A Novel Polymorphism of FcgammaRIIIa (CD16) Alters Receptor Function and Predisposes to Autoimmune Disease

A novel polymorphism in the extracellular domain 2 (EC2) of FcgammaRIIIA affects ligand binding by natural killer (NK) cells and monocytes from genotyped homozygous normal donors independently of receptor expression. The nonconservative T to G substitution at nucleotide 559 predicts a change of phenylalanine (F) to valine (V) at amino acid position 176. Compared with F/F homozygotes, FcgammaRIIIa expressed on NK cells and monocytes in V/V homozygotes bound more IgG1 and IgG3 despite identical levels of receptor expression. In response to a standard aggregated human IgG stimulus, FcgammaRIIIa engagement on NK cells from V/V (high-binding) homozygotes led to a larger rise in [Ca2+]i, a greater level of NK cell activation, and a more rapid induction of activation-induced cell death (by apoptosis). Investigation of an independently phenotyped normal cohort revealed that all donors with a low binding phenotype are F/F homozygotes, while all phenotypic high binding donors have at least one V allele. Initial analysis of 200 patients with SLE indicates a strong association of the low binding phenotype with disease, especially in patients with nephritis who have an underrepresentation of the homozygous high binding phenotype. Thus, the FcgammaRIIIa polymorphism at residue 176 appears to impact directly on human biology, an effect which may extend beyond autoimmune disease characterized by immune complexes to host defense mechanisms

The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT1 receptor agonistic autoantibodies (AT1-AAs) that contribute to the disease features. However, the exact role of AT1-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT1 receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT1-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT1-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT1-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT1-AA–induced placental damage. Our findings highlight AT1-AAs as important therapeutic targets

Fc gamma RIII expressed on cultured monocytes is a N-glycosylated transmembrane protein distinct from Fc gamma RIII expressed on natural killer cells.

Abstract Fc gamma RIII is a family of protein isoforms encoded by at least two distinct, yet highly homologous, genes. Fc gamma RIII on neutrophils is a glycosylphosphatidylinositol-linked protein with an allelic polymorphism (NA1/NA2) while Fc gamma RIII on NK cells (Fc gamma RIIINK) is an exclusively transmembrane protein without the NA polymorphism. The relationship of the isoform of Fc gamma RIII expressed on cultured monocytes (Fc gamma RIIIM phi) to these two forms, however, is unclear because some evidence suggests lowered expression of Fc gamma RIIIM phi in paroxysmal nocturnal hemoglobinuria (unlike Fc gamma RIIINK) and a unique deglycosylated m.w. for Fc gamma RIIIM phi. In this study we demonstrate that, as with Fc gamma RIIINK, Fc gamma RIIIM phi is resistant to the action of phosphatidylinositol-specific phospholipase C and is expressed at normal levels on affected (glycosylphosphatidylinositol-anchor negative) cultured monocytes from patients with paroxysmal nocturnal hemoglobinuria. Fc gamma RIIIM phi is also shed from the cell surface upon incubation at 37 degrees C. However, Fc gamma RIIIM phi and Fc gamma RIIINK have different m.w. as glycosylated proteins despite the same deglycosylated m.w. Thus, each cell type appears to express distinct glycoforms. These differences in glycosylation may influence the functional properties of the receptor.</jats:p