Cerebral malaria and immunogenetics

Cerebral malar ia depends largely on. the capacity of Plasmodium falciparum infected red blood cells to adhere to the endothelia of microvessels, leading to their occlusion. The most important players include receptors expressed on the surface of the endothelial cell and known to interact with the parasite, cytokines modulating the expression of these adhesion molecules and nitric oxide (NO). Platelets, monocytes and lymphocytes have the ability to adhere to these endothelial receptors and to one another; leading to a more complex situation and an increase in the degree of vessel occlusion. The polymorphism of all these molecules, implicated either in adhesion, in modulation of this adhesion or activation of the expression of diverse endothelial mediators should be art important field of study. Polymorphism of five of these molecules has been explored so far: ICAM-1, TNF-alpha, IL-1-beta, inducible NOS and complement receptor-1 (CR-1). To these studies can be added those concerning mannose binding protein (MBP), a protein playing a role in innate immunity, and the class-I antigen HLA-B53. To date, the only clear cut result concerns TNF-alpha. With the other polymorphisms, either no association is found (IL-IRA, CR-I, MBP), or the results are geographically heterogeneous (ICAM-1, HLA-B53), or contradictory (iNOS2). Most often the candidate gene approach has been followed, as part of case control studies. One of the main problems in this approach is the difficulty of establishing the control cohort. This difficulty disappears in family studies, which include their own controls. So far, the only results based on complex segregation analysis have been focused on parasite multiplication and not on cerebral malaria.