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

Journal article

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 FcgammaRIIb is found at an increased frequency in African and Asian populations, broadly corresponding to areas where malaria is endemic. Here, we show that FcgammaRIIb-deficient mice have increased clearance of malarial parasites (Plasmodium chabaudi chabaudi) and develop less severe disease. In vitro, the human lupus associated FcgammaRIIb polymorphism enhances phagocytosis of Plasmodium falciparum-infected erythrocytes. These results demonstrate that FcgammaRIIb is important in controlling the immune response to malarial parasites and suggests that the higher frequency of human FcgammaRIIb polymorphisms predisposing to SLE in Asians and Africans may be maintained because these variants reduce susceptibility to malaria.

Authors: Clatworthy, MR; Willcocks, L; Urban, B; Langhorne, J; Williams, T

• Publication status: Published
• Journal: Proceedings of the National Academy of Sciences of the United States of America
• Volume: 104
• Issue: 17
• Pages: 7169-7174
• Publication date: 2007-04-01
• DOI: 10.1073/pnas.0608889104
• EISSN: 1091-6490
• ISSN: 0027-8424
• Language: English
• Keywords: Animals; Receptors, IgG; Severity of Illness Index; Titrimetry; Mice; Antigens, CD; Plasmodium falciparum; Polymorphism, Genetic; Macrophages; U937 Cells; Gene Frequency; African Continental Ancestry Group; Lupus Erythematosus, Systemic; Genotype; Plasmodium chabaudi; Africa, Eastern; Malaria; Antibody Formation; Tumor Necrosis Factor-alpha; Antibodies, Protozoan; Disease Susceptibility; Phagocytosis; Erythrocytes; Humans; Parasitemia