Human Gm, Km, and Am Allotypes and Their Molecular Characterization: A Remarkable Demonstration of Polymorphism

Abstract

Human immunoglobulin allotypes are antigenic determinants (or "markers") determined serologically, classically by hemagglutination inhibition, on the human immunoglobulin (IG) heavy and light chains. The allotypes have been identified on the gamma1, gamma2, gamma3, and alpha2 heavy chains (they are designated as G1m, G2m, G3m, and A2m allotypes, respectively), and on the kappa light chain (Km allotypes). Gm-Am allotypes are inherited in fixed combinations, or Gm-Am haplotypes, owing to the linkage of the human IGHC genes (IGHG3, IGHG1, IGHA1, IGHG2, IGHG4, IGHE, and IGHA2 from 5' to 3' in the IGH locus on chromosome 14). Gm and Am allotypes have been one of the most powerful tools in population genetics and very instrumental in molecular characterization of the human IGHC genes (gene conversion, copy number variation, gene order). They represent a major system for understanding immunogenicity of the polymorphic IG chains, in relation with amino acid and conformational changes. The correlation between G3m allotypes and amino acid changes has been possible with the sequencing of many alleles of the IGHG3 gene, from individuals from different populations and with known allotypes. In this chapter, we integrate genetics and sequence data and provide an updated overview of the Gm-Am haplotypes and Km allotypes. We propose, for the first time, a complete elucidation of the G3m allotypes, illustrated by the "IMGT G3m allele butterfly" concept that allows a graphical representation of the G3m alleles (variants of a gene expressing a given set of allotypes). Knowledge of allotypes is important in antibody engineering and humanization of monoclonal antibodies to improve immunotherapy.