The HLA system consists of a series of closely linked genetic loci situated in the major histocompatibility complex (MHC) on the short arm of chromosome 6. shows the classification of these antigens. All loci are highly polymorphic, i.e. a large number of different alleles occur; more than 20 HLA-A, 50 HLA-B, 10 HLA-C, 15 HLA-DR, 3 HLA-DQ and 6 HLA-DP antigens have been identified so far. The class III senes of genes express complement.
The genes at a given locus are inherited as co-dominants, so that each individual expresses both alleles, one transmitted from the mother and the other from the father. Because of the close linkage between the loci, all the genes in the MHC tend to be inherited together. The term ‘haplotype’ is used to indicate the particular set of HLA genes an individual carries on each chromosome 6. ‘Crossing over’ can occur within the HLA region. However,
certain alleles occur more frequently in the same haplotype than expected by chance and this is known as ‘linkage disequilibrium’; for example, the haplotype Al B8 occurs more frequently than would be expected from the individual gene frequencies of Al or B8.
There is a wide inter-racial variation in HLA antigens; for example, the HLA haplotype Al,B8 is found mainly in Caucasians, while the antigen B42 is seen only in Africans.
Products of the H LA genes
The HLA genes code for cell-surface glycoproteins that extend from the plasma membrane to the cytoplasm and are known as class I and class II molecules. These glycoproteins consist of two chains of unequal size (a and 13 chains), and are antigenic.
Class I molecules
Class I antigens are expressed on all cell types except erythrocytes and trophoblasts. Striated muscle cells and liver parenchymal cells are normally negative but become strongly positive in inflammatory reactions. HLA-A, -B and -C antigens can be distinguished serologically by the rnicrolymphocytotoxic test. Lymphocytes from the peripheral blood are incubated with a range of antibodies of known specificity (obtained from parous women or immunized individuals) in the presence of complement and trypan blue dye (which penetrates and stains cells with a damaged cell membrane). If the antibody does not react with the antigen, the lymphocytes survive and exclude the dye; in a positive reaction the dye enters the dead cells, indicating the presence of the specific antigen on that cell.
Class II molecules
Class II antigens are expressed on B cells, monocytes, dendritic cells and activated T cells. Inflammation causes aberrant class II expression in many other tissues. They are important in presenting antigens to certain subpopulations of T cells.
HLA-D antigens are recognized by the mixed lymphocyte culture (MLC) technique, which requires a panel of different HLA-D homozygous standard typing cells. The homozygous typing cell (HIC) is treated with mitomycin or irradiation to prevent it dividing when it is cultured with the test responder lymphocytes. The latter will not proliferate (measured by incorporation of tritiated thymidine) if it possesses the same D antigen as the HIC, but it will proliferate if it lacks this antigen. The DR (Drelated)
antigens are very closely related to D antigens and are also detected on B cells (B cell alloantigens) using a cytotoxic antibody test. These antigens are probably the counterpart of the ‘immune-associated’ (Ia) antigens on the surface of B cells and macrophages in the mouse. Immunoregulatory function of H LA molecules In the mouse, the IT gene controls the magnitude of the immune response by helping T-cell recognition of the macrophage-bound antigen. Thus, T cells use HLA antigens as recognition molecules.
Helper T (TH)
cells (identified by monoclonal antibody CD4) usually use Coeliac disease was originally thought to be associated with HLA-DR3 and HLA-DR7 but it has now been shown that the association is much stronger with HLADQw2 which is in linkage disequilibrium with HLA-DR3 and HLA-DR7. One or two diseases are linked to specific HLA haplotypes, suggesting that there is a single abnormal gene on chromosome 6, e.g. haemochromatosis is an autosomal recessive disease associated with the A3 B14 haplotype; congenital adrenal hyperplasia is also an autosomal recessive with a defect of steroid 21-hydroxylase, resulting in failure to synthesize cortisol and an increased production of androgenic hormones
HLA alleles and adverse drug reactions
There are associations between HLA antigens and adversedrug reactions. For example, HLA-DR4 is present in 75% of patients with systemic lupus erythematosus (SLE) due hydralazine, compared with 25% of idiopathic SLE tients and slow acetylators who do not develop SLE on _dralazine. Autosomal genes also control the acetylator status, with the ‘rapid’ allele being dominant to the ‘slow’ allele. Homozygotes for the ‘slow’ allele have reduced levels of N-acetyltransferase in the liver. Acetylation is the controlling factor for the rate of drug metabolism. The percentage of rapid acetylators varies in different ethnic populations-50% in the West, 90% of Japanese and 100% in Eskimos.