Erythrocytes (RBCs) opsonized by
IgG and
complement are prevalently recognized and phagocytosed by
complement receptor CR1. This mechanism, effective in senescent and damaged RBCs seems to be operative in ring-parasitized RBCs, since
infection by Plasmodium falciparum induces stage-dependent binding of auto-
antibodies and activated C3 to the RBC membrane. Later, parasite forms are also recognized by non-opsonic receptors, such as
scavenger receptor CD36.
Malaria parasites induce the oxidative formation of hemichromes which are the trigger for the auto-
antigen development.
Band 3 protein is the most plausible candidate of the RBC auto-
antigen, induced by hemichromes. Auto-
antigens isolated from trophozoites were found only in a high-molecular-weight
protein aggregates not present in the normal RBC. The immunocomplex was purified by
protein-A affinity chromatography, purified
proteins digested by
trypsin and analyzed by MALDI-TOF.
Peptide mapping showed that the main
antigen consisted of
band 3 protein aggregates that also contained hemichromes, IgGs,
complement factor 3 (C3), and traces of
spectrin and
glycophorin but no parasite
proteins. Two cysteines located in the band 3 cytoplasmic domain were found to be particularly reactive to
oxidants and mediated band 3 covalent dimerization via
disulfide bonds. Thus, parasites promote oxidative alterations in the membrane of the host which lead to exposure of antigenic sites recognized by anti-band 3 auto-
antibodies. Formation of band 3 clusters appears to be mediated by cytoplasmic binding of hemichromes and also by direct band 3 oxidation, whereby clustered, oxidized and antigenic band 3 was underglycosylated.