Genetics of HLA: the major human histocompatibility system

The HLA system was first defined as a cell surface genetic polymorphism with the aim of using it for transplantation matching. The originally defined specificities of the system, usually identified by a microcytotoxicity assay on peripheral blood lymphocytes, are controlled by the alleles of three closely linked loci HLA-A, B and C. These loci are highly polymorphic with at least 19 A alleles, 26 B alleles and 5 C alleles defined. There is extensive cross reaction amongst the determinants controlled by each locus, though not usually between loci. Skin or kidney grafts exchanged between HLA-A, B and C identical sibs survive much longer than those between unmatched sibs showing that the HLA system is indeed a histocompatibility system. The mixed lymphocyte culture reaction has been shown to be controlled by a series of alleles at a fourth locus, closely linked to A, B and C, the HLA-D locus. Eight alleles have been identified at this locus by use of the mixed lymphocyte culture reaction as a typing procedure. The H-2 system is the mouse equivalent of HLA. The HLA system, and other similar systems in other species, are remarkable examples of complex gene clusters containing several hundreds, and possibly even a few thousand, gene loci. Such gene clusters of which other well known examples are the haemoglobin and immunoglobulin genes, seem to be a characteristic feature of higher organism genetic organization. It is commonly assumed that such clusters have arisen by a series of duplication events.