Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb 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 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.
Clatworthy
Menna R
MR
Cambridge Institute for Medical Research and Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
Willcocks
Lisa
L
Urban
Britta
B
Langhorne
Jean
J
Williams
Tom N
TN
Peshu
Norbert
N
Watkins
Nicholas A
NA
Floto
R Andres
RA
Smith
Kenneth G C
KG
D000351:Africa, Eastern; D000818:Animals; D000913:Antibodies, Protozoan / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics*; D044383:Black People / Q000235:genetics; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000469:parasitology; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications*; D008264:Macrophages / Q000469:parasitology; D008288:Malaria / Q000150:complications* / Q000469:parasitology; D051379:Mice; D018512:Parasitemia; D010587:Phagocytosis; D016788:Plasmodium chabaudi / Q000502:physiology; D010963:Plasmodium falciparum / Q000502:physiology; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics*; D012720:Severity of Illness Index; D017186:Titrimetry; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells
D000913:Antibodies, Protozoan; D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha