletion of immune cells recognising self-antigens, and cytotoxic killing. Some of
the molecular regulators of these processes, such as CD95 and bcl-2 family
proteins are the subjects of intense research. Malfunctioning of the immune system
may lead to increased or decreased cell death. Conversely, dysregulation of
apoptotic pathways themselves may lead to a spectrum of human disease,
including autoimmune disease and immunodeficiency.
Correspondence to:
David t.Vaux,
Walter and Eliza Hall
Institute for Medical
Research,
Royal Melbourne
Hospital, Melbourne,
Victoria 3050, Australia
The immune system is charged with the complex task of providing
defence against a vast array of potential pathogens, whilst ensuring that
those same protective mechanisms are not turned against the self.
Mechanisms of physiological cell death (apoptosis) play key roles in the
development, regulation and functioning of the immune system.
Malfunctioning of the cell death process can cause autoimmune disease,
immunodeficiencies, and lymphoid malignancies.
Apoptosis is the physiological process of cell death that occurs in all
multicellular organisms. The process of apoptosis may be divided into
stages: the stimuli that trigger a cell death response; the pathway by
which the message is transduced to the cell; and the effector mechanisms
that implement the death program1. Diverse stimuli may trigger a death
response in cells but the pathways converge upon the same, evolutionally
conserved effector mechanisms, the key components of which are a
family of cysteine proteases2.* Upon activation, these cysteine proteases
directly or indirectly cause the morphological and biochemical changes
characteristic of apoptosis, such as chromatin condensation and DNA
fragmentation. The apoptotic cells are efficiently phagocytosed by
neighbouring or inflammatory cells.
"Note added in proof: These cysteine proteases are now referred to as caspases. The
nomenclature is described in Alnemn et al?*
British Medical Bullmtin 1997,53 (No 3) 591-603
©TtiB Brihih Council 1997
Apoptoiis
Developmental apoptosis in lymphocytes
The vast majority of developing T and B lymphocytes die during
development. As these cells differentiate from progenitor cells, they
rearrange the genes for their antigen receptors and express them on
the plasma membrane. This process of recombination of the variable,
diversity and joining segments of the genes coding for these surface
receptors, is termed V(D)J recombination. Rearrangement of immunoglobulin (Ig) genes in B cells occurs independently of antigen,
and generates diversity in Ig receptor antigen specificity3. As the cell
progresses through the pro B to pre BI and to pre BII stages, the
rearrangements of the receptor genes follow a recognisable pattern.
The pro B cell joins the DH to JH regions and then subsequently joins
the VH to the now joined DH gene. In later stages of development,
light chain rearrangements occur such as at the pre BII stage. Many
rearrangements produce genes in a reading frame that cannot be
translated into functional protein. Yet other rearrangements are
successfully transcribed and translated but the receptor is not
expressed on the cell membrane or does not transduce a signal. In
all these instances, the cell fails to receive survival signals, the
apoptotic pathway is activated and the cell dies by neglect. When the
Ig genes are correctly rearranged and Ig is expressed on the cell
surface, it sends a signal to the cell that interrupts default activation
of the cell death process.
Thymocyte development is marked by a progression of changes in the
expression of surface antigens, including the CD4 and CD 8 markers4.
These developing cells undertake genetic rearrangements of the T cell
receptor genes (TCR) in a process analogous to the rearrangements of B
cell antigen receptor genes5. Their fate, either survival and clonal
expansion, or deletion, is dependent on the specificity of the interactions
between the TCR and MHC antigens. Those cells failing to make
successful receptor gene rearrangements die by initiating their intrinsic
apoptotic machinery. The importance of this process is illustrated by the
phenotype of severe combined immunodeficiency (sad) mice, and the
recombinase activating gene knockout (rag-l~'~ and rag-2~'~) mouse
strains6"9. These mice do not have circulating receptor-null lymphocytes;
rather, the developing lymphocytes, which cannot produce functional
antigen receptors, are deleted. Thus rag-1 or rag-2 deficient mice display
hypoplasia of lymphoid organs and are devoid of mature T and B cells.
In the SCED mouse, the same phenotype arises as a result of failure of
double-stranded DNA repair during the recombination process associated with defective DNA-dependent protein kinase activity. Antigen
receptor-null lymphocytes do not persist in these mice, they die early in
development. Death of the lymphocyte precursors in these genetically
592
BnhshAWreol Bulletin 1997,53 (No 3)
Apoptosis and the immune system
abnormal (sad) or modified (rag~ /- ) mice represents default activation
of the apoptotic pathway and death by neglect on a grand scale.
The development and differentiation of immune cells, like all other
cells, is governed by the autocrine, paracrine and endocrine actions of
various growth factors. The interleukins are a family of cytokines with
important developmental and regulatory functions in the immune
system. One of the effects of certain interleukins is to regulate survival
by preventing apoptosis by default. For example, IL-7 promotes
proliferation and hence survival of pre B cells, in its absence the cells
undergo apoptosis10. Similarly, IL-4 is able to promote survival,
proliferation and differentiation of more mature lymphocytes in vitro11.
The withdrawal of interleukins from dependent cells rapidly provokes
apoptosis. A defect in the common gamma chain of the IL-2 receptor
underlies the immune failure in X-linked severe combined immune
deficiency. In this case, the failure to receive signals from IL-2, IL-4, IL-7
and IL-15 results in apoptosis of the lymphocyte population12.
Glucocorticoids also have a profound effect on lymphocytes. Release
of cortisone from the adrenals or injection of dexamethasone can lead to
apoptosis of the majority of cortical thymocytes and early B cell
precursors. The sensitivity of lymphocytes to steroids is exploited in the
treatment of lymphoid malignancies by dexamethasone.
Positive and negative selection
Lymphocytes that manage to express antigen receptors must undergo
further selection. In the thymus, apoptosis is used to remove T cells with
receptors that fail to interact with self MHC peptides (positive selection)
and is used to remove T cells with receptors that have high affinity for
self antigens (negative selection)13. Direct evidence for apoptosis during
the selection of developing T cells in the thymus was provided by
TUNEL staining, a method which detects the DNA breaks characteristic
of apoptosis in situ. Apoptosis was evident in the thymic cortex of
normal mice and also in MHC-deficient mice which suggested that the
majority of cells died independently of interactions between TCR and
MHC molecule14. Thus, cells not positively selected died by apoptosis.
Further, thymocytes in the medulla of transgenic mice expressing TCRs
specific for self-antigens undergo apoptosis, implicating apoptosis as the
mechanism for negative selection. Dendritic cells are thought to be the
cells which present the antigen leading to negative selection and inducing
apoptosis of developing T cells within the thymus15.
Negative selection of B cells is required to remove populations which
express antibodies recognising self-antigens. The V(D)J rearrangements
Bn/i«/iM»dKolBu//.hn 1997^3 (No 3)
593
Apoptosis
occurring during B cell development lead to the surface expression of
IgM and IgD receptors. Experiments using transgenic mice expressing
antibodies towards membrane bound self-antigens showed that one
mechanism whereby self-reactive B cells are suppressed is clonal deletion
by apoptosis16-17. This process of deletion involves firstly an arrest of
maturation and, secondly, activation of the intrinsic cell death pathway
in the self-reactive lymphocyte, which can be delayed, at least in the
bone marrow, by the over-expression of the anti-apoptotic gene bcl-2.
Apoptosis of activated lymphocytes and homeostasis
of lymphocyte numbers
After development of lymphocytes in the primary lymphoid organs,
lymphocytes are exported to the secondary lymphoid organs, there to
encounter the 'antigenic universe'13. Upon exposure to an antigen, and
receiving the appropriate accessory signals, mature T and B cells become
activated, enter the cell cycle, proliferate and differentiate. Once the
foreign threat has been overcome, and they have served their effector
functions, such as producing antibodies (B cells) or secreting cytokines or
killing target cells (helper and cytotoxic T cells), the lymphocytes must
be removed. The death of activated cells serves to limit an immune
response by killing cells which are no longer needed. It can also allow for
deletion of cells which may have developed the potential to recognise
and generate a response to self-antigens, but which have eluded the
selection process in the thymus18. In most cases activation-induced cell
death (AICD) appears to be mediated by the induction on cells of both
CD95 (Fas/APO-1) and its ligand, leading to the induction of suicide or
fratricide by the activated cells19. Other TNF receptor family members,
such as TNFR2, p75 and APO-2 have also been implicated in AICD.
Affinity maturation
Within the germinal centres of lymphoid tissues, the V regions of Ig
genes undergo somatic hypermutation after activation, which results in
the generation of antibodies with increased affinity for antigen. Cells
that do not generate antibodies of higher affinity, and those bearing
mutations that allow the antibody to react with self-antigens, must be
removed. Once again, this is achieved by apoptosis20"23.
594
Brit../) AUdKo/Bul/ohn 1997,53 (No 3)
Apoptojii and the immune system
Apoptosis activation pathways
As with immature lymphocytes, the survival of mature T and B cells can
be regulated by signals from soluble cytokines and molecules expressed
on their own surface or the surface of other cells.
CD95 (Fas/APO-7j
CD95 is a cell surface receptor of the tumour necrosis factor (TNF)
family24*25. Other members of this family include TNF receptors TNF-R1
and TNF-R2, CD30, CD40 and APO-2. Binding of CD95 by its ligand
or anti-CD95 antibodies usually results in apoptosis of the CD95bearing cell. The cytoplasmic domain of CD95 bears a motif termed the
'death domain' that, upon ligation of CD95 ligand, allows it to bind the
death domain of cytoplasmic proteins FADD/Mort-1 and RIP. FADD
has a carboxy-terminal death domain, and a 'death effector domain' at
its N terminus that allows it to interact with the cysteine protease
FLICE/Mach-1. In this way, ligation of CD95 can lead to activation of
the cysteine proteases that are the common effectors of apoptosis26"28.
In addition to mediating AICD of T cells, T cells bearing CD95L can
kill other cell types bearing CD95. Two strains of mice, Ipr and gld,
carry mutations in the CD95 gene and its ligand, respectively29-30. These
mice develop lymphadenopathy, splenomegaly, and autoimmune disease
as a direct result of defects in the CD95 pathway and accumulation of
lymphocytes. As positive and negative selection of lymphocytes in the
thymuses of these mice is unaffected, the pathology is thought to be a
consequence of failure of activated lymphocytes to die. Humans with a
mutated CD95 gene develop an disease similar to that of Ipr and gld
mice31. Lymphocytes from patients with this rare autoimmune lymphoproliferative disorder show defective CD95-mediated apoptosis. Genetic
abnormalities in the CD95 signalling pathway have not been found in
more common human autoimmune diseases such as systemic lupus
erythematosis (SLE).
Other TNF receptor family members and apoptosis
Several other members of the TNF receptor family are important
modulators of cell death in the immune system. TNF may signal through
2 receptors, tumour necrosis factor receptor 1 (p55) and receptor 2
(p75). These receptors transduce signals via intermediary molecules
leading in some instances to apoptosis via FADD and FLICE, which also
Bnhsh Medical Bul/.tm 1997,53 (No 3)
595
Apoptosis
mediate death signals from CD9527-32. TNF is a pro-inflammatory
cytokine which plays an important role in immune responses and toxic
shock. Mice lacking p55 TNF receptors have an increased susceptibility
to Listeria monocytogenes infection but are resistant to induction of
shock by lipopolysaccharide33.
The CD40 receptor can mediate both pro-apoptotic and deathprotective signals. Binding of CD40 ligand to its receptor can inhibit
apoptosis in B cells stimulated through their Ig receptors, and stimulates
B cell proliferation and isotype switching. However, the same receptorligand interaction also induces the expression of CD95 and enhances B
cell susceptibility to CD95 mediated death34. Mutations of CD40 ligand
cause the X-linked hyper-IgM syndrome, which is an immunodeficiency
syndrome characterised by elevated IgM levels, low or absent IgG, IgA
and IgE, lack of germinal centres, susceptibility to bacterial infections
and autoimmunity35. Clearly, normal signalling through the CD40
pathway, including the control of apoptosis, is important for normal
immune function. Signalling through the CD30 receptor may also
transduce a death signal and may be involved in the negative selection of
lymphocytes36.
Cytotoxic killing
Cell-mediated cytotoxicity is the ability of a specialised immune cells
(cytotoxic T lymphocytes [CTL] and natural killer cells) to destroy target
cells whilst remaining intact themselves. The recognition of the target
cells is dependent on the interaction between receptors on the surface of
the killer cell (TCR) and antigens on the surface of the target. There are
two pathways by which the CTL is able to induce death in the target cell.
One pathway is mediated by directed exocytosis of granules containing
perforin and granzymes. The other pathway involves signalling by CD95
ligand.
Perforin is a protein that can form pores in the surface of a target cell,
and granzymes are serine proteases stored in the granules of killer cells.
Recognition of a target cell such as a virally infected cell is dependent
upon the TCR expressed on the surface of the CTL. Degranulation then
occurs, allowing perforin to punch holes in the target cell and granzymes
enter37. One of the granzymes, granzyme B, has been shown to be
essential for the induction of the DNA degradation associated with
apoptosis in the target cell38, and can cleave and activate the apoptotic
cysteine protease CPP3239.
CD95-mediated cytotoxicity has been demonstrated in vitro, but is
less important than perforin-granzyme mediated CTL killing in vivo40.
596
Bnh»/iM»dico/Bu//.tin 1997^3 (No 3)
Apoptojii and the immune system
Apoptosis effector mechanisms
Cysteine proteases
Cloning of the ced-3 gene, which is essential for apoptosis in the
nematode Caenorhabditis elegans, showed that it resembled the
mammalian cysteine protease interleukin ip converting enzyme
(ICE)41. Many other ced-3/ICE homologues have since been identified
that mediate apoptosis in mammalian cells. These proteases are the key
effector proteins of apoptosis. They are produced as inactive precursors
that in order to be activated are cleaved at aspartate residues and
assembled into tetramers. In all of them the active catalytic residue is a
cysteine. Once activated, these proteases cleave their substrates at
aspartate residues, and some cysteine proteases can activate their own
precursors or activate other cysteine proteases. Many proteins are
cleaved once these cysteine proteases become active, and endonucleases
are released that gain access to the chromatin. The cell then displays the
characteristic apoptotic morphology.
Apoptosis triggered by TNF or CD95 leads to activation of the
cysteine proteases FLICE/Mach-1, ICE and CPP32, and protease
inhibitors that target either ICE or CPP32 can inhibit TNF and CD95
mediated apoptosis. It seems that these enzymes work in a hierarchy:
FLICE -> ICE -> CPP3228.
ICE is not required for apoptosis during development, since mice with
mutated ICE genes do not show any developmental abnormalities. ICE
does seem to be required for apoptosis triggered by CD95 or TNF since
CD95 killing is of thymocytes is inhibited in ICE knockout mice42 and
protease inhibitors that target ICE block TNF and CD95 induced cell
death43-44, and ICE activates the pro-inflammatory cytokine interleukin
1 (3. This suggests that some cysteine proteases may be used for apoptosis
when inflammation is not required, such as during development, but
when apoptosis is being used as a defence mechanism, proteases such as
ICE are used so that IL-ip is released simultaneously with the occurrence
of cell death. This action may serve to recruit immune cells to the site of
apoptosis in response to viral infection.
Apoptosis regulatory mechanisms
Bc/-2 family
Bcl-2 is a member of a family of proteins which regulate apoptosis. It
was originally found at the site of chromosomal translocations
Bntab AW.cc/ Bulletin 1997£3 (No 3)
597
Apoptosij
frequently observed in follicular lymphoma. Expression of bcl-2 or its
homologues, including bcl-x and bcl-w, inhibits apoptosis in many cell
types. Bcl-2 does this by inhibiting activation of the apoptotic cysteine
proteases, but how it does this has not been determined. The antiapoptotic activity of bcl-2, bcl-x and bcl-w can be antagonised by the
proteins bax, bad, bik and bak, which also resemble bcl-2 in structure.
Thus the bcl-2 family consists of pro- and anti-apoptotic members which
can heterodimerise and antagonise each other. It is likely that the relative
abundance of these two types of proteins determines whether a cell
responds to an apoptotic signal by ignoring it (bcl-2, bcl-x, bcl-w
predominate) or by dying (bax, bad, bik or bak predominate)45"48.
Bcl-2 expression is regulated during lymphocyte development. Very
early precursors express low levels but this increases at later stages (prepro B cells and pro T cells). Receptor gene arrangement is associated
with a reduction in bcl-2 expression, and mature cells express the protein
in high levels49-50.
Many lines of evidence suggest a role for bcl-2 and bcl-2-like proteins
in immune function and homeostasis, in addition to the apoptotic
effector mechanisms they regulate. Analysis of mice lacking bcl-2, bax or
bcl-x has revealed their role in development and in the immune system,
and analysis of transgenic mice over expressing bcl-2, or bcl-x has shown
the effect of inhibiting apoptotic processes upon immune function.
Lymphocyte development is initially normal in bcl-2 knockout mice,
but over time extensive apoptosis of lymphocytes occurs in the spleen
and thymus51. Thymocytes taken from these mice show accelerated
death rate in response to apoptotic stimuli, demonstrating a critical role
for bcl-2 in the maintenance of mature and active lymphocytes.
Transgenic experiments where bcl-2 is overexpressed in lymphocytes
have shown that it can inhibit deletion of cells that would occur during
positive selection, such as B cells which fail to make productive receptor
rearrangements52, or T cells expressing receptors which do not recognise
MHC antigen present in the experimental system53'54. Interestingly, in
the later experiments, self-tolerance was maintained. These data imply a
role for the apoptotic processes that bcl-2 can control in positive
selection of B cells and T cells.
Whilst negative selection of thymocytes is only very mildly perturbed
in bcl-2 transgenic mice, some B cells recognising self-antigens can be
found and some strains of such mice develop autoimmune disease55.
Transgenic bcl-2 expression does not prevent CD95 mediated apoptosis
of lymphocytes or rescue T or B cells from activation induced death56-57.
Mice lacking either bax or bcl-x have been generated and suggest these
genes also play significant roles in the regulation of immune system
apoptosis58-59. The bcl-x knockout mice die during embryonic development. There is extensive apoptosis throughout the nervous system and
598
Bnhih Mod.ro/ BuHet.n 1997,53 (No 3)
Apoptojii and the immune system
among haemopoietic precursors in the liver. Bcl-x~'~ lymphocytes in
chimeric mice undergo extensive apoptosis during development, but less
once mature. Bax knockout mice show a mild lymphoid hyperplasia of
both thymocytes and B cells, supporting the idea that appropriate
expression is required for the control of B and T cell populations.
Clinical implications of apoptosis in the immune system
When either too much or too little apoptosis is seen in association with a
disease, the changes in cell death may be an indirect, secondary
consequence of the disease, or the disease may be the direct effect of
alterations to the apoptotic mechanism itself. As apoptosis is one of a
number of cellular responses to stress, cells which have, for instance,
become infected by a pathogen, or made hypoxic, or have a genetic
defect, may die by apoptosis. The SCID and rag-'- mice cited earlier
illustrate this point. The extensive death of immature lymphocytes is a
normal response to non-productive receptor gene rearrangements.
Increased apoptosis occurs, but abnormalities of cell death mechanisms
are not the cause of the disease. Transplant rejection is another example.
Whilst the rejection of the graft is harmful to the patient, the CTL attack
on the graft is a normal response to foreign antigen60"62. On the other
hand, abnormalities of the cell death mechanism itself can also cause
disease. For example, follicular lymphoma is caused by over expression
of bcl-2, and mutations to CD95 cause a lymphoproliferative phenotype
in humans. In the Chediak-Higashi syndrome, CTLs are unable to
degranulate and destroy target cells, resulting in immunodeficiency63,
and abnormalities in the CD95 gene result in autoimmune lymphoproliferative disorder31.
Apoptosis is used as a defence against viral infection, as viruses need
to use the cell's machinery to replicate. Defensive apoptosis in response
to a viral infection can be cell suicide, when a cell detects the virus and
activates the intrinsic apoptotic program, or cell killing, as when a CTL
recognises a virally infected cell and kills it. The majority of cytopathic
effects associated with viral infection are part of this defensive apoptotic
response, rather than being a direct effect of viral infection itself.
Sometimes, for example in the case of fulminant hepatic necrosis
following infection with hepatitis B or hepatitis C, the defensive
apoptosis (possibly mediated by CD95) of liver cells does more harm
than good64-65.
In the future, therapies designed to target specifically the apoptotic
mechanism may become available. One day, apoptotic protease
inhibitors may be available to combat graft rejection by blocking CTL
Bntith Mtdical Bulletin 1997,53 (No 3)
599
Apoptosis
killing, or to prevent T cell death in AIDS. Bcl-2 antagonists may be used
to treat follicular lymphoma, and apoptosis activators may be used to
kill lymphocytes mediating auto-immune disease66-67. In retrospect, some
therapies already in existence target apoptosis pathways. When
radiation or steroids are used for cancer therapy or immunosuppression,
their primary effect is by the activation of apoptosis.
Conclusion
Apoptosis is an evolutionary conserved process which plays a vital role
in the normal development of the immune system and in the regulation
of the immune response. Apoptosis is a contributor to the pathology of
many human diseases, including disorders of immune function, either as
a secondary phenomenon activated by the underlying abnormality or as
a primary phenomenon where the abnormality is a dysregulation of
apoptosis. There remains much that is unknown about the molecular
controls of apoptosis in the immune system, but significant detail is
understood about key genes involved in the process.
References
1 Vaux DL, Strasser A. The molecular biology of apoptosis. Proc Natl Acad Set USA 1996; 93:
2239-44
2 Vaux DL, Haecker G, Strasser A. An evolutionary perspective on apoptosis. Cell 1994; 76777-9
2a Alnemri ES, Livingstone DJ, Nicholson DW et al. Human ICE/CED-3 protease nomenclature.
Cell 1996; 87: 171
3 Tonegawa S. Somatic generation of antibody diversity. Nature 1983; 302- 575-81
4 Godfrey DI, Zlotnik A. Control points in early T-cell development. Immunol Today 1993; 14.
547-53
5 Raulet DH, Garman RD, Saito H, Tonegawa S. Developmental regulation of T-cell receptor
gene expression. Nature 1985; 314. 103-7
6 Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the
mouse. Nature 1983; 301: 527-30
7 Blunt T, Finnie NJ, Taccioli GE et al. Defective DNA-dependent protein kinase activity is
linked to V(D)J recombination and DNA repair defects associated with the munne scid
mutation. Cell 1995; 80: 813-23
8 Mombaerts P, Iacomini J, Johnson RS et al. RAG-1-deficient mice have no mature B and T
lymphocytes. Cell 1992; 68: 869-77
9 Shinkai Y, Rathbun G, Lam KP et al. RAG-2-deficient mice lack mature lymphocytes owing to
inability to initiate V(D)J rearrangement Cell 1992; 68 855-67
10 Tsujimoto T, Lasukov IA, Huang N, Mahmoud MS, Kawano MM. Plasma cells induce
apoptosis of pre-B cells by interacting with bone marrow stromal cells. Blood 1996; 87. 337583
11 Spinozzi F, Nicoletn I, Agea E et al. IL-4 is able to reverse the CD2-mediared negative apoptotic
signal to CD4-CD8- alpha beta and/or gamma delta T lymphocytes. Immunology 1995; 86:
379-84
600
Bnhth Medical Bulletin 1997,53 (No 3)
Apoptosis and the immune system
12 Noguchi M, Yi H, Rosenblatt HM et al. Interleukin-2 receptor gamma chain mutation results
in X-hnked severe combined immunodeficiency in humans. Cell 1993; 73: 147-57
13 Nossal GJ. Negative selection of lymphocytes. Cell 1994; 76 229-39
14 Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the
thymus [see comments]. Nature 1994; 372: 100-3
15 Miller JF, Heath WR. Self-ignorance in the peripheral T-cell pool. Immunol Rev 1993; 133:
131-50
16 Nemazee DA, Burki K. Clonal deletion of B lymphocytes in a transgeruc mouse bearing antiMHC class I antibody genes. Nature 1989; 337: 562-6
17 Hartley SB, Cooke MP, Fulcher DA et al. Elimination of self-reactive B lymphocytes proceeds
in two stages: arrested development and cell death. Cell 1993; 72: 325-35
18 Russell JH. Activation-induced death of mature T cells in the regulation of immune responses.
Curr Opm Immunol 1995; 7: 382-8
19 Alderson MR, Tough TW, Davis-Smith T et al. Fas hgand mediates activation-induced cell
death in human T lymphocytes. / Exp Med 1995; 181: 71-7
20 Shlomchik MJ, Marshak-Rothstein A, Wolfowicz CB, Rothstein TL, Weigert MG. The role of
clonal selection and somatic mutation in autoimmuruty. Nature 1987; 328: 805—11
21 Liu YJ, Joshua DE, Williams GT et al. Mechanism of antigen-driven selection in germinal
centres. Nature 1989; 342: 929-31
22 Pulendran B, Kannourakis G, Noun S, Smith KG, Nossal GJ Soluble antigen can cause
enhanced apoptosis of germinal-centre B cells [see comments]. Nature 1995; 375: 331-4
23 Shokat KM, Goodnow CC Antigen-induced B-cell death and elimination during germinalcentre immune responses. Nature 1995; 375: 334-8
24 Itoh N, Yonehara S, Ishn A et al. The polypeptide encoded by the cDNA for human cell surface
antigen Fas can mediate apoptosis. Cell 1991; 66: 233-43
25 Oehm A, Behrmann I, Falk W et al. Purification and molecular cloning of the APO-1 cell
surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor
superfamily. Sequence identity with the Fas antigen / Btol Chem 1992; 267: 10709-15
26 Tewan M, Dixit VM. Fas- and tumor necrosis factor-induced apoptosis is inhibited by the
poxvirus crmA gene product. / Biol Chem 1995; 270: 3255-60
27 Varfolomeev EE, Boldin MP, Goncharov TM, Wallach D. A potential mechanism of 'crosstalk' between the p55 tumor necrosis factor receptor and Fas/APOl: proteins binding to the
death domains of the two receptors also bind to each other. / Exp Med 1996; 183: 1271-5
28 Muzio M, Chinnaiyan AM, Kischkel FC et al. Flice, a novel fadd-homologous ice/ced-3-hke
protease, is recruited to the cd95 (fas/apo-1) death-inducing signaling complex. Cell 1996; 85:
817-27
29 Takahashi T, Tanaka M, Brannan CI et al. Generalized lymphoproliferaDve disease in mice,
caused by a point mutation in the Fas hgand Cell 1994; 76: 969—76
30 Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S. Lymphoprohferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 1992;
356- 314-17
31 Fisher GH, Rosenberg FJ, Straus SE et al. Dominant interfering Fas gene mutations impair
apoptosis in a human autoimmune lymphoproliferative syndrome. Cell 1995; 81. 935-46
32 Chinnaiyan AM, O'Rourke K, Tewan M, Dixit VM. FADD, a novel death domain-containing
protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995; 81: 505-12
33 Pfeffer K, Matsuyama T, Kundig TM et al. Mice deficient for the 55 kD tumor necrosis factor
receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell
1993, 73: 457-67
34 Lens SM, Tesselaar K, den Dnjver BF, van Oers MH, van Lier RA. A dual role for both CD40hgand and TNF-alpha in controlling human B cell death. / Immunol 1996; 156: 507—14
35 Callard RE, Armitage RJ, Fanslow WC, Spnggs MK. CD40 hgand and its role in X-hnked
hyper-IgM syndrome. Immunol Today 1993; 14: 559-64
36 Amakawa R, Hakem A, Kundig TM et al. Impaired negative selection of T cells in Hodgkin's
disease antigen CD30-deficient mice. Cell 1996; 84: 551-62
37 Shiver JW, Su L, Henkart PA. Cytotoxicity with target DNA breakdown by rat basophihc
leukemia cells expressing both cytolysin and granzyme A. Cell 1992; 71: 315-22
Bnhj/iM«dico/Bu//ehn1997;53(No.3)
601
Apoptojis
38 Shresta S, Maclvor DM, Heusel JW, Russell JH, Ley TJ. Natural killer and lymphokineactivated killer cells require granzyme B for the rapid induction of apoptosis in susceptible
target cells. Proc Natl Acad Set USA 1995; 92 5679-83
39 Darmon AJ, Nicholson DW, Bleackley RC. Activation of the apoptoac protease CPP32 by
cytotoxic T-cell-denved granzyme B. Nature 1995, 377- 446-8
40 Rouvier E, Luciani MP, Golstein P. Fas involvement in Ca2+-independent T cell-mediated
cytotoxicity. / Exp Me<f 1993; 177 195-200
41 Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3
encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993; 75:
641-52
42 Kuida K, Lippke JA, Ku G et al. Altered cytokine export and apoptosis in mice deficient in
interleukin-1 beta converting enzyme. Science 1995, 267: 2000-3
43 Los M, Van de Craen M, Penning LC et al. Requirement of an ICE/CED-3 protease for Fas/
APO-1-mediated apoptosis Nature 1995; 375: 81-3
44 Enan M, Hug H, Nagata S. Involvement of an ICE-hke protease in Fas-mediated apoptosis.
Nature 1995; 375. 78-81
45 Oltvai ZN, Milhman CL, Korsmeyer SJ. Bcl-2 heterodimenzes in tnvo with a conserved
homolog, Bax, that accelerates programmed cell death Cell 1993, 74 609-19
46 Yang E, Zha J, Jockel J et al. Bad, a heterodimenc partner for Bcl-XL and Bcl-2, displaces Bax
and promotes cell death. Cell 1995; 80. 285-91
47 Sedlak 1W, Oltvai ZN, Yang E et al. Multiple Bcl-2 family members demonstrate selective
dimenzations with Bax. Proc Natl Acad Sa USA 1995, 92: 7834-8
48 Boyd JM, Gallo GJ, Elangovan B et al. Bik, a novel death-inducing protein shares a distinct
sequence motif with Bcl-2 family proteins and interacts with viral and cellular survivalpromoting proteins. Oncogene 1995; 11: 1921-8
49 Merino R, Ding L, Veis DJ, Korsmeyer SJ, Nunez G Developmental regulation of the Bcl-2
protein and susceptibility to cell death in B lymphocytes. EMBO J 1994; 13- 683-91
50 Gratiot-Deans J, Merino R, Nunez G, Turka LA. Bcl-2 expression during T-cell development:
early loss and late return occur at specific stages of commitment to differentiation and survival.
Proc Natl Acad Sa USA 1994; 91: 10685-9
51 Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant
lymphoid apoptosis, polycystic kidneys, and hypopigmented hair Cell 1993; 75: 229^40
52 Strasser A, Harris AW, Corcoran LM, Cory S. Bcl-2 expression promotes B- but not Tlymphoid development in scid mice. Nature 1994, 368: 457-60
53 Linette GP, Grusby MJ, Hedrick SM et al. Bcl-2 is upregulated at the CD4+ CD8+ stage during
positive selection and promotes thymocyte differentiation at several control points. Immunity
1994; 1: 197-205
54 Strasser A, Harris AW, von Boehmer H, Cory S. Positive and negative selection of T cells in Tcell receptor transgenic mice expressing a bcl-2 transgene. Proc Natl Acad Set USA 1994; 91:
1376-80
55 Strasser A, Whittingham S, Vaux DL et al. Enforced BCL2 expression in B-lymphoid cells
prolongs antibody responses and elicits autoimmune disease. Proc Natl Acad Sa USA 1991; 88:
8661-5
56 Sentman CL, Shutter JR, Hockenbery D, Kanagawa O, Korsmeyer SJ. bcl-2 inhibits multiple
forms of apoptosis but not negative selection in thymocytes. Cell 1991; 67: 879—88
57 Strasser A, Harris AW, Huang DC, Krammer PH, Cory S. Bcl-2 and Fas/APO-1 regulate
distinct pathways to lymphocyte apoptosis. EMBO J 1995; 14: 6136-47
58 Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ. Bax-deficient mice with
lymphoid hyperplasia and male germ cell death. Science 1995; 270: 96—9
59 Motoyama N, Wang F, Roth KA et al. Massive cell death of immature hematopoietic cells and
neurons m Bcl-x-deficient mice. Science 1995; 267. 1506-10
60 Ito H, Kasagi N, Shomon K, Osaki M, Adachi H. Apoptosis in the human allografted kidney.
Analysis by terminal deoxynucleondyl transferase-mediated DUTP-biotin nick end labeling
Transplantation 1995, 60 794-8
61 Afford SC, Hubscher S, Strain AJ, Adams DH, Neuberger JM. Apoptosis in the human liver
during allograft rejection and end-stage liver disease. / Pathol 1995; 176: 373-80
602
Bnhih Mtdical Bulletin 1997^3 (No 3)
Apoptosis and the immune system
62 [Crams SM, Egawa H, Quinn MB et al. Apoptosis as a mechanism of cell death in liver allograft
rejection [see comments]. Transplantation 1995; 59: 621-5
63 Baetz K, Isaaz S, Griffiths GM. Loss of cytotoxic T lymphocyte function in Chediak-Higashi
syndrome arises from a secretory defect that prevents lync granule exocytosis. / Immunol 1995;
154: 6122-31
64 Galle PR, Hofmann WJ, Walczak H et at. Involvement of the CD95 (APO-1/Fas) receptor and
hgand in liver damage. ] Exp Med 1995, 182: 1223-30
65 Hiramatsu N, Hayashi N, Katayama K et al Immunohistochemical detection of Fas antigen in
liver tissue of patients with chronic hepatitis C. Hepatology 1994, 19' 1354-9
66 Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science 1995; 267:
1456-62
61 Nicholson DW. Ice/ced3-like proteases as therapeutic targets for the control of inappropriate
apoptosis. Nature Biotech 1996; 14: 297-301
Bnttth M.d.col BuHehn 1997J3 (No 3)
603