Page 106 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHAPtER 5 The Major Histocompatibility Complex 91

HLA typing by NGS has been introduced only recently, it is Hyphen used to separate Suffix used to denote
likely that this new method will transform the way HLA typing gene name from HLA prefix changes in expression
is performed in the coming years.
Field separators
Separator
KEY CoNCEPtS
The Resolution of the Human Leukocyte Antigen HLA-A*02:101:01:02N
(HLA) Typing Problem HLA prefix Gene Field 4; used to show
differences in a
• Currently HLA typing is performed primarily through DNA-based Field 1; allele group noncoding region
methodologies. Field 2; specific HLA protein
• It appears that the dominant methodology will soon be the single
molecule DNA sequencing (next-generation sequencing [NSG]) and Field 3; used to show a synonymous DNA
most likely with platforms sequencing the length of the whole gene, substitution within the coding region
whether class I or class II. FIG 5.6 Human Leukocyte Antigen (HLA) Nomenclature.
[Courtesy of Steven G. E. Marsh, Anthony Nolan Research
Institute, London, United Kingdom.]
HLA NOMENCLATURE

The HLA genes/alleles are very polymorphic (about 15,000 have allele strings, the codes “P” and “G” were introduced. A group
been named, and close to 30,000 sequence entries have not been of alleles having nucleotide sequences that encode the same
named yet), and their numbers are expected to further increase, protein sequence for the peptide binding domains (exon 2 and
approaching hundreds of thousands, possibly millions. This has 3 for HLA class I and exon 2 only for HLA class II alleles) will
led to the development of comprehensive systems for their be designated by an upper case “P,” which follows the two-field
naming. allele designation of the lowest-numbered allele in the group.
The WHO Nomenclature Committee for factors of the HLA For example, HLA-A*01:01:01:01, HLA-A*01:01:01:03, or
system undertook the first systematic approach for the naming HLA-A*01:37 could be named HLA-A*01:01P.
of HLA alleles in 1968. The HLA naming convention has A group of alleles that have identical nucleotide sequences
undergone a substantial number of iterations because the earlier across the exons encoding the peptide binding domains
naming conventions were unable to address the growing numbers (exons 2 and 3 for HLA class I and exon 2 for HLA class II) were
and complexity of alleles (i.e., A*02 and B*15 have more than named after the first allele in the sequence and given the code
100 alleles). The most recent nomenclature was introduced in “G” as a suffix. The upper case “G” follows the first three fields
2010 to address the growing numbers of new alleles being dis- of the allele designation. For example, HLA-A*01:01:01:01,
covered and to reduce naming complexity and confusion. The HLA-A*01:01:01:03, or HLA-A*01:37 could be named HLA-
changes added colons (:) into the allele names to act as delimiters A*01:01:01G. More details regarding HLA nomenclature can be
of the separate fields (field separator). Thus each HLA allele found on the website: http://hla.alleles.org.
name has a unique number corresponding to up to four sets of To manage and to have access to the sequences of the ever-
digits separated by colons. growing number of alleles, the IMGT/HLA Database project
The first field following the asterisk in the allele name was initiated in 1997 as part of a European collaboration. The
(XX:xx:xx:xx) describes the allele family and generally corresponds database is an invaluable resource, as it provides detailed DNA
to the serological assignment carried by the allele. HLA typing sequences and protein sequences for all known HLA alleles. It
defined only at the first field is often referred to as “low-resolution is also interactive and incorporates tools for data retrieval and
typing.” The second field following the first colon (xx:XX:xx:xx) analysis so that the user can select what segments of the gene/
is assigned sequentially as new alleles are determined (e.g., 01, molecule to examine and make comparisons among different
02, 03….101, etc.). Together, these two fields (XX:XX) indicate alleles. It can also be used for new data submission.
one or more nucleotide substitutions that change the HLA protein
coding sequence and are often referred to as “high-resolution oN tHE HoRIZoN
typing.” Indeed, the Harmonization of Histocompatibility Typing
Terms Working Group recently defined a high-resolution typing • Advanced technologies for the sequencing and detailed characterization
result “as a set of alleles that encode the same protein sequence of human leukocyte antigens (HLAs) and of the whole major histo-
compatibility complex (MHC) should allow a clearer elucidation of the
for the region of the HLA molecule called the antigen-binding functional interrelationships of the different genes within the MHC
site and that exclude alleles that are not expressed as cell-surface and the genomic elements responsible for many MHC-associated
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proteins.” The third field (xx:xx:XX:xx) is for designating diseases.
synonymous nucleotide substitutions within the coding sequence • Computational approaches for the accurate definition of peptide-binding
that do not change the amino acids of the protein, and the fourth properties of individual HLA alleles, whether class I or class II, will
field (xx:xx:xx:XX) identifies sequence polymorphisms in introns, influence our ability to control the tri-molecular complex of HLA–
peptide–TCR and therefore control some processes, such as responses
or in the 5’ and 3’ untranslated regions (Fig. 5.6). to infectious diseases, autoimmunity, transplantation, vaccine design,
All alleles receive a name that includes at least the first two and cancer.
fields. At the end of the allele name, specific characters have • Immunotherapies for cancer involving neoantigens will require individual-
been added (N = null; L = low expression; S = secreted; C = ized approaches when HLA alleles play a critical role.
cytoplasm; A = aberrant; Q = questionable) to designate unique • Understanding the genomic organization of the MHC, the most complex
characteristics for an allele, such as whether a protein is not genomic region in the human genome, will most likely reveal and
expressed (i.e., HLA-A*24:09N) or whether the expression of teach us important lessons relevant to the organization and operation
of the rest of the genome as well.
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the protein is unclear (i.e., HLA-A*32:11Q). For ambiguous