Apoptosis and the Immune System


In preparation.


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- based mechanism. 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).


(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 Stage 3:Symptomatic stage

Transmission of AIDS
Transmission correlates 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:

Other body fluids:

Estimated probability of HIV transmission by type of exposure
AIDS tests
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).
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).

AIDS and Apoptosis

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.