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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 and some forms of drug hypersensitivity. 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. 343-1). 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 3400 alleles at HLA-A, 4300 alleles at HLA-B, and 3100 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.

FIGURE 343-1

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 designation of HLA genes and their products is based on a World Health Organization (WHO) nomenclature, in which alleles are given a single designation that indicates locus, allotype, and sequence-based subtype. For example, HLA-A*02:01 indicates subtype 1 of a group of alleles that encode HLA-A2 molecules. 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*07:02:01 and HLA-B*07:02:02 are two variants of HLA-B*07:02, both encoding the same HLA-B7 molecule). The nomenclature of class II genes, discussed below, is made more complicated by the fact that both ...

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