The Role of Annexin A5 in the Modulation of the Immune Response Against Dying and Dead Cells

Abstract

Annexins are characterized by the ability to bind phospholipids of membranes in the presence of Ca2+. Annexin A5 represents a typical member of this protein family and is a natural occurring highly specific ligand for phosphatidylserine (PS). The exposure of PS is one major "eat me" signal for phagocytes of apoptotic and necrotic cells. Apoptotic cells are normally cleared via an anti-inflammatory pathway. In contrast, the uptake and removal of necrotic cells normally involves inflammation and an immune response. Interestingly, the lack of endogenous annexin A5 also leads to a reduced inflammatory potential of necrotic cells. Annexin A5 may interfere in vivo with the immunosuppressive effects of apoptotic cells since it preferentially binds PS with high affinity and inhibits apoptotic cell uptake by macrophages. In this review we focus on how defects in the clearance process can lead to chronic autoimmunity. Furthermore, the role of annexin A5 as important adjuvant for apoptotic cell-based tumour vaccines is discussed. The mechanism of how the immunogenicity of apoptotic cells can be restored by blocking their PS-dependent clearance is outlined in detail. Taken together, annexin A5 is an important modulator of the immune response against PS-exposing particles like apoptotic cells, necrotic cells, and certain viruses.

In vivo imaging of apoptosis

“…40 The function(s) of annexin V despite its widespread intracellular distribution are still unknown but a variety of in vitro and in vivo properties have been described. [41][42][43][44] The first clinical imaging studies of therapy induced tumor apoptosis were conducted using human rh-annexin V labeled with 99m Tc-pertechnetate by the penthioate radioligand (N 2 S 2 ) method. 45 This method begins with the chelation of 99m Tc in the presence of stannous gluconate to yield 99m Tc-gluconate which is then reacted with acidified phenthioate ligand under heating to form a stable 99m Tc-N 2 S 2 complex.…”

Collectins, C3 complement protein, annexin V and C-reactive protein in acute ischemic stroke: interrelation and implication to upregulated apoptosis and inflammation

“…This protein is expressed by many types of cells and is an in vivo marker of cellular injury and death. cANXV can be released from smooth muscle cells and endothelial cells of the vascular wall, hepatic and splenic secretory cells or from apoptotic particles derived from injured tissues, lymphocytes, monocytes, etc [56,57] . High blood levels of cANXV indicate high rate of apoptosis and the severity of cell damage [56,57] .…”

“…cANXV can be released from smooth muscle cells and endothelial cells of the vascular wall, hepatic and splenic secretory cells or from apoptotic particles derived from injured tissues, lymphocytes, monocytes, etc [56,57] . High blood levels of cANXV indicate high rate of apoptosis and the severity of cell damage [56,57] . Therefore, the present study demonstrating elevated levels of cANXV in the blood of IS-affected individuals provide additional evidence on increased rate of apoptosis after IS on a systemic level.…”

Imaging the Molecular Signatures of Apoptosis and Injury with Radiolabeled Annexin V

“…The binding to membrane-bound PS is quite complex (beyond the scope of this article), and may involve the binding of eight PS molecules per molecule annexin V at low levels of membrane occupancy (with respect to protein) (11). The function(s) of annexin V, despite its widespread intracellular distribution are still unknown but a variety of in vitro and in vivo properties have been described (12,13).…”