Multiple cross-reactivities amongst antigens of Plasmodium falciparum impair the development of protective immunity against malaria

The majority of protein antigens of the malaria parasite Plasmodium falciparum contain short sequences that are extensively repeated in tandem arrays. Some antigens contain a single block of repeats whereas in other antigens there may be two or more blocks of related repeats. The repetitive sequences in an individual antigen may be highly conserved but more usually there is some degeneracy which occasionally is extensive. The repetitive sequences encode immunodominant epitopes to which much of the antibody response in malaria is directed. Recently, we have found that there are extensive cross-reactions amongst the epitopes encoded by related repetitive sequences. These cross-reactions may involve different blocks of repeats in the one antigen or repetitive sequences in different antigens. It is proposed that these cross-reactions interfere with the normal maturation of a high affinity antibody response in malaria by causing an abnormally high proportion of somatically-mutated B cells to be preserved during clonal expansion.