Hla Nomenclature

Two nomenclature systems exist for the HLA system. The HLA system was originally described using alloan-tisera reactive with antigenic determinants of HLA molecules expressed at the cell surface and a nomenclature developed around that typing system. With the advent of DNA-based methods in the mid-1980s a dramatic increase in the level of polymorphism was revealed and required an additional nomenclature system. Alleles identified by DNA typing were grouped according to nucleotide sequence homology, but to the degree possible the allele names retained a relation to the serologic or antigen-level names.

Figure 93.6 outlines the basics of the DNA-based nomenclature. HLA allele names indicate the locus (e.g., HLA-A*) followed by up to eight digits that refer to a unique nucleotide sequence. With the exception of HLA-DPBI* the first two digits of an HLA allele name can be referred to as a family or group designation that signifies a high level of sequence homology. DPBI* allele names are not grouped into homology-related families in general. This group or family in many, but not all, cases correlates with the serologic or antigen-level typing of the allele product. The third and fourth digits relate to the encoded protein product of the allele. The fifth and sixth digits, when present, indicate nucleotide sequence variant alleles that encode the same protein product due to codon redundancy (synonymous alleles). The seventh and eighth digits refer to allele nucleotide polymorphism outside of

HLA-A*020101 HLA-A* 020101 HLA-A*020101 HLA-A*020I01 HLA-A*020101 HLA-A* 02 0102

A locus

Group / Family Allele identifier

Distinct bases Same protein

Synonymous alleles

HLA-DRB4*01030101 HLA-DRB4*01030102N-

Intron & regulatory variants

HLA-DRB4*01030102N Null allele

HLA-A*24020102L Low-expression allele

Figure 93.6 HLA nomenclature. HLA DNA-based nomenclature consists of the HLA complex name followed by the locus identifier and a multidigit allele identifier with or without a qualifying letter designation. The significance of various positions is indicated in this figure the coding portions (exons) of the allele. In some cases, these noncoding variations cause important functional characteristics of the allele, such as null or low expression. These expression variants can also be shown with an appended letter suggestive of the expression variation (e.g., N = null, L = low, S = soluble). The most current listing of HLA alleles can be foundathttp://www.ebi.ac.uk/imgt/hla/index.html.54

In the laboratory, HLA alleles or molecules can be defined at different levels. Serologic HLA typing defines HLA products based on the pattern of reactivity with selected antibodies. DNA typing systems generally test for particular sequence motifs using sequence-specific oligonucleotide primer amplification (PCR-SSP) and/or oligonucleotide probe hybridization (PCR-SSOP) or direct sequencing (SBT) of amplified gene segments. Low-to-intermediate level resolution DNA test systems identify group or family level types (two digit nomenclature) that correlate in large part to antigen- or serologic-level typing. High-resolution DNA systems indicate specific alleles or a very limited set of allele possibilities. Aside from expression variant alleles, the first four digits of an allele name can be considered to fully define the expressed HLA product (four digit nomenclature).

In many cases, the first two digits of the HLA allele name correspond to the serologic or antigen name of the encoded product. For example, A*01, A*02, B*07, B'08 alleles serologically type as A1, A2, B7, and B8 for all of the characterized alleles. In other cases, the allele group and serologic antigen name do not have this mnemonic similarity. For example, the B*40 group of alleles encode B60 (e.g., B*4001) and B61 (e.g., B*4002) antigens by serology. In these cases, the alle-les are clearly related based on sequence homology, but are distinct in key residues that are involved in formation of epitopes recognized by antibodies (and T cells). The best source that correlates serologic antigen names with HLA alleles is that of Schreuder and colleagues.55 Since many new HLA alleles discovered in DNA-based testing are not serologically characterized, the antigen-level assignment is not formally known. In many cases the probable antigen-level assignment can be surmised by a knowledge of which amino acid sequence motifs are important in antigen definition. A useful resource for this can be found at http://tpis.upmc.edu/tpis/HLAMatchmaker/.56

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