The major histocompatibility complex (MHC) occupies about 1% of the short arm of human chromosome 6 including ~3000 kb of DNA within which are the class I genes encoding the highly polymorphic, classical human leukocyte antigens (HLA) genes, the products of which bind peptides for presentation to T cells; the class I E, F and G genes of the MHC and their products are not T-cell- restricting.¹ The MHC also includes the class II genes² (HLA-DR, DQ, DP, DN and DO as well as putative transmembrane peptide transporters of the ABC [ATP-binding cassette] superfamily³) and class III genes⁴ (Bf, C2, C4, TNF, hsp70 and BAT2&3), among others. Class II genes are centromeric to and class I genes are telomeric to a central interval of ~1000 kb (the MHC class III region).⁵

Among the 100-2000 genes of the MHC gene superfamily,⁶ the relative positions and orientations of at least 50 genes are documented;⁷ new genes are periodically identified.⁸ Below are examples of the approved nomenclature for HLA genes, their molecular characteristics, alleles and specificity.^9-11

The proteins encoded by MHC class I genes are composed of a glycoprotein heavy chain complexed with b2-microglobulin. All nucleated cells and platelets express class I molecules on their surface in high copy number. Products of class II genes are glycoprotein a /b heterodimers; expression of these molecules on the cell surface is highly restricted to macrophages, dendritic cells and activated T cells. One major function of these gene products is to bind and display peptides from foreign antigens to enable their recognition by T cells. Differences in stability of peptide binding by class I heavy chains compared with the class II heterodimers probably reflect differences in biological function.¹² Complexes of class I molecules with a single species of specific peptide⁵ of uniform (8-9 residues) length (e.g., viral peptides derived from proteolysis in infected cells)¹³ are recognized by specific receptors on CD8⁺ cytotoxic T cells, sometimes with resultant death of cells presenting such complexes. Complexes of specific peptides (which are processed from internalized exogenous proteins) with class II molecules presented by B-cells, macrophages and other cells are recognized by and cause proliferation of CD4⁺ helper T cells. Only cells of similar MHC type can interact with each other; the mechanisms are MHC restricted.^9-11,14 Current evidence,¹⁵ however, points up the oversimplification of grouping antigens into two discrete categories,¹⁴ i.e., the grouping of antigens as: 1) non-replicating, exogenous entities that after endosomal processing are presented at the cell surface in association with class II molecules in preparation for CD4⁺ T-cell activation (as required for antibody production or CD4⁺ class II-restricted cytotoxic T cells); or 2) as endogenously synthesized and processed proteins (e.g., viral peptides) that are presented with class I molecules as primers for CD8⁺ cytotoxic T cells.¹⁶ Peptides are bound with high affinity not only by class II a /b heterodimers, but also by monomers of the a and b chains.¹⁷ Peptide selection by MHC class I molecules is size-dependent.¹⁸ A variety of tests are used to detect HLA polymorphism. The microcytotoxicity (Terasaki tray) assay is the gold standard against which all other methods are compared. Newer methods include flow cytometric evaluation, EIA for soluble B27, isoelectric focusing and polymerase chain reaction with nucleotide sequencing of MHC genes.¹⁹

A prodigious amount of work relates the amino acid sequences of certain class II molecules with susceptibility to certain autoimmune diseases (e.g., non-aspartate at position 57 in the DQB chain with susceptibility to IDDM in Caucasians,²⁰ HLA-DQw1.2 (one of the polymorphic forms of the DQb molecule) with protection against IDDM,²¹ DRb1 (DR4-associated) and DQB1.3 (DRw6-associated) with pemphigus vulgaris,²² a DPB2.1 allele with pauciarticular juvenile rheumatoid arthritis but not adult rheumatoid arthritis,²³ and DRB1 with adult rheumatoid arthritis.^24,25 Nevertheless, the clinical utility of disease associations with susceptibility or immunoinhibitory genes²⁶ has yielded less-than-hoped-for clinical utility over the past 10 years; enormous rewards for these diligent efforts should, however, soon be available. In addition to alleles at one locus of importance to susceptibility (or resistance), alleles at other linked loci may be important (such as the association of arginine at positions 13 or 70-71 in pocket 4 of DRB1 allele with susceptibility to tuberculoid leprosy²⁷). At present, at least four diseases are recognized in which the same HLA antigen is present in essentially all patients (DR2/DQw1 in narcolepsy,²⁸ most subtypes of B27 in ankylosing spondylitis except HLA-B*2703,^29-31 DR4 in pemphigus vulgaris,³² and DRw52a in primary sclerosing cholangitis.³³ HLA typing (A3, B7 and B14) on the unshared haplotypes of family members is very useful for predicting risk for hereditary hemochromatosis; a gene called HLA-H was identified and associated with hereditary hemochromatosis.³⁴ As unclear is the explanation of the highly stable persistence in the MHC of a number of non-immune class I genes with low polymorphism side-by-side with highly polymorphic immune genes; differential stimulation of the relevant cell populations might be important.³⁵ The nature, genetics and implications for transplantation and autoimmunity of minor histocompatibility antigens (peptides of <16 amino acids derived from cellular proteins) are being defined.³⁶ Persistence of DNA and RNA viruses in neurons and neuronal resistance to activated cytotoxic T lymphocytes (CTL), which can cross the blood-brain barrier³⁷ probably reflects lack of neuronal expression of MHC class I glycoprotein necessary for display of viral peptides on cell surfaces,³⁸ hence for lysis of infected cells by CTL.    Spontaneous antibody responses to CT antigens detected in the sera of patients with cancer, and the correlation of antibody titres with the course of the disease, suggest the presence of antigen specific CD4+ T cells against peptides presented by MHC class II molecules on the surface of tumor cells.³⁹ Recent reviews on the immune system and HLA-associated diseases are avialble.^40-42