[Immunogenetics and cerebral malaria]

Since the identification, in 1954, of the first gene associated with resistance to Plasmodium falciparum, several genes, some of them being implicated in the regulation of the immune response, have been described as possible influences on cerebral pathology. This pathology depends primarily on the capacity of infected red blood cells to adhere to the endothelia of micro-vessels, leading to their occlusion. The major players of cerebral malaria potentially include: receptors expressed on the surface of the endothelial cell and known to interact with infected red blood cells, cytokines modulating the expression of these adhesion molecules, nitric oxide (NO) and Fc epsilon RII/CD23. Cells other than infected red blood cells, such as platelets, monocytes and lymphocytes, have the ability to adhere to these endothelial receptors and to one another, via different ligands, 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 an important field of study. Polymorphism of five of these molecules has been explored so far: ICAM-1, TNF-alpha, IL-1 beta, iNOS2 (inducible NOS) and CR-1 (complement receptor-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-1RA, CR-1, MBP), or results are geographically heterogeneous (ICAM-1, HLA-B53), or contradictory (iNOS2). Most often, the approach followed has been the candidate gene approach, 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.