Systemic lupus erythematosus-associated defects in the inhibitory receptor FcγRIIb reduce susceptibility to malaria

Polygenic autoimmune diseases, such as systemic lupus erythematosus (SLE), are a significant cause of morbidity and mortality worldwide. In recent years, functionally important genetic polymorphisms conferring susceptibility to SLE have been identified, but the evolutionary pressures driving their retention in the gene pool remain elusive. A defunctioning, SLE-associated polymorphism of the inhibitory receptor Fc gamma RIIb is found at an increased frequency in African and Asian populations, broadly corresponding to areas where malaria is endemic. Here, we show that Fc gamma RIIb-deficient mice have increased clearance of malarial parasites (Plasmodium chabaudi chabaudi) and develop less severe disease. In vitro, the human lupus associated Fc gamma RIIb polymorphism enhances phagocytosis of Plasmodium falciparum-infected erythrocytes. These results demonstrate that Fc gamma RIIb is important in controlling the immune response to malarial parasites and suggests that the higher frequency of human Fc gamma RIIb polymorphisms predisposing to SLE in Asians and Africans may be maintained because these variants reduce susceptibility to malaria.