Malaria Inhibits Surface Expression of Complement Receptor 1 in Monocytes/Macrophages, Causing Decreased Immune Complex Internalization

Abstract

Complement receptor 1 (CR1) expressed on the surface of phagocytic cells binds complement-bound IC playing an important role in the clearance of circulating immunecomplexes (IC). This receptor is critical to prevent accumulation of IC, which can contribute to inflammatory pathology. Accumulation of circulating IC is frequently observed during malaria, although the factors contributing to this accumulation are not clearly understood. We have observed that the surface expression of CR1 on monocyte/macrophages and B cells is strongly reduced in mice infected with Plasmodium yoelii, a rodent malaria model. Monocyte/macrophages from these infected mice present a specific inhibition of complement-mediated internalization of IC caused by the decreased CR1 expression. Accordingly, mice show accumulation of circulating IC and deposition of IC in the kidneys that inversely correlates with the decrease in CR1 surface expression. Our results indicate that malaria induces a significant decrease on surface CR1 expression in the monocyte/macrophage population that results in deficient internalization of IC by monocyte/macrophages. To determine whether this phenomenon is found in human malaria patients, we have analyzed 92 patients infected with either P. falciparum (22) or P. vivax (70), the most prevalent human malaria parasites. The levels of surface CR1 on peripheral monocyte/macrophages and B cells of these patients show a significant decrease compared to uninfected control individuals in the same area. We propose that this decrease in CR1 plays an essential role in impaired IC clearance during malaria.

CR1 exon variants are associated with lowered CR1 expression and increased susceptibility to SLE in aPlasmodium falciparumendemic population

“…Lower CR1 expression has been associated with improper IC clearance in mice models. 24 Furthermore, CR1 expression was found to be inversely correlated with IC deposition in the kidney 24 increasing the possibility of renal damage.…”

“…In a recent case-control study and meta-analysis, we showed that the CR1 minor alleles associated with lower levels of expression of CR1 are associated with protection against severe Plasmodium falciparum malaria, and they are highly prevalent in malaria endemic areas 18. In a murine model, Plasmodium yoelli infection decreased CR1 expression on monocytes and hindered IC internalisation which recovered after the clearance of parasites 24. Furthermore, human subjects infected with P. falciparum or P. vivax also display lower CR1 expression on monocytes compared with uninfected individuals 24.…”

“…18 In a murine model, Plasmodium yoelli infection decreased CR1 expression on monocytes and hindered IC internalisation which recovered after the clearance of parasites. 24 Furthermore, human subjects infected with P. falciparum or P. vivax also display lower CR1 expression on monocytes compared with uninfected individuals. 24 Differential CR1 expression has been reported based on malarial endemicity.…”

“…24 Furthermore, human subjects infected with P. falciparum or P. vivax also display lower CR1 expression on monocytes compared with uninfected individuals. 24 Differential CR1 expression has been reported based on malarial endemicity. 25 26 In view of the fact that in malaria endemic areas CR1 expression is reduced, and lowered CR1 expression is associated with improper clearance of IC, a feature observed in SLE, we hypothesised that this factor could predispose genetically susceptible subjects living in malaria endemic areas for development of SLE.…”

The immunological balance between host and parasite in malaria

“…Circulating ICs can interact with CD16/Fcγ RIII resulting in phagocyte activation and augmentation of the inflammatory response. Both in patients and in mice with malaria, CR1 surface expression is reduced on monocytes, macrophages and B cells (but not on PMNs) resulting in increased levels of circulating ICs (Fernandez-Arias et al 2013). Furthermore, by the presence of CR1 on the surface of human RBCs, RBCs participate in IC clearance by transferring CR1-bound ICs to phagocytic cells (Fernandez-Arias et al 2013).…”