No abstract

Background: Severe anemia due to Plasmodium falciparum malaria is a major cause of mortality among young children in western Kenya. The factors that lead to the age-specific incidence of this anemia are unknown. Previous studies have shown an age-related expression of red cell complement regulatory proteins, which protect erythrocytes from autologous complement attack and destruction. Our primary objective was to determine whether in a malaria-endemic area red cells with low levels of complement regulatory proteins are at increased risk for complement (C3b) deposition in vivo. Secondarily, we studied the relationship between red cell complement regulatory protein levels and hemoglobin levels.

Aims: Erythrocyte complement regulatory proteins, complement receptor 1 (CR1) and decay accelerating factor (CD55) protect red blood cells (RBCs) from complement mediated damage by controlling complement activation cascade and potentially protect RBCs from complement mediated damage that may occur when immune complexes are

SummaryGiven the ability of erythrocytes to bind immune complexes (ICs), we postulated that they can serve a dual role during inflammatory or infectious processes. Erythrocytes could restrict stimulation of macrophages by free ICs by binding C3b-opsonized ICs via their complement receptor 1 (CR1). Conversely, IC-loaded erythrocytes could stimulate macrophages to produce proinflammatory cytokines such as tumour necrosis factor (TNF)-a. To test our hypothesis we selected 72 individuals with low, medium or high red cell CR1 expression and determined their IC binding capacity. We tested the in vitro ability of red cells to inhibit IC-mediated stimulation of TNF-a production by macrophages or to stimulate TNF-a production when loaded with ICs. Plain erythrocytes inhibited IC-induced TNF-a production by macrophages and low CR1 expressors showed the lowest inhibitory capacity. IC-loaded erythrocytes stimulated macrophages to release TNF-a, but the effect was not proportional to the CR1 level. These data support our hypothesis that erythrocytes can serve a dual role in regulation of cytokine responses in a setting of IC formation. Our findings suggest that individuals with low CR1 expression are ill-equipped to clear ICs and prevent IC-mediated stimulation of macrophages. In addition, IC-loaded red cells in areas of sluggish circulation such as in the spleen or in brain capillaries blocked by sequestered malariainfected red cells may induce inflammation by stimulating monocytes and macrophages, the latter leading to the development of cerebral malaria.