Apoptosis and the Immune System
Activation Induced Cell Death (AICD) represents the mechanism of T cell clonal deletion in vivo.
The development and ongoing function of a non-autoreactive and self-limiting immune repertoire is dependent on the
ability to selectively activate and either expand or delete lymphocytes as a function of their antigenic reactivity
throughout the developmental history of the cell.
The induction of activation-driven cell death in non-transformed cells requires combinations of two mitogenic stimuli
at relatively high doses - one an antigen or mitogen acting via the TCR or an alternative activation molecule, and the
other a lymphokine such as IL-2 or IL-4. Non-transformed IL-2 expressing CD8+ T lymphocytes only die in presence
of lymphokine IL-2 and an activating stimulus, but neither alone!
It is also important to note that stimuli required to drive a proliferative response differ only quantitatively
from those needed to induce AICD. The production of lymphokines, in fact, serves both to recruit new responder cells
and to attenuate previously responsive cells. Significantly, by stimulating
the production of factors that trigger activation-driven cell death, an immune response will always be self-limiting.
Strikingly, in transformed T-cells, oncogene expression appears to provide one of the mitogenic signals
constitutively, and the addition of a single mitogenic stimulus supplies the second signal for cell death.
The difference in the requirements for induction of AICD between transformed and non-transformed T cells may provide
a mechanistic rationale for a strategy of selective antitumor therapy!
lpr-/- and gld-/- mice were shown to
be defective in AICD of peripheral T lymphocytes, and because Fas expression is induced by activation of
T cells, the role of an initial activation stimulus in sensitizing cells to subsequent AICD likely represents
the induction of Fas expression. Fas does not appear to be involved in AICD of immature thymic cells.
(see review by D. Ucker, 1997, Advances in Pharmacology)
Functional inactivation, leading to a chronically unresponsive state of immune cells (anergy) has been
suggested to represent a mechanism for attenuating immune responses. Conditions that trigger clonal anergy
in vitro are similar to those that induce AICD. It was demonstrated that anergic
B lymphocytes in vivo are short-lived, suggesting that anergy may represent a delayed cell death and that
the distinction between anergy and cell death may not be significant.
T cell-mediated cytotoxicity
Cytotoxic T lymphocytes (CTLs) are the main effectors of the immune system responsible
for eliminating virus-infected cells. The CTLs can both specifically recognize and
lyse their targets. Two molecular mechanisms are known to confer T cell-mediated cytotoxicity
by eventual lysis of target cells: a perforin-granzyme-based mechanism and a Fas-
There seems to be little cross-talk between these two mechanisms because cytotoxic cells from perforin knockout mice
as well as cytotoxic cell lines that do not express perforin can lyse my means of the Fas-pathway, whereas
gld cytotoxic cells and lpr target cells
can lyse or be lysed, respectively, by means of the perforin pathway. No other mechanism of cytotoxicity has been
described thus far (Nagata and Golstein, 1995, Science, 267:1449-56; Kägi et al, 1994, Science, 265: 528-30).
AIDS (see interesting AIDS website)
Clinical History of AIDS
The natural history of
HIV infection can be considered as progress through three
stages of infection. The initial acute infection is associated
with high viraemia levels and infection of CD4+ T cells,
macrophages, lymphoid tissues and other body cells. With the
development of antiviral cellular immune responses and the
development of antibodies to HIV, the levels of virus fall.
The second, asymptomatic stage of infection lasts on average 5
to 8 years, although in some individuals it may last more than
10 years. During this stage continued viral replication is
somewhat balanced by cellular immune responses though
specific anti HIV antibody levels decline during this
period. The third
symptomatic stage is associated with a progressive decline in
CD4+ T cell levels, impaired immune function and an increase
in viral load. Systemic and focal symptoms of HIV infection,
opportunistic infections and neoplasms may occur.
Immunological events during HIV infection
The pathogenesis of human immunodeficiency virus (HIV) infection is complex and multifactorial.
Primary infection with HIV is rapidly followed by dissemination of the virus to the lymphoid organs
where virus replication takes place. Subsequently, an intense cellular and humoral immune response
is generated, initially inhibiting viral replication, but eventually the virus usually escapes
from immune control, leading to the development of AIDS. The targets of HIV infection are CD4 expressing cells,
such as lymphocytes and monocytes. CD4 serves as a receptor for HIV with CXCR4 being a co-receptor
responsible for the efficient entry of so called T-tropic HIV strains into CD4+ T lymphocytes, and
CCR5 being a co-receptor for entry of so called M-tropic HIV strains into CD4+ T lymphocytes and monocytes.
CD4+ T lymphocyte depletion is a hallmark of HIV infection. CD4+ T lymphocytes are the orchestrators
of the immune system. They produce cytokines and thereby help the effectors of the innate immunity, such as
natural killer cells (NK), gamma delta lymphocytes or monocytes in the elimination of virus-infected cells.
In addition, they are essential to the specific activation and maturation of B lymphocytes into antibody-secreting
plasmocytes, and they are required for the differentiation of CD8+ T cells into virus-specific cytotoxic
T lymphocytes (CTL). Finally they are the source of chemokines, which are suppressor factors of HIV replication.
Therefore, the progressive disappearance of CD4+ T lymphocytes during infection with HIV leads to the lack of control
of HIV replication and to the development of the severe immune deficiency responsible for the occurrence
of opportunistic infections associated with AIDS.
Clinical stages of the infection
Stage 1: Primary seroconversion illness
Stage 2:Asymptomatic stage
misdiagnosed, differential includes many other viral
- may be minimally symptomatic
1 to 3 weeks after exposure
rash may occur
settle usually within weeks but can persist for months
stage is associated with very high circulating levels of
infectious virus (viral load) and is extremely infectious
(by usual means of transmission)
with suspected seroconversion illness must be advised
about the risks of transmitting the infection through
unprotected sex or needle/equipment sharing for drug
Stage 3:Symptomatic stage
direct clinical signs of HIV infection
high rate of turnover of virus and virus-infected cells
but low levels of circulating virus
cell function and cell count slowly decline
destruction of the architecture and function of lymphatic
cell count 200 - 500/: L: generally asymptomatic but
subtle signs and symptoms of immune compromise may
appear eg oral candidiasis
cell count < 200/: L: increasing risk of
cell count < 100/: L: increasing risk of major
opportunistic infections, malignancies and HIV-related
including Mycobacterium tuberculosis,and M.
avium complex, Salmonella species
including CMV, HSV, EBV, Varicella zoster
including Candida species, Cryptococcus
neoformans, Aspergillus species
including Pneumocyctis carinii, Toxoplasma
Transmission of AIDS
with high levels of infectious virus in blood and genital
fluids and the nature and duration of contact with these
fluids. The viraemia of HIV tends to be highest with primary
acute infection, drops to low levels during the asymptomatic
stage of infection then rises steadily throughout progression
to disease. During the asymptomatic stage of infection there
may be as few as 5,000 infectious virus particle per ml of blood
compared with hepatitis B in which there may be as many as one
billion infectious virus particles per ml.
There are three dominant
modes of transmission:
and blood products
of blood and blood products prior to 1985:
solvent/detergent and heat treatment of blood products
and improved donor screening have greatly reduced
risks associated with these products
shared during intravenous drug use
- occupational needlestick injury
transmission is the most important mode of
transmission of HIV worldwide
western countries sexual transmission is predominantly through
male to male sexual contact although heterosexual
transmission does occur, and may be slowly
presence of other sexual transmitted infections enhances transmission of HIV
insertive intercourse, the insertive partner is at
lower risk than the receptive partner
intervention, the rate of transmission is between 13
can occur in utero (infectious virus can be found in
cord blood, amniotic fluid and placental tissue) or
of transmission is highest during acute HIV infection
and advanced HIV disease, as both these stages are
associated with a high viral load
can occur postnatally through breast milk
Other body fluids:
virus occasionally detectable at low levels but is not
generally believed to be infective
and tears: low or undetectable levels of infectious virus
and faeces: undetectable levels of infectious virus
milk: significant levels of infectious virus
high levels of infectious virus (but not normally a
Estimated probability of HIV transmission by type of exposure
- Unprotected receptive anal intercourse: risk at 1:125 to 1:30
- Unprotected receptive vaginal intercourse: risk at 1:2000 to 1:650
- Unprotected insertive anal or vaginal intercourse: risk at 1:3300 to 1:1100
- Puncture of health care worker by contaminated needle: risk at 1:300
- Use of contaminated drug injecting equipment: risk at 1:150
Enzyme immunoassay (ELISA) detects anti-HIV antibodies and is useful for screening.
Western Blot (Immunoblot) detects serum antibodies against specific HIV proteins:
Regardless of seroprevalence, EIA and Western Blot together have a
positive predictive value of greater than 99.99% (false positives less than one in 100,000).
proteins (p17, p24, p55)
proteins (p31, p51, p66)
proteins (gp41, gp120/160)
Treatment of AIDS by drugs
Drugs used in HIV treatment
A considerable improvement in the treatment of AIDS was the introduction of
the so called Highly Active Anti-Retroviral Therapy (HAART).
HAART is composed of multiple anti-HIV drugs, that is prescribed to HIV-positive people, even before they develop symptoms of AIDS.
The therapy usually includes one nucleoside analog (DNA chain terminator),
one protease inhibitor and either a second nucleoside analog or a non-nucleoside reverse
transcription inhibitor (NNRTI).
- Nucleoside Reverse Transcriptase Inhibitors (NRTIs):
Zidovudine (AZT), Didanosine (ddI), Zalcitabine (ddC), Stavudine (d4T), Lamivudine (3TC),
Abacavir, AZT & 3TC: Combivir
- Non Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):
Nevirapine, Delavirdine, Efavirenz
- Protease Inhibitors (PIs):
Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir
- Non Nucleoside Reductase Inhibitors:
Infection of CD4+ T cell cultures with HIV is associated with a cytopathic effect of the virus,
manifested by ballooning of cells and formation of syncytia leading to cell death by apoptosis of both infected
and non-infected cells.
CD4+ T cell destruction can be mediated directly by HIV replication as a consequence of viral gene expression,
such as gp120-gp41, or indirectly through priming of uninfected cells to apoptosis.
Expression of the viral envelope gp120-gp41 complex in infected
cells mediates onset of apoptosis of both infected and non-infected cells. Thus chronically HIV-infected cells can
serve as effector cells to induce apoptosis in uninfected target CD4+ T cells.
Peripheral T lymphocytes from HIV-infected subjects are prematurely primed for apoptosis, this means that those cells
are obviously more sensitive to the induction of apoptosis in response to various stimuli than T lymphocytes
from uninfected controls. Interestingly, not only T cells of the CD4 subset but also of the CD8 subset
are primed for apoptosis. It also was observed that not only T cells but all blood mononuclear cells,
including B cells, T cells, NK cells, granulocytes and monocytes, show increased sensitivity to apoptosis.
The central paradox of HIV pathogenesis is that the viral burden, either free or cellular, seems too low to deplete
the CD4+ population by direct killing. The observation that an important fraction of T cells are prematurely primed
for apoptosis in HIV-infected subjects prompted the hypothesis that some indirect mechanisms are responsible for
inappropriate cell death and significantly contribute to CD4+ T cell depletion as well as to CD8+ destruction in
AIDS. Indeed, it has been observed that apoptotic T cells in lymph nodes of HIV-infected individuals contained many
apoptotic but uninfected bystander cells whereas infected cells were not found to be apoptotic.
See review by Gougeon in "Apoptosis and its Modulation by Drugs", Springer, 2000.