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^ ^-^ Figure 1 Map of the expressed genes of

Class II antigens (HLA-D) Class I antigens the HLA class I and class II regions.

diseases have also been associated with specific HLA types, perhaps reflecting the role of the immune system in responding to the tumor or to the pathogen. In addition, some diseases like narcolepsy, a sleep disorder of unknown etiology and with no obvious connection to the immune system, show a strong HLA association.

The initial reports of HLA disease associations all relied on the serologic definition of class I and class II antigens, and to a lesser extent, the cellular definition of HLA class II antigens by the mixed lymphocyte reaction was also used. More recently, polymorphism at the HLA loci has been analyzed at the nucleotide sequence level, revealing a wealth of allelic diversity, and simple and rapid polymerase chain reaction (PCR)-based typing methods have been applied to studies of HLA disease associations. The capacity of PCR-based typing to distinguish alleles relative to serology has resulted in a much more precise understanding of disease associations; there are about 15 serological DR specificities but >150 DRB1 DNA sequence-defined alleles. Because DNA typing can reveal where and how alleles differ, the application of these methods has provided insight into the contribution of individual polymorphic amino acid residues to disease susceptibility. For example, the DR4 specificity can be encoded by any of 22 DRB1 alleles; some DR4-associated diseases (e.g. IDDM, rheumatoid arthritis (RA)) are positively associated with specific DR4 alleles, and negatively associated with others. The negatively and positively associated alleles can differ by as little as a single codon.

The HLA loci

The HLA loci on the short arm of human chromosome 6 (Figure 1) encode two distinct classes of highly polymorphic cell surface molecules that bind and present processed antigens in the form of peptides to T lymphocytes; recognition by the T cell of the HLA-peptide complex, along with a costimu-latory signal results in T cell activation. The class I molecules, HLA-A, -B and -C, are found on most nucleated cells. They are cell surface glycoproteins that bind and present peptides derived primarily from endogenously synthesized proteins (e.g. viral and tumor peptides) to CD8" T cells. These heterodi-mers consist of an HLA-encoded a chain associated with the non-MHC-encoded monomorphic polypeptide, (^-microglobulin. These loci are highly polymorphic; the numbers of alleles at the HLA-A, -B and -C loci are shown in Table 2.

The class II molecules are encoded in the HLA D region (Figure 1). These cell surface glycoproteins consist of HLA-encoded a and (3 chains associated as heterodimers on the cell surface of antigen-presenting cells such as B cells and macrophages. Class II molecules serve as receptors for processed peptides; however, these peptides are derived predominantly from membrane and extracellular proteins (e.g. bacterial peptides) and are presented to CD4+T cells. The HLA-D region contains several class II genes and has three subregions: HLA-DR, -DQ and -DP. Both the HLA-DQ and -DP regions

Table 2 Allelic diversity at the HLA class I and class II loci

Locus No. of alleles

HLA-A 83

HLA-B 185

HLA-C 42

DRA1 2

DRB1 184

DRB3 11

DRB4 8

DRB5 12

DQA1 18

DQB1 31

DPA1 10

DPB1 77

The number of alleles listed here includes silent variants and is based on the 1996 WHO Nomenclature Report.

contain one functional gene for each of their a and P chains. The HLA-DR subregion contains one functional gene for the a chain; the number of functional genes for the p chain varies from one to two. All individuals express a DRB1-encoded polymorphic polypeptide that is found on the cell surface in association with the DRA-encoded polypeptide. The other functional class II DRB genes, DRB3, DRB4 and DRB5 encode polypeptides which are found on the cell surface in association with a DRA-encoded polypeptide but at a lower level and only in certain class II haplotypes. In general, the DRB3 locus is found on haplotypes where DRB1 is *03, Ml, *12, *13 or *14; the DRB4 locus is found on haplotypes where DRB1 is *04, *07, *09 and the DRB5 locus is found on haplotypes where DRB1 is *02 (either »15 or *16).

With the exception of the DRA and the DPA1 loci, the genes encoding the functional class II molecules are highly polymorphic (see Table 2). Analysis of the HLA class II structure has shown that these polymorphic amino acid residues line the peptide-binding cleft and interact directly with the peptide and/or the T receptor. The extensive polymorphism at both the class I and II loci and its localization to the peptide-binding groove have led to the notion that HLA polymorphism is maintained in the population because different allelic products have the capacity to bind different peptides; consequently, the more alleles an individual or a population has, the better it is able to cope with a variety of infectious pathogens.

Allelic sequence diversity

The allelic sequence diversity of the HLA class I and class II loci is the highest among mammalian coding sequence polymorphisms, with the number of alleles at some loci approaching 200 as of 1996 (see Table 2). The functional significance of this extensive polymorphism as well as the genetic mechanisms and the evolutionary forces that have generated and maintained this sequence diversity are the subject of many immunological and genetic investigations. For the HLA class II genes, the loci encoding the a and p chains of the DR, the DQ and the DP antigens, virtually all of the polymorphism is localized to the second exon. This exon encodes the a-helical 'walls' and the P-pleated sheet 'floor' of the peptide-binding groove formed by the ap heterodimer. Among the a chain loci (e.g. DRA), only the DQA1 locus, with over 15 alleles, shows extensive polymorphism. The P chain loci, however, are highly polymorphic. Population surveys in a variety of human populations have identified over 77 alleles at the DPB1 locus and over 184 at the DRB1 locus. A small number of these alleles are identical in amino acid sequence and differ only at the nucleotide level through silent substi tutions. The other DRB loci (i.e. DRB3) show a relatively modest number of alleles (Table 2) although some of the alleles at DRB.3 differ at many different sites.

In contrast, the HLA class I HLA-A, -B and -C antigens contain polymorphic «1 and a.2 protein domains that comprise the peptide-binding groove encoded within a single heavy chain. The a 1 and «2 domains are encoded in the second and third exons respectively. Like the class II loci, the class I loci are highly polymorphic: population studies have revealed 80 alleles at the HLA-A locus, 175 alleles at the HLA-B locus, and 38 alleles at the HLA-C locus. In general, a given population contains only a subset of the class I or class II alleles that have been identified worldwide and different populations have different allele frequency distributions.


In the WHO nomenclature for HLA alleles, the locus (e.g. DRB1) is followed by an asterisk (*) and by two digits that identify the allele group (e.g. DRB1*04 which, in this case, corresponds to the serologic DR4 type) and two digits that identify the allele or DR4 subtype (e.g. DRB1*0401, DRB1*0402, etc.). An additional digit is used to designate silent variants, that is, different nucleotide sequences that encode the same amino acid sequence (e.g. DRB1*08041 and *08042). For some loci, all the alleles within a single allele group designation (e.g. HLA-B* 15) do not necessarily encode the same serologic type.

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