The HLA system: genetics, immunology, clinical testing, and clinical implications

Abstract

The human major histocompatibility complex HLA is located on the short arm of chromosome 6. It is known to be the most polymorphic genetic system in humans. The biological role of the HLA class I and class II molecules is to present processed peptide antigens. The HLA system is clinically important as transplantation antigens. Molecular HLA allele typing is routinely performed to provide HLA class I and class II allele matching in unrelated donor hematopoietic stem cell transplantation. Prospective lymphocyte crossmatching is critical in solid organ transplantation to prevent allograft rejection. HLA alloimmunization causes various problems in transfusion therapy. The HLA system is associated with certain diseases, but its underlying mechanisms are not yet fully explained.

Fig. 1

The human MHC on the short arm of chromosome 6. The HLA-DR, DP, and DQ regions consist of one or more A and B genes, respectively. TNF (tumor necrosis factors); C' (complement genes).

Fig. 2

Mendelian inheritance of HLA haplotypes demonstrated in a family study. HLA haplotypes and genotypes can be inferred from phenotype data in an informative family study as illustrated. For example, the father's HLA phenotype is HLA-A1, 3; B7, 8; DR15, 17. From the family study, his genotype is A1, B8, DR17/A3, B7, DR15. The paternal HLA haplotypes are A1, B8, DR17 ("a") and A3, B7, DR15 ("b"); and the maternal HLA haplotypes are A2, B44, DR4 ("c") and A29, B44, DR7 ("d").

Fig. 3

Schematic diagram of HLA class I (a) and class II (b) molecules. The class I molecule consists of a heavy chain and a light chain β₂-microglobulin. The class II molecule is a heterodimer consisting of α and β chains. PBS (peptide-binding site).