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MULTICENTRE
STUDIES
THE ROLE OF
ANNEXIN V IN THE MODULATION OF THE IMMUNE RESPONSE
COORDINATORS
Udo S.Gaipl1,
PhD, Martin Herrmann1, PhD MD, Ernst Poschl2, PhD,
Friederike Pausch2, Ahmed Sheriff1, PhD, and Joachim R.
Kalden1, MD
1Institute
for Clinical Immunology, Department of Internal Medicine 3,
Friedrich-Alexander-University of Erlangen-Nuremberg, Glückstrasse 4a, D-91054
Erlangen
2Department of Experimental Medicine I, Nikolaus
Fiebiger Centre of Molecular Medicine, Friedrich-Alexander-University of
Erlangen-Nuremberg, Glückstrasse 6, D-91054 Erlangen
PROJECT
Apoptosis is defined as programmed cell
death or cellular suicide, whereas necrosis arises due to a violent external
stimulus. A hallmark of apoptotic cells, in contrast to necrotic one, is that
they maintain their membrane integrity over time. Thus, the release of
intracellular components that could damage the surrounding tissue, induce
inflammation, or elicit immune responses is prevented. To ensure immediate
recognition and uptake by phagocytes apoptotic cells undergo very early
membrane modifications. One such event is the exposure of phosphatidylserine
(PS) in the outer leaflet of the plasma membrane associated with loss of phospholipid
asymmetry. The recognition of exposed PS triggers the release of
immunosuppressive cytokines, which quench inflammation and prevent the
maturation of antigen presenting DC.
AnnexinV (AxV)
represents a typical member of the annexin family, characterized by the ability
to bind to phospholipids of membranes in the presence of Ca2+. AxV is a natural
occurring highly specific ligand for PS and may interfere in vivo with the
immunosuppressive effects of apoptotic cells.
We
analyzed whether apoptotic cell immunogenicity could be restored by blocking
their PS-dependent clearance. Treatment with
AxV decreased apoptotic cell uptake by peritoneal macrophages and concomitantly
increased apoptotic cell uptake by CD8+/11c+ DC. Vaccination with AxV treated
irradiated tumor cells augmented tumor rejection. We suggest that the impaired
clearance of the dying tumor cells leads to an efficient immune response [1] and conclude that AxV heightens the immunogenicity of apoptotic/primary
necrotic tumour cells in vivo. It was also reported that binding of antibodies
against the phospholipids ligand β2-GPI increases the immunogenicity of
apoptotic cells [2].
Defects in the clearance
process of dying cells have been shown to play a crucial role in the
development of autoimmune diseases. We described for the first time the
accumulation of cellular debris in germinal centers of the lymph nodes in
humans with SLE [3]. Not properly cleared apoptotic cells lose their membrane integrity,
release danger signals, and give access to intracellular autoantigens. A
pro-inflammatory milieu is generated, which ultimately may lead to a chronic
autoimmune response [4-6].
The antiphospholipid syndrome (APS) is an
autoimmune disorder in which vascular thrombosis and/or recurrent pregnancy
losses occur in patients accompanied by thrombocytopaenia and elevated titres
of antiphospholipid antibodies (aPLs). The interference of aPLs with AxA5 (AxA5
is the new name for AxV) function either by competition of those antibodies for
the phospholipid surface or by direct autoantibody-mediated recognition of the
protein itself are being investigated as potential mechanisms for thrombosis in
APS [7].
An AxA5-deficient mouse mutant [8] was established by E. Poschl and colleagues. This enables us to
analyse the physiological function of this protein in the removal of apoptotic
and necrotic cells, in the induction of an immune response, and in the specific
modulation of immunological reactions. Data from wild type and AxA5-deficient mice which were
immunized with apoptotic or necrotic cells will be shown.
References:
1. Bondanza A, Zimmermann VS,
Rovere-Querini P, Turnay J, Dumitriu IE, Stach CM, et al. Inhibition of phosphatidylserine recognition heightens the
immunogenicity of irradiated lymphoma cells in vivo. J Exp Med 2004;200(9):1157-65. Epub 2004 Oct 25.
2. Rovere P, Manfredi AA,
Vallinoto C, Zimmermann VS, Fascio U, Balestrieri G, et al. Dendritic cells preferentially internalize apoptotic cells opsonized
by anti-beta2-glycoprotein I antibodies. J Autoimmun
1998;11(5):403-11.
3. Baumann I, Kolowos W, Voll
RE, Manger B, Gaipl U, Neuhuber WL, et al. Impaired
uptake of apoptotic cells into tingible body macrophages in germinal centers of
patients with systemic lupus erythematosus. Arthritis Rheum 2002;46(1):191-201.
4. Gaipl US, Franz S, Voll RE, Sheriff A, Kalden JR, Herrmann
M. Defects in the disposal of dying cells lead to autoimmunity. Curr Rheumatol
Rep 2004;6(6):401-7.
5. Gaipl US, Beyer TD, Baumann I, Voll RE, Stach CM, Heyder P,
et al. Exposure of anionic phospholipids serves as anti-inflammatory and
immunosuppressive signal--implications for antiphospholipid syndrome and
systemic lupus erythematosus. Immunobiology 2003;207(1):73-81.
6. Gaipl US, Brunner J, Beyer TD, Voll RE, Kalden JR, Herrmann
M. Disposal of dying cells: a balancing act between infection and autoimmunity.
Arthritis Rheum 2003;48(1):6-11.
7. Rand JH, Wu XX. Antibody-mediated interference with annexins
in the antiphospholipid syndrome. Thromb Res
2004;114(5-6):383-9.
8. Brachvogel B, Dikschas J,
Moch H, Welzel H, von der Mark K, Hofmann C, et al. Annexin
A5 is not essential for skeletal development. Mol Cell Biol 2003;23(8):2907-13.
For additional
information and applications, please e-mail: udo.galpl@med3.imed.uni-erlangen.de
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Last updated: 17 November 2005 |
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