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Comprehensive PS Review Published
Review Cites Over 100 Recent Studies Validating:

PS is Immunosuppressive

PS is Utilized by Tumors, Viruses, and Protozoan Parasites to Evade Immune Response

Targeting Exposed PS can have Broad Beneficial Therapeutic Results

Phospholipids: Key Players in Apoptosis and Immune Regulation

Ricardo A. Chaurio 1, Christina Janko 1, Luis E. Muñoz 1, Benjamin Frey 2, Martin Herrmann 1,# and Udo S. Gaipl 2,#,*
Department for Internal Medicine 3, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, 91054 Erlangen, Germany

Published in:Molecules 2009, 14, 4892-4914; doi:10.3390/molecules14124892
link to full text: http://www.mdpi.com/1420-3049/14/12/4892/pdf
excerpts:

Taken together, PS seems to be the major “eat me” signal and immune suppressor in the clearance process of apoptotic cells.

Since millions of cells die constantly in multicellular organisms and since there is a robust system for their rapid recognition and removal, the “silent clearance” of the apoptotic cells is thought to participate in some conditions associated with an impaired cell-mediated immunity and increased apoptosis. Cancer, exposure to radiation, and some parasite and viral infections are considered to take advantage of this ubiquitous mechanism. Apoptotic promastigotes from Leishmania parasites induce release of TGF-ß by neutrophils, suggesting that the presence of apoptotic parasites provides survival advantage for the viable parasites fostering disease development.
5.1. Annexin A5 in cancer therapy

Normally, apoptotic cells are poorly immunogenic. This property can be used by tumour cells to escape from the immune system creating a local immunosuppressive milieu defined by IL-10, TGF-ß, soluble FAS and FAS-ligand, as well as soluble PS [15]. Blocking the clearance of apoptotic tumour cells by exogenous AnxA5 may open a new strategy for developing tumour vaccines. We found that the disruption of the clearance of apoptotic tumour cells by AnxA5 may trigger a pro-inflammatory response contributing to a specific immune reaction against tumor cells. Incubation of apoptotic cells with AnxA5 prior to immunisation significantly increased the immunogenicity of the cells undergoing apoptosis [134]. Interestingly, AnxA5 decreased apoptotic cell uptake by peritoneal macrophages and increased their uptake by dendritic cells [133,135].

These data suggest that AnxA5 influences the phagocytosis of dying cells and modulates the immunological response against both allogeneic and syngeneic cells. This mechanism may be employed for future cancer therapies aiming to induce a specific immune reaction, a reduced tumour- load, and a long-lasting anti-tumour immunity by combining standard therapies with the application of exogenous AnxA5.

5.2. Annexin A5 in infections

It has been shown that many viruses can induce both apoptosis and PS exposure in the infected cells. PS can also be found in the outer membrane of enveloped retrovirus [136]. We studied the influence of AnxA5 on chronic macrophage infection with HIV-1, known to expose PS on its surface. We found that infectivity in human macrophages of HIV-1 was significantly reduced in the presence of AnxA5 [131]. Zandbergen and colleagues explored the role of PS during Leishmania disease and discovered that virulent inoculums of Leishmania promastigotes contained a high ratio of PS exposing apoptotic parasites. However, after apoptotic parasites depletion from the virulent inoculum, Leishmania did not survive in phagocytes in vitro losing their disease inductor capacity in vivo [107]. In summary, AnxA5-based therapy strategies may be also useful to improve immune reactions against various infectious agents which use the PS exposure as a tool to improve their survival by fooling the immune system as well as against apoptotic cancer cells (Figure 4).


Figure 4. Annexin A5 as modulator of immune responses. Apoptotic cells expose PS leading to an efficient clearance by macrophages. The interaction of apoptotic cells with macrophages can be blocked by AnxA5, a specific ligand for PS. Therefore, AnxA5-based therapy strategies result in the accumulation of secondary necrotic cells. Under those circumstances, dendritic cells get the chance to take up dead-cell derived antigens, and are co-stimulated by danger signals released from secondary necrotic cells. The presented antigens lead to activation of T cells, which provide survival signals for B cells leading to a specific immune reaction against apoptotic cell-derived antigens. This strategy is useful to improve immune reactions against cancer cells (A) as well infectious agents like PS exposing virus (B) and Leishmania parasites (C), which use PS exposure as a tool to improve their survival by fooling the immune system.
























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