The human leukocyte antigens (HLAs) were first identified by detecting antibody responses in the sera of multi-transfused patients to white blood cells. Although these antigens are found in many tissues, their highest concentrations are in lymphocytes. The HLA antigens comprise the major histocompatibility complex (MHC), which plays a critical role in the immune system's ability to recognize and respond to foreign antigens, such as microorganisms or proteins released by tumor cells. The MHC gene complex is found on the short arm of chromosome 6 and is divided into six sub-regions: HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP. These genes have multiple alleles, resulting in a high degree of polymorphism in humans. This accounts for the difficulty in finding matches in unrelated donors, especially if the transplant recipient has a mixed ethnic background. Siblings from identical birth parents have a 1 in 4 chance of having an identical HLA match.
Based on their discovery order, the HLA antigens have been assigned to two classes. Class I molecules include HLA-A, HLA-B, and HLA-C. Class II molecules include HLA-DR, HLA-DQ, and HLA-DP.
Class I molecules play a significant role in the immune response by binding to peptides and presenting them on the surface of the cell for detection by CD8 T lymphocytes. These T lymphocytes can then mount a cytotoxic response to these foreign antigens and destroy them. Class I molecules are the principal antigens recognized by host cells during transplantation, and if significantly different, they will trigger graft rejection.
Class II molecules act as antigen receptors by binding to degraded peptide fragments from foreign cells introduced into the cell by endocytosis. A complex of Class II molecules and peptide fragments is transported to the cell surface and recognized by circulating T lymphocytes. CD4 T cells can help B lymphocytes differentiate into plasma cells and produce antibodies, or they may help other T cells differentiate into cytotoxic T cells that kill any cells containing the targeted antigen.
Another group of molecules that are part of the MHC are the Class III molecules, which include complement components C2, C4a, C4b, and tissue necrosis factor. The genes that regulate the production of these products are also located on chromosome 6 between the HLA-DR and HLA-B loci.
