Molecular basis for evasion of host immunity and pathogenesis in malaria.

The article relates the ability of the malaria parasite Plasmodium falciparum to avoid a protective immune response, and to induce pathological changes, to the properties of specific parasite molecules. Cytoadherence and rosetting are important features of cerebral malaria and involve proteins located on the surface of the infected red blood cell. Proinflammatory cytokines, particularly tumour necrosis factor (TNF), play a role in protective immunity and in inducing pathology. Glycophosphatidyl inositol membrane anchors of parasite proteins possess insulin like activity and induce TNF synthesis. People subject to repeated infections in malaria endemic areas rarely develop complete or sterile immunity to malaria. They frequently carry small numbers of parasites in the blood, with little symptoms of the disease, illustrating a phenomenon termed semi-immunity. The basis for semi-immunity is incompletely understood. Malaria parasites are susceptible to several immunological effector mechanisms. The presence of extensive repetitive regions is a feature of many P. falciparum proteins. Available evidence suggests that the structural characteristics of the repeats and their location on the surface of parasite proteins promote immunogenicity. The repeats may help the parasite evade host immunity by (i) exhibiting sequence polymorphism, (ii) preventing the normal affinity and isotype maturation of an immune response, (iii) functioning possibly as B cell superantigens, (iv) generating predominantly thymus independent antibody responses, and (v) acting as a sink for binding protective antibodies. Sequence diversity in non-repetitive regions and antigenic variation in parasite molecules located on the surface of infected red blood cells also play a role in immune evasion. Some sequence homologies between parasite and human proteins may be due to molecular mimicry. Homologies in other instances can cause autoimmune responses. The immune evasion mechanisms of the parasite need to be considered in developing vaccines. Protective immunity and pathology may be delicately balanced in malaria.