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Published online before print September 27, 2006
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,2
* Institute for Clinical Immunology, Department of Internal Medicine 3,
Department of Experimental Medicine I and
IZKF Research Group 2, Nikolaus Fiebiger Centre of Molecular Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany;
Franz von Prümmer Klinik, Akutklinik für Rheumatologie und Allgemeinkrankenhaus, Bad Brückenau, Germany; and
¶ Chemotherapeutisches Forschungsinstitut Georg Speyer Haus, Frankfurt, Germany
2Correspondence: Institute for Clinical Immunology, Friedrich-Alexander-University of Erlangen-Nuremberg, Glueckstrasse 4a, 91054 Erlangen, Germany. E-mail: udo.gaipl{at}med3.imed.uni-erlangen.de
ABSTRACT
Apoptotic and necrotic cells expose phosphatidylserine (PS). This membrane modification ensures a swift recognition and uptake by phagocytes of the dying and dead cells. Annexin V (AxV) preferentially binds to anionic phospholipids and thereby, modulates the clearance process. First, we analyzed the influence of AxV on the immunogenicity of apoptotic cells. The addition to apoptotic cells of AxV prior to their injection into mice increased their immunogenicity significantly. Next, we studied the influence of endogenous AxV on the allogeneic reaction against apoptotic and necrotic cells. To preserve heat-labile, short-lived "danger signals," we induced necrosis by mechanical stress. Wild-type mice showed a strong, allogeneic delayed-type hypersensitivity (DTH) reaction. In contrast, AxV-deficient animals showed almost no allogeneic DTH reaction, indicating that endogenous AxV increases the immune response against dead cells. Furthermore, AxV-deficient macrophages had a higher immunosuppressive potential in vitro. Next, we analyzed the influence of AxV on chronic macrophage infection with HIV-1, known to expose PS on its surface. The infectivity in human macrophages of HIV-1 was reduced significantly in the presence of AxV. Finally, we show that AxV also blocked the in vitro uptake by macrophages of primary necrotic cells. Similar to apoptotic cells, necrotic cells generated by heat treatment displayed an anti-inflammatory activity. In contrast, mechanical stress-induced necrotic cells led to a decreased secretion of IL-10, indicating a more inflammatory potent-ial. From the experiments presented above, we conclude that AxV influences the clearance of several PS-exposing particles such as viruses, dying, and dead cells.
Key Words: immunogenicity • apoptotic cells • necrotic cells • clearance • macrophages • annexin
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