FcyRIIa Polymorphisms In Disease A Determining the FcyRIIa Polymorphism

The FcyRIIa-Arg/His131 polymorphism was first identified on the basis of functional differences effected by anti-CD3 monoclonal antibodies of the murine IgGl subclass (Tax et al., 1983, 1984). Proliferation assays distinguished "high" and "low" responders relative to the effects of these anti-CD3 murine monoclonal antibodies on T-cell-dependent mitogenesis. Subsequently, individuals bearing the FcyRIIa-Arg131 phenotype were identified as the "high responders" and the functional differences between the two variants were later confirmed using other FcyRIIa-dependent assays such as erythrocyte antigen-rosetting, phagocytosis, and platelet activation (Clark et al., 1989; Warmerdam et al., 1991; Parren et al., 1992; Salmon et al., 1992). Murine monoclonal IgGl activate platelets of all three Arg/ His131 phenotypes, but the homozygous FcyRIIa-Arg131 variant requires less murine monoclonal antibody for platelet activation to occur.

The high-affinity binding of human IgG2 to FcyRIIa results when histidine is substituted at amino acid 131 of the mature protein (Warmerdam et al., 1991). FcyRIIa-His131 has a greater affinity for human IgG2 but a lower affinity for murine IgGl. Therefore, the terms high and low responder, used historically for the effects of murine monoclonal antibodies on Arg131 and His131 FcyRIIa phenotypes, respectively, is confusing, as the opposite reaction profile is observed with human IgG2. The high/low responder terminology has been largely replaced in favor of referring simply to the amino acid polymorphism.

The FcyRIIa-Arg/His131 variant polymorphism can be determined in three ways: (1) by functional assay such as T-cell-dependent proliferation or murine monoclonal antibody activation; (2) by specific binding using 41H16, a monoclonal antibody that binds exclusively to the FcyRIIa Arg131 variant; and (3) by molecular genotyping. Several DNA-based methods have been developed to genotype for the FcyRIIa-Arg/His131 nucleotide substitution (Clark et al., 1991; Osborne et al., 1994; Bachelot et al., 1995; Burgess et al., 1995; Jiang et al., 1996; Denomme et al., 1997; Flesch et al., 1998; Carlsson et al., 1998).

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