Antigen-induced cell death

Programmed cell death plays an important role during lymphocyte development, by eliminating autoreactive cells, as well as in the effector phase of the immune response, when antigen induced cell death halt cell activation. Several groups have been studied the function of PTEN in the immune response. PTEN heterozygous (PTEN+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/-mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. PI3-K inhibitors restored Fas responsiveness in PTEN+/- cells. These results indicate that PTEN is an essential mediator of the Fas response and a repressor of autoimmunity, thus implicate the P13-Kinase/Akt pathway in Fas-mediated apoptosis (DiCristofano et al, 1999)... 

The anthrax toxin is a tripartite toxin and consists ofthe binding component protective antigen (PA), the lethal factor (LF), which is a metalloprotease, and the edema factor (EF), which is a calmodulin-dependent adenylyl-cyclase. Both enzyme components are translocated via PA into target cells. PA is activated by furin-induced cleavage and forms heptamers, which are similar to the binding components of C2 toxin and iota toxin. In the low pH compartment of endosomes, the heptamers form pores to allow translocation of LF and EF. LF cleaves six of the seven MEKs (MAPK-kinases) thereby inhibiting these enzymes. The functional consequence is the blockade of the MAPK pathways that control cell proliferation, differentiation, inflammation, stress response, and survival. Whether this is the reason for the LT-induced cell death of macrophages is not clear [1]. 

Figure 22.2 Cellular activation by CpG DNA. CpG DNA directly activates dendritic cells (DCs), monocytes and macrophages, to express increased levels of co-stimu-latory molecules, to increase antigen presentation, and to secrete high levels of chemokines and cytokines, such as interleukin 12 (IL-12), interferon-a(IFN-a), and tumor necrosis factor-a (TNF-a), and monocytes and macro-phages have increased antibody-dependent cellular cytotoxicity (ADCC) activity. NK cells are induced to express IFN-7 by these cytokines acting in concert with CpG, and have increased lytic activity. B cells rapidly produce IL-b and IL-10 and express increased levels of costimulatory molecules. B cells rapidly enter the cell cycle and become resistant to some forms of activation-induced cell death. T cells are not directly activated by CpG, but because of the T helper 1 (Thl)-like cytokine environment, and the increased antigen presenting cell (APC) activity, antigen-specific Thl cells and cytotoxic T lymphocytes (CTL) are generated.

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Another effector function/mode of action of mAbs is the so-called complement-dependent cytotoxicity or complement-mediated cell death . Activation of the complement system can lead to lysis of the antigen-presenting cell, or can induce inflammation reactions aimed at eliminating these cells efficiently. The successive steps of the complement activation can be summarized in a simplified way [9] ... 

Shokat, K. M., and Goodnow, C. C., Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 375, 334-338 (1995). 

Renschler MF, Bhatt RR, Dower WJ, Levy R, Synthetic peptide ligands of the antigen binding receptor induce programmed cell death in a human B cell lynphoma, Proc. Natl. Acad. Sci. USA, 91 3623-3267, 1994. 

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