HLA II: The emergence of the molecular model for the human major histocompatibility complex

The known complexity of the HLA system continues to grow. Simultaneously, investigators are constructing a molecular model for the human major histocompatibility complex that accounts for the extensive variation at the HLA loci. Three alleles were given new WHO nomenclature at the HLA-A locus, 7 at HLA-B, 7 at HLA-D, and 6 at HLA-DR. Two entirely new loci were given WHO status: HLA-DQ and HLA-DP. The HLA-A, -B, and -C loci (class I genes) code for a polypeptide chain containing cytoplasmic, transmembrane, and extracellular regions. In turn the extracellular region can be divided into three domains. The molecular organization of the class I gene is discussed. The class II genes in the HLA-D/DR complex can be grouped into three regions, DR, DC, and SB, with one WHO-defined locus associated with each: HLA-DR, HLA-DQ, and HLA-DP, respectively. Class II molecules have both an alpha- and a beta-chain, which can be divided into cytoplasmic, transmembrane, and extracellular regions. The extracellular region of both polypeptide chains has two domains. The molecular organization of the alpha- and beta-chain genes is discussed. Serological polymorphism for both the class I and II molecules has been located in the domains most distal to the cellular membrane. The domain closest to the membrane in both alpha- and beta-chains of class II molecules is conserved and exhibits homology with one another and with the constant regions of IgG molecules and with beta-2-microglobulin. Therefore, it is likely that the genes of the major histocompatibility complex have evolved from a primordial gene which has differentiated into at least four related families: HLA class I, HLA class II, IgG immunoglobulin heavy and light chains, and beta-2-microglobulin.