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The WHO Nomenclature Committee for Factors of the HLA System met following the 14th International HLA and Immunogenetics Workshop in Melbourne, Australia in December 2005 and Buzios, Brazil during the 15th International HLA and Immunogenetics Workshop in September 2008. This report documents the additions and revisions to the nomenclature of HLA specificities following the principles established in previous reports (1–18).
A number of HLA gene fragments have been reported and named. These are HLA-T previously known as HLA-16 (19), HLA-U previously known as HLA-21 (19), HLA-V previously known as HLA-75 (19), HLA-W previously known as HLA-80 (19), HLA-P previously known as HLA-90 (19) and HLA-Y previously known as HLA-BEL/COQ/DEL (20, 21). A full list of all recognised HLA genes is given in Table 1.
a. Conditions for acceptance of new allele sequences
As emphasised in previous reports, there are required conditions for acceptance of new sequences for official names.
Although at present it is only a recommendation that full-length sequences of the coding region of novel alleles be submitted it was widely felt that in the future this should become a requirement for submission. Such requirement would remove many of the currently encountered ambiguities in the assignment of names to alleles for which partial sequences have been submitted and should not be burdensome as sequencing techniques have improved substantially since the submission conditions were first devised. In cases where novel mutations or polymorphisms are detected in non-coding regions of the gene, it will be a requirement that full-length sequences be submitted of both the novel allele and its most closely related allele.
It should be noted with some caution that cells from which only partial sequences have been obtained may later be shown to have different or novel alleles when further sequencing is performed. This is of particular importance in cases where partial sequences of what appears to be the same allele have been obtained from several different cells. In such cases, all cells studied have been listed in this report.
Current practice is that official designations will be promptly assigned to newly described alleles in periods between Nomenclature Committee meetings, provided that the submitted data and its accompanying description meet the criteria outlined above. A list of the newly reported alleles is published each month in nomenclature updates in the journals Tissue Antigens, Human Immunology and the International Journal of Immunogenetics. The listing of references to new sequences does not imply priority of publication. The use of numbers or names for alleles, genes or specificities which pre-empt assignment of official designations by the Nomenclature Committee is strongly discouraged.
The list of those genes in the HLA region considered by the WHO Nomenclature Committee is given in Table 1.
b. New Allele Sequences
A total of 2558 HLA alleles have been named since the last report (18). The newly named alleles are shown in bold typeface in Tables 2 to to11.11. For HLA class I, 616 HLA-A, 913 HLA-B, 446 HLA-C, four HLA-E, 19 HLA-F, 31 HLA-G, 12 HLA-H, nine HLA-J, six HLA-K, five HLA-L, four HLA-P and three HLA-V alleles were named, making a total of 3249 class I alleles with official names. For HLA class II, 368 HLA-DRB1, 12 HLA-DRB3, one HLA-DRB4, one HLA-DRB5, seven HLA-DQA1, 45 HLA-DQB1, six HLA-DPA1, 22 HLA-DPB1, one HLA-DMB and four HLA-DOA alleles were named, making a total of 1198 class II alleles with official names. Eleven MICA alleles were named bringing their total to 68 and 12 MICB alleles bringing their total to 30 alleles, see Table 12. The total number of alleles at each locus assigned with official names as of 31st December 2009 is given in Table 13. A full list of all allele names that have been deleted is given in Table 14.
In February 2005 the allele A*30:14L was named. The allele has a mutation in codon 164 encoding a cysteine residue contributing to a structurally critical disulphide bond in the α2 domain of the HLA molecule. Expression studies performed on cells with this allele showed its protein to have a much-reduced expression compared to normal, and the allele name was thus given the suffix ‘L’ to indicate this low expression. Since then several other alleles have been reported that have also lost one of the two cysteine residues (position 101 and 164) that form the α2 domain disulphide bond. It has not, however, been possible to ascertain the expression status of these alleles, due to a lack of viable material. The Nomenclature Committee considered the naming of these alleles during the 14th HLA and Immunogenetics Workshop. As a result of these discussions, it was decided to introduce an additional suffix, Q, to indicate a ‘Questionable’ expression level. The first seven alleles to receive this suffix have been named and are included in this report, A*23:19Q, A*32:11Q, B*13:08Q, B*35:65Q, B*39:38Q, C*02:25Q and C*03:22Q. It is anticipated that when further examples of these alleles are described, their expression status will be determined and the suffix changed accordingly.
As the database of HLA allele sequences has expanded, it has become increasingly difficult to maintain consistent linkage between allele names assigned on the basis of nucleotide sequences and the serological profiles of the encoded proteins. These difficulties are in part technological and in part due to the inherent biological properties of the HLA system. In the first category there is the increasing emphasis on DNA technology and consequent lack of a serological description for many newly discovered HLA alleles. In the second category is the finding that a newly defined antigen does not comfortably fit within any known serological grouping. This is especially true of the HLA-DRB1*03, *11, *13, *14 and *08 family of alleles, for which the description of new alleles has revealed a continuum of allelic diversity rather than five discrete sub-families. It should be stressed that, although a goal is to indicate the serological grouping into which an allele will fall, this is not always possible. Most importantly the allele name should be seen as no more than a unique designation.
Where this information is known, lists of the serological specificities or antigens associated with the alleles, is given in Tables 2–7. In most cases these data are based on the serological typing obtained for the cells that were sequenced for the individual alleles and from information submitted to the Committee. In many cases no serological information is available and the entry in the table has been left blank. This is also true for cases when the serological pattern associated with an expressed allele does not correspond to a single defined specificity. A comprehensive dictionary of antigen and allele equivalents is published periodically by the World Marrow Donor Association (WMDA) Quality Assurance Working Group on HLA Serology to DNA Equivalents (22–26). Where additional or superior serological data are available from the dictionary, this has been included in Tables 2–7 and the source of this information indicated. A full list of all officially named serological specificities is given in Table 15. The specificity B82 was assigned following the 14th International HLA and Immunogenetics Workshop in 2005 having been clearly identified as a novel antigen in a number of UCLA cell exchanges.
The convention of using a four-digit code to distinguish HLA alleles that differ in the proteins they encode was introduced in the 1987 Nomenclature Report (8). Since that time additional digits have been added, and currently an allele name may be composed of four, six or eight digits dependent on its sequence.
The first two digits describe the allele family, which often corresponds to the serological antigen carried by the allotype. The third and fourth digits are assigned in the order in which the sequences have been determined. Alleles whose numbers differ in the first four digits must differ by one or more nucleotide substitutions that change the amino-acid sequence of the encoded protein. Alleles that differ only by synonymous nucleotide substitutions within the coding sequence are distinguished by the use of the fifth and sixth digits. Alleles that only differ by sequence polymorphisms in introns or in the 5′ and 3′ untranslated regions that flank the exons and introns are distinguished by the use of the seventh and eight digits.
In 2002 we faced the issue of the A*02 and B*15 allele families having more than 100 alleles (17). At that time the decision taken was to name further alleles in these families in the rollover allele families A*92 and B*95 respectively. For HLA-DPB1 alleles, it was decided to assign new alleles within the existing system, hence once DPB1*9901 had been assigned, the next allele would be assigned DPB1*0102, followed by DPB1*0203, DPB1*0302 etc.
When these conventions were adopted it was anticipated that the nomenclature system would accommodate all the HLA alleles likely to be sequenced. Unfortunately this is not the case, as the number of alleles for certain genes is fast approaching the maximum possible with the current naming convention.
With the ever increasing number of HLA alleles described it has been decided to introduce colons (:) into the allele names to act as delimiters of the separate fields. To facilitate the transition from the old to the new nomenclature, a single leading zero must be added to all fields containing the values 1 to 9 but beyond that no leading zeros are allowed. This will help to lessen any confusion in the conversion to the new style of nomenclature.
A*01010101 becomes A*01:01:01:01
A*02010102L becomes A*02:01:01:02L
A*260101 becomes A*26:01:01
A*3301 becomes A*33:01
B*0808N becomes B*08:08N
DRB1*01010101 becomes DRB1*01:01:01:01
For allele families that have more than 100 alleles such as the A*02 and B*15 groups it will be possible to encode these in a single series. Thus the A*92 and B*95 alleles have now been renamed in to the A*02 and B*15 allele series. For example:
A*9201 becomes A*02:101
A*9202 becomes A*02:102
A*9203 becomes A*02:103 etc
B*9501 becomes B*15:101
B*9502 becomes B*15:102
B*9503 becomes B*15:103 etc
The names A*02:100 and B*15:100 will not be assigned. In cases of other allele families where the number of alleles reaches 100 these will be numbered sequentially, for example A*24:99 will be followed by A*24:100.
The DPB1 allele names that have been previously assigned names within the existing system have also be renamed, for example:
DPB1*0102 becomes DPB1*100:01
DPB1*0203 becomes DPB1*101:01
DPB1*0302 becomes DPB1*102:01
DPB1*0403 becomes DPB1*103:01
DPB1*0502 becomes DPB1*104:01 etc
The ‘w’ will be removed from the HLA-C allele names, but will be retained in the HLA-C antigen names, to avoid confusion with the factors of the complement system and epitopes on the HLA-C molecule often termed C1 and C2 that act as ligands for the Killer-cell Immunoglobulin-like Receptors.
Cw*0103 becomes C*01:03
Cw*020201 becomes C*02:02:01
Cw*07020101 becomes C*07:02:01:01 etc
Details of the new format allele names are given in column 1 of Tables 2–12, with the previous name listed in column 2. These changes to the HLA Nomenclature will be officially introduced in April 2010. A full listing of old and new HLA allele names will be made available through the IMGT/HLA Database (www.ebi.ac.uk/imgt/hla) (27, 28) and be implemented with the April 2010 release of the database.
The level of resolution achieved by many of the HLA typing technologies employed today does not always allow for a single HLA allele to be unambiguously assigned. Often it is only possible to resolve the presence of a number of closely related alleles. This is referred to as an ambiguous ‘string’ of alleles. In addition, typing strategies are frequently aimed at resolving alleles that encode differences within the peptide binding domains, but fail to exclude those that differ elsewhere. For some purposes it is helpful to provide codes that aid the reporting of certain ambiguous alleles ‘strings’. The decision was taken to introduce codes to allow for the easy reporting of:
a. HLA alleles that encode for identical peptide binding domains
HLA alleles having nucleotide sequences that encode the same protein sequence for the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) will be designated by an upper case ‘P’ which follows the allele designation of the lowest numbered allele in the group.
For example the string of allele names below share the same α1 and α2 domain protein sequence encoded by exons 2 and 3.
A*02:01:01:01/A*02:01:01:02L/A*02:01:01:03/A*02:01:02/A*02:01:03/A*02:01:04/A*02:01:05/A*02:01:06/A*02:01:07/A*02:01:08/A*02:01:09/A*02:01:10/A*02:01:11/ A*02:01:12/A*02:01:13/A*02:01:14/A*02:01:15/A*02:01:17/A*02:01:18/A*02:01:19/A*02:01:21/A*02:01:22/A*02:01:23/A*02:01:24/A*02:01:25/A*02:01:26/A*02:01:27/ A*02:01:28/A*02:01:29/A*02:01:30/A*02:01:31/A*02:01:32/A*02:01:33/A*02:01:34/A*02:01:35/A*02:01:36/A*02:01:37/A*02:01:38/A*02:01:39/A*02:01:40/A*02:01:41/ A*02:01:42/A*02:09/A*02:66/A*02:75/A*02:89/A*02:97:01/ A*02:97:02/A*02:132/A*02:134/A*02:140
This string can be reduced to A*02:01P
b. HLA alleles that share identical nucleotide sequences for the exons encoding the peptide binding domains
HLA alleles that have identical nucleotide sequences for the exons encoding the peptide binding domains (exon 2 and 3 for HLA class I and exon 2 only for HLA class II alleles) will be designated by an upper case ‘G’ which follows the allele designation of the lowest numbered allele in the group.
For example the string shown below consists of alleles that have identical nucleotide sequences in exons 2 and 3.
This string can be reduced to A*02:01:01G
These reporting codes will be implemented in April 2010 and will be made available through the IMGT/HLA Database (www.ebi.ac.uk/imgt/hla) (27, 28) and will be implemented with the April 2010 release of the database.
Discussions took place on the use of nomenclature for defining HLA allele sequences at the gene and protein level. The committee recommended the use of standard genetic nomenclature where gene symbols are in uppercase and italicised and protein symbols are the same as the gene symbols but are not italicised. Using this approach it is possible to discriminate between an allele of the HLA-A gene, for example A*03:01 and the expressed protein product of the same gene A*03:01.
Additionally it was recommended that when reporting an ambiguous string of HLA alleles, a forward slash (/) should be used as the separator to indicate ‘or’. When reporting genotypes it was recommended to use a comma (,) to indicate ‘and’. Hence an HLA type may be reported as:
A*02:01/02:09, 03:01; B*07:02, 15:02/15:73; C*03:03, 07:02
The IMGT/HLA Sequence Database continues to act as the official repository for HLA sequences named by the WHO Nomenclature Committee for Factors of the HLA System (27, 28). The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools, and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. New releases of the database are made every three months, in January, April, July and October, with the latest version (release 2.28.0 January 2010) containing 4447 HLA alleles. The database may be accessed via the worldwide web at www.ebi.ac.uk/imgt/hla.
The IMGT/HLA Database is currently supported by the following organisations: Histogenetics, Abbott, Biotest, Invitrogen, One Lambda, Olerup SSP, Gen-Probe, The Anthony Nolan Trust (ANT), The American Society for Histocompatibility and Immunogenetics (ASHI), The European Federation for Immunogenetics (EFI), Innogenetics, BAG Healthcare, Be the Match Foundation and the National Marrow Donor Program.
The Committee would like to thank James Robinson, Kavita Mistry, Matthew Waller and Sylvie Fail for their work with the IMGT/HLA Sequence database, and Kavita Mistry for her help in the preparation of tables for this report. Also thanked are Rodrigo Lopez, Hamish McWilliam and Peter Stoehr and the staff at the European Bioinformatics Institute for their continued support of the IMGT/HLA Database. We would also like to thank the many organisations that provide financial support for the IMGT/HLA database and Angie Dahl of the ‘Be the Match Foundation’ for her work in soliciting and coordinating the funding of this project.
SGE Marsh, Anthony Nolan Research Institute, London, UK (Chairman)
ED Albert, Munich, Germany
WF Bodmer, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK
B Dupont, Sloan-Kettering Institute for Cancer Research, New York, USA
HA Erlich, Roche Molecular Systems, Alameda, USA
M Fernández-Viña, MD Anderson, Houston, USA
DE Geraghty, Fred Hutchinson Cancer Center, Seattle, USA
R Holdsworth, Victorian Transplantation and Immunogenetics Service, Melbourne, Australia
CK Hurley, Georgetown University, Washington, USA
M Lau, UCLA School of Medicine, Los Angeles, USA
KW Lee, Hallym University, Anyang City, South Korea
B Mach, University of Geneva, Geneva, Switzerland
M Maiers, National Marrow Donor Program, Minneapolis, USA
WR Mayr, Medical University of Vienna, Vienna, Austria
CR Müller, Zentrales Knochenmarkspender-Register, Ulm, Germany
P Parham, Stanford University School of Medicine, Stanford, USA
EW Petersdorf, Fred Hutchinson Cancer Center, Seattle, USA
T Sasazuki, International Medical Centre of Japan, Tokyo, Japan
JL Strominger, Harvard University, Cambridge, USA
A Svejgaard, State University Hospital, Copenhagen, Denmark
PI Terasaki, Los Angeles, USA
JM Tiercy, Hôpital Cantonal Universitaire, Geneva, Switzerland
J Trowsdale, Cambridge University, Cambridge, UK
RE Bontrop, Biomedical Primate Research Centre, Rijswijk, The Netherlands
New sequences should be communicated to Prof Steven Marsh via the sequence submission tool of the IMGT/HLA Database to receive official names, www.ebi.ac.uk/imgt/hla.