Attenuating a sickle cell crisis with annexin V.

A sickle cell crisis is a painful and dangerous condition that defies effective treatment but fortunately it usually terminates spontaneously and patients spend far more time crisis free than in its painful throes. This suggests that an unstable physiologic balance exists between steady state sickle cell disease (SCD) and the crisis state and if this is so a therapeutic nudge during a crisis may help to terminate it. Annexin V may be able to provide this push. The phosphatidylserine (PS) molecules normally appear on the surface of senescent erythrocytes where they are recognized by macrophages and rapidly removed so that normally only about 1% are present in the circulation but in SCD 30-40% are prematurely senescent and their removal is delayed. The PS+ sickle erythrocytes remaining in the circulation adhere to the endothelium and their exposed PS acts as a platform for the initiation of the coagulation cascade that is responsible for clot propagation. Annexin V's great affinity for PS allows it to bond to it forming a shield that blocks both of these actions suggesting that its therapeutic administration during a sickle crisis may be able to hasten its termination.

An autologous falciparum vaccine using the erythrocyte's band 3 molecule.

Protection against the serious complications of falciparum malaria is provided to people with the minor forms of hematological conditions such as sickle cell disease and thalassemia and as a result natural selection has increased their incidence in malaria endemic areas. The explanation for this has thus far not been determined but experimental evidence that is now available suggest an explanation that also has therapeutic implications. The hypothesis presented suggests that the erythrocytes of these blood disorders experience premature senescence and are then eliminated by the same process that normally disposes of senescent erythrocytes. Erythrocytes express approximately one million widely dispersed band 3 molecules on their surface but when these erythrocytes age they form band 3 clusters that are recognized by the immune system which results in their elimination. In addition to senescent erythrocytes, both sickle and falciparum infected erythrocytes also display these clusters suggesting that band 3 antibodies contribute to their erythrocytes removal. Supporting band 3's involvement in falciparum erythrocyte elimination are the facts that band 3 specific antibodies are elevated in falciparum endemic areas and the documentation that the falciparum erythrocytes displaying these clusters are rapidly phagocytized. Both sickle and falciparum infected erythrocytes adhere to endothelium and band 3 antibodies and adhesive band 3 peptides block this adhesion. This proves that the band 3 molecule is responsible for at least some of the endothelial adhesion and implies that band 3 antibodies are active in eliminating falciparum infected erythrocytes. It is proposed that the band 3 peptides could be used to develop a vaccine to reduce the lethality of falciparum infections. A conjugate vaccine using these peptides in early infancy may allow those infants to survive a falciparum infection and develop comprehensive natural immunity to the local endemic parasite.

Modulation of sickle cell crisis by naturally occurring band 3 specific antibodies -- a malaria link.

This paper's focus is prevention of sickle cell adhesion resulting from the erythrocyte's prematurely denatured hemoglobin. This denatured hemoglobin causes a molecule called band 3 to cluster on the erythrocyte's surface and adhere to the CD36 molecule located on the microvascular endothelium. Natural antibodies recognize these clusters on senescent erythrocytes and prevent their endothelial adhesion and target them for reticuloendothelial elimination. Band 3 is also displayed on the erythrocytes of individuals with falciparum malaria and the vaso-occlusive pathology in these patients is prevented in individuals with sickle trait. The hypothesis is that prematurely denatured sickle hemoglobin results in an up regulation of natural antibodies which control erythrocyte adhesion in both malaria and sickle cell disease.