The human major histocompatibility complex (MHC), commonly called the human leukocyte antigen (HLA) complex, is a 4-megabase (Mb) region on chromosome 6 (6p21.3) that is densely packed with expressed genes. The best known of these genes are the HLA class I and class II genes, whose products are critical for immunologic specificity and transplantation histocompatibility, and they play a major role in susceptibility to a number of autoimmune diseases. Many other genes in the HLA region are also essential to the innate and antigen-specific functioning of the immune system. The HLA region shows extensive conservation with the MHC of other mammals in terms of genomic organization, gene sequence, and protein structure and function.
The HLA class I genes are located in a 2-Mb stretch of DNA at the telomeric end of the HLA region (Fig. 315-1). The classic (MHC class Ia) HLA-A, -B, and -C loci, the products of which are integral participants in the immune response to intracellular infections, tumors, and allografts, are expressed in all nucleated cells and are highly polymorphic in the population. Polymorphism refers to a high degree of allelic variation within a genetic locus that leads to extensive variation between different individuals expressing different alleles. More than 650 alleles at HLA-A, 1000 at HLA-B, and 360 at HLA-C have been identified in different human populations, making this the most highly polymorphic segment known within the human genome. Each of the alleles at these loci encodes a heavy chain (also called an α chain) that associates noncovalently with the nonpolymorphic light chain β2-microglobulin, encoded on chromosome 15.
Physical map of the HLA region, showing the class I and class II loci, other immunologically important loci, and a sampling of other genes mapped to this region. Gene orientation is indicated by arrowheads. Scale is in kilobase (kb). The approximate genetic distance from DP to A is 3.2 cM. This includes 0.8 cM between A and B (including 0.2 cM between C and B), 0.4–0.8 cM between B and DR-DQ, and 1.6–2.0 cM between DR-DQ and DP.
The nomenclature of HLAgenes and their products reflects the grafting of newer DNA sequence information on an older system based on serology. Among class I genes, alleles of the HLA-A, -B, and -C loci were originally identified in the 1950s, 1960s, and 1970s by alloantisera, derived primarily from multiparous women, who in the course of normal pregnancy produce antibodies against paternal antigens expressed on fetal cells. The serologic allotypes were designated by consecutive numbers (e.g., HLA-A1, HLA-B8). Currently, under World Health Organization (WHO) nomenclature, class I alleles are given a single designation that indicates locus, serologic specificity, and sequence-based subtype. For example, HLA-A*0201 indicates subtype 1 of the serologically defined allele HLA-A2. Subtypes that differ from each other at the nucleotide but not the amino acid sequence level are designated by an extra numeral (e.g., HLA-B*07021 and HLA-B*07022 are two variants of the HLA-B702 subtype of HLA-B*07). The nomenclature of class II genes, discussed below, is made more complicated by the fact that both chains of a class II molecule are encoded by closely linked HLA-encoded loci, both of which may be polymorphic, and by the presence of differing numbers of isotypic DRB loci in different individuals. It has become clear that accurate HLA genotyping requires DNA sequence analysis, and the identification of alleles at the DNA sequence level has contributed greatly to the understanding of the role of HLA molecules as peptide-binding ligands, to the analysis of associations of HLA alleles with certain diseases, to the study of the population genetics of HLA, and to a clearer understanding of the contribution of HLA differences to allograft rejection and graft-versus-host disease. Current databases of HLA class I and class II sequences can be accessed by the Internet (e.g., from the IMGT/HLA Database, http://www.ebi.ac.uk/imgt/hla), and frequent updates of HLA gene lists are published in several journals.
The biologic significance of this MHC genetic diversity, resulting in extreme variation in the human population, is evident from the perspective of the structure of MHC molecules. As shown in Fig. 315-2, the MHC class I and class II genes encode MHC molecules that bind small peptides, and together this complex (pMHC; peptide-MHC) forms the ligand for recognition by T lymphocytes, through the antigen-specific T cell receptor (TCR). There is a direct link between the genetic variation and this structural interaction: The allelic changes in genetic sequence result in diversification of the peptide-binding capabilities of each MHC molecule and in differences for specific TCR binding. Thus, different pMHC complexes bind different antigens and are targets for recognition by different T cells.
A. The trimolecular complex of TCR (top), MHC molecule (bottom) and a bound peptide form the structural determinants of specific antigen recognition. Other panels (B. and C.) show the domain structure of MHC class I (B) and class II (C) molecules. The α1 and α2 domains of class I and the α1 and β1 domains of class II form a β-sheet platform that forms the floor of the peptide-binding groove, and α helices that form the sides of the groove. The α3 (B) and β2 domains (C) project from the cell surface and form the contact sites for CD8 and CD4, respectively. (Adapted from EL Reinhertz et al: Science 286:1913, 1999; and C Janeway et al: Immunobiology Bookshelf, 2nd ed, Garland Publishing, New York, 1997; with permission.)
The class I MHC and class II MHC structures, ...