FcgammaRIIa is an activating FcgammaR, unique to humans and non-human primates. It induces antibody-dependent proinflammatory responses and exists predominantly as FcgammaRIIa1. A unique splice variant, we designated FcgammaRIIa3, has been reported to be associated with anaphylactic reactions to intravenous immunoglobulins (IVIg) therapy. We aim to define the functional consequences of this FcgammaRIIa variant associated with adverse responses to IVIg therapy and evaluate the frequency of associated SNPs. FcgammaRIIa forms from macaque and human PBMCs were investigated for IgG-subclass specificity, biochemistry, membrane localization, and functional activity. Disease-associated SNPs were analyzed by sequencing genomic DNA from 224 individuals with immunodeficiency or autoimmune disease. FcgammaRIIa3 was identified in macaque and human PBMC. The FcgammaRIIa3 is distinguished from the canonical FcgammaRIIa1 by a unique 19-amino acid cytoplasmic insertion and these two FcgammaRIIa forms responded distinctly to antibody ligation. Whereas FcgammaRIIa1 was rapidly internalized, FcgammaRIIa3 was retained longer at the membrane, inducing greater calcium mobilization and cell degranulation. Four FCGR2A SNPs were identified including the previously reported intronic SNP associated with anaphylaxis, but in only 1 of 224 individuals. The unique cytoplasmic element of FcgammaRIIa3 delays internalization and is associated with enhanced cellular activation. The frequency of the immunodeficiency-associated SNP varies between disease populations but interestingly occurred at a lower frequency than previously reported. None-the-less enhanced FcgammaRIIa3 function may promote a proinflammatory environment and predispose to pathological inflammatory responses.
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