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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. 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.

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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.

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Figure 315-1
Graphic Jump Location

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.

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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 ...

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