Genetics of HLA: The Major Human Histocompatibility System

W. F. Bodmer, E. A. Jones, C. J. Barnstable, J. G. Bodmer

Abstract

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, the mouse equivalent of HLA, has been shown to encompass genes controlling certain immune responses, in addition to those controlling cell surface determinants equivalent to those controlled by the HLA-A, B and C loci. Genes controlling the second and fourth components of complement and factor B of the alternative pathway have also been assigned to the HLA and H-2 regions. The evidence for the existence of immune response genes in man is mainly indirect and comes from a number of striking associations between HLA and certain diseases, a number of which have a presumptive or suspected auto-immune etiology. In the mouse, a series of antigens called Ia for immune associated, have been defined which have a tissue distribution restricted mainly to B lymphocytes and monocytes. This contrasts with the distribution of the HLA-A, B and C antigens and their mouse equivalents, which are present on virtually all tissues except, generally, red cells in man. A variety of approaches are being used to define the human homologues of the mouse Ia antigens. They depend on the use of an appropriate source of B lymphocytes either purified from the peripheral blood, from patients with chronic lymphocytic leukaemia or from B cell derived transformed cell lines. Cytotoxic assays by using blocking techniques or absorption with platelets, which do not have Ia antigens, can produce sera which will react with the human equivalent of Ia antigens, but not to HLA-A, B and C determinants. Using such sera several human Ia determinants have been defined. These have been shown to be associated closely with the HLA-D determinants identified by the mixed lymphocyte culture reaction and there is much evidence to suggest that the Ia and D determinants may in fact be one and the same. As in the case of the HLA-A, B and C determinants, there is extensive cross-reaction among these newly defined Ia antigens. A combination of family studies and somatic cell genetics has shown that the HLA region is located on chromosome 6. The gene for $\beta _{2}$ microglobulin, the polypeptide which is non-covalently bound to the product of the HLA-A, B and C loci, has, however, been shown by the use of human/mouse somatic cell hybrids to be located on chromosome 15. A series of such hybrids showing all possible combinations of presence and absence of chromosomes 6 and 15 and presence and absence of HLA-A and B specificities and $\beta _{2}$ microglobulin has been obtained. In these hybrids the expression of the HLA-A and B antigens has been shown to depend on their association with mouse $\beta _{2}$ microglobulin, in the absence of human $\beta _{2}$ microglobulin. Further investigation of co-expression of $\beta _{2}$m and of HLA-A and B products has depended on studies of hybrids made with the Daudi cell line which lacks $\beta _{2}$m and HLA-A, B or C specificities. Hybrids between Daudi and the HeLa derivative D98/AH-2 express determinants of the A and B loci which must be attributed to Daudi. Two of these determinants have also been found in hybrids made between Daudi and a mouse L cell derivative containing only one copy of Daudi's chromosome 6. These results show that the HLA-A and B determinants of Daudi can be re-expressed in the presence of either human or mouse $\beta _{2}$m and suggest that control of expression of HLA-A, B and C products is somehow dependant on $\beta _{2}$ microglobulin. The HLA system is a remarkable example of a complex gene cluster containing probably several hundreds at least, if not a few thousand, loci, and has probably arisen by a series of duplication events.

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