Development of immunity to malaria may not be an entirely active process

Summary It has never been explained why it takes so long for humans to develop immunity to malaria, although factors such as antigenic variation, antigenic polymorphism, and poor immunological responses to critical antigens are thought to be important. Models of malaria, particularly in rodents, have not been helpful. The course of malaria infection differs considerably between humans and rodents. Mice rapidly develop immunity whereas for most humans it takes several years of exposure for this to occur. Mice typically exhibit high parasitaemias whereas humans typically do not. A significant difference in the immune response of humans and mice to malaria parasites might, in part, explain these differences. Most humans have a preexisting population of activated malaria parasite‐specific T cells (cross‐reactive T cells) which we have referred to as ‘natural’ T cells, but such cells have not been observed in mice. These cells, many of which secrete interferon‐γ), might control parasitaemia early in the infection, but a by‐product of their further activation by malaria parasites might be disease symptoms. Development of immunity has been thought of as an active process–acquisition of specific antibody and effector T cell responses. However, it might in part reflect induction of tolerance of this preexisting population of disease‐inducing Tcells as a result of chronic parasitaemia. The initial presence of these Th1‐like cells may also impede the development of a Th2‐like response necessary for the production of protective antibodies. Persistent cross‐reactive stimulation may significantly impede this process.