Does the mechanism of protection from falciparum malaria by red cell genetic disorders involve a switch to a balanced T(H)1/T(H)2 cytokine production mode?

The mechanism of protection from falciparum malaria by red cell genetic disorders still remains controversial. Decreased survival of parasites in variant red cells has previously been proposed. However, in vitro experiments were not conclusive and do not seem sufficient to explain the substantial degree of in vivo protection afforded to red cell genetic trait carriers. Evidence has recently been accumulating in favour of enhancement of the host immune response by these genetic traits. Malaria-infected variant red cells undergo modifications to their antigenicity which lead to accelerated and selective removal of early blood-stage parasites by splenic macrophages, resulting in fewer parasites reaching schizogony. Consequently there will be alterations in antigen processing, presentation and recognition which could explain the differences observed in T-cell responses between trait carriers and normal individuals. It is suggested that exposure to a lower dose of early parasite-stage antigens rather than the exoantigens of late mature schizonts could lead during primary and subsequent secondary infections to differentiation of T-helper cells into balanced T(H)1/T(H)2 subsets that promote protection, reversing the susceptibility to the fatal complications of falciparum malaria.