Attempting to identify epitopes targeted by inhibitory antibodies, we compared differences in rabbit and rat antibody reactivity to linear peptides covering the entire DBL4e domain. We previously did this with DBL4e-FCR3, DBL4e-3D7, DBL1X-3D7 and DBL3X-HB3 specific sera from rats [17] . The average reactivity to DBL4e linear epitopes was apparently slightly skewed when comparing rat and rabbit antibodies. Otherwise, the majority of responses in rats and rabbits were surprisingly similar. This similarity, combined with the lack of functional activity of the rabbit antibodies, both with regard to surface activity and inhibitory capacity, probably shows that surface-reactive and binding-inhibitory rat antibodies are not targeting linear epitopes in the native protein. The most pronounced areas of reactivity against the linear sequence were mapped to regions in the DBL4e model containing unstructured loops. This is in line with the findings that patches of high sequence diversity in VAR2CSA are concentrated in flexible loops [20, 31, 32] and that naturally acquired antibodies also are directed against these regions [33] . However, partly denatured antigen induced by Freund's adjuvant could increase the response to flexible loop regions in experimental immunizations [34] . Interestingly, a fraction of the expressed PfEMP1 during the maturation of the parasite in the IE remains intracellular [35] . Whether this intracellular pool of protein is denatured at the point of schizont rupture, promoting responses in natural infections to flexible loops more tolerant to mutations, as seen in other organisms [36] , remains to be investigated.