Human leukocyte antigen gene polymorphism and the histocompatibility laboratory

Abstract

The human leukocyte antigens (HLA) encoded by genes within the major histocompatibility complex display an impressive degree of polymorphism. This variability is apparently maintained in human populations through the need to successfully display a wide range of processed foreign peptides to the T cell antigen receptor. The large number of alleles at the Class I and Class II loci pose a significant problem for molecular diagnosis. Knowledge of allele groups and specific alleles present in individuals has important implications in organ and stem cell transplantation and in disease association studies. Histocompatibility laboratories have transformed themselves during the past decade as they have adapted the techniques of molecular diagnostics to the challenge of identifying HLA alleles.

Figure 1.

Structure of the Class I and II heterodimers.

Figure 2.

DRB1 Gene polymorphism. Single letter amino acid codes are shown for DRB1 exon 2 codons 6–94. About half of the positions are invariant while the remainder display polymorphism with a few codons encoding as many as seven different amino acids. For example, all DRB1 alleles have glycine encoded by position 20 while alleles may encode glycine, valine, or aspartic acid at codon 86. The 289 known DRB1 alleles arise through the many possible combinations of these polymorphisms. The polypeptide encoded by DRB1*0101 is shown on the top line.

Figure 3.

Class I and Class II alleles arise from existing alleles through several postulated mechanisms. DRB1*1120 likely arose via interallelic recombination between DRB1*1302 and a DRB1*11 allele, while DRB1*0811 probably is derived from DRB1*0802 by a point mutation.