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

Abstract

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.

Fig. 1.

Frequency of FcγRIIb^T/T232 genotype and FcγRIIb^T232 allele frequency in populations worldwide. Data in boxes labeled i obtained from Li et al. (9), box ii from Floto et al. (12), boxes iii from Kyogoku et al. (8), box iv from Chu et al. (11), box v from Siriboonrit et al. (10), and boxes vi by sequencing DNA samples obtained from Kenya (18) or the U.K., demonstrating higher frequency of FcγRIIb^T232 allele in areas where malaria is or has been endemic. [Reproduced with permission from ref. (Copyright 2002, WHO).]

Fig. 2.

P. chabaudi chabaudi infection in control (white) and FcγRIIb-deficient (black) mice. Percent parasitemia (A), fall in hematocrit (B), and temperature (C) 6 and 9 days after inoculation with 5 × 10⁶ (Upper) or 1 × 10⁵ (Lower) P. chabaudi chabaudi-parasitized erythrocytes i.p.

Fig. 3.

Macrophage and antibody responses to malarial parasites. Percent phagocytosis (% CFSE-positive macrophages) (A) and phagocytic index (geometric mean fluorescence of CFSE-positive macrophages) (B) in control and FcγRIIb-deficient macrophages after a 40-min incubation with P. chabaudi chabaudi-parasitized erythrocytes opsonized with hyperimmune serum. (C) Up-regulation of surface CD86 on control and FcγRIIb-deficient macrophages after an 18-h incubation with P. chabaudi chabaudi-parasitized erythrocytes opsonized with hyperimmune serum. (D) TNF-α production by control and FcγRIIb-deficient macrophages after an 18-h incubation with P. chabaudi chabaudi-parasitized erythrocytes opsonized with hyperimmune serum. (E) Serum TNF-α levels in control and FcγRIIb-deficient mice 8 days after inoculation with 1 × 10⁵ P. chabaudi chabaudi-parasitized erythrocytes. (F) Antimalarial IgG titers in control and FcγRIIb-deficient mice 7 and 28 days after inoculation with 1 × 10⁵ P. chabaudi chabaudi-parasitized erythrocytes.

Fig. 4.

Analysis of phagocytosis rates (percent of CFSE-positive cells). Phagocytosis rates in differentiated U937 (hatched), FcγRIIb^I232 (white), and FcγRIIb^T232 (black) cells (A) and phagocytosis rates in monocyte-derived macrophages from subjects with the FcγRIIb^I/I232 (white), FcγRIIb^I/T232 (gray), and FcγRIIb^T/T232 (black) genotype (B) after a 4-h incubation with P. falciparum-parasitized erythrocytes opsonized with nonimmune serum or immune serum obtained from children or adults previously infected with P. falciparum.