Red Cell Immunogenetics and Blood Group Terminology
The term ’blood group’ usually refers to an individual’s combination of Red Blood Cell (RBC) surface antigens. Antigens are specific sites on different proteins, glycoproteins or glycolipids that form parts of the RBC membrane which the immune system can interact with. These proteins have numerous functions such as: membrane transporters (Diego, Kidd), receptor and adhesion molecules (Duffy, Lutheran), complement regulatory glycoproteins (Cromer, Knops), enzymes (Yt, Kell, Dombrock), structural components (Diego, Gerbich) or components of the glycocalyx (MNS).
Antigens are defined by antibodies which occur either ‘naturally’ due to encountering antigens ubiquitous in the environment or are formed as a result of active immunisation to non-self RBC antigens following exposure to human RBCs from another individual. It is the presence and absence due to inherited variation of red cell surface antigens that defines the blood group of an individual.
Blood group systems are officially defined as ’systems of one or more antigens governed by a single gene or complex of two or more closely linked homologous genes’. Each system is genetically discrete from every other blood group system. In order for a blood group system and its antigens to be recognised the underlying genetic variation must be identified, sequenced and confirmed to affect phenotype.
The International Society of Blood Transfusion (ISBT) Working Party for Red Cell Immunogenetics and Blood Group Terminology (ISBT WP) maintains an official record of all currently recognised blood group systems. There are currently 43 recognised blood group systems containing 345 red cell antigens (June 2021). The 43 systems are genetically determined by 48 genes. For more information please click on the following links:
ISBT also maintain three categories for antigens that have not yet been linked to blood group systems. Collections (the 200 series) were designed to group antigens which are biochemically, genetically or serologically similar where the genetic basis has not yet been discovered. There are also two antigen series; the 700 Series contains antigens which do not fit into any system or collection which have an incidence of <1% across all human ethnic populations, and the 901 Series contains antigens which have a frequency >99% across populations of different ethnic ancestry.
We are involved in the genetically based numerical terminology for red cell surface antigens. By definition, these antigens must be defined serologically by the use of specific antibodies. All antigens receive a unique ISBT number and must have been shown to be inherited characters. We advise, maintain and monitor the terminology for blood group genes and genetic classification for blood group antigens. We offer members the opportunity to participate in the development/maintenance of nomenclature. We discuss all issues related to molecular typing as well as the analysis of blood group genes.
Our Chairpersons are Catherine Hyland and Christoph Gassner.
We meet at the ISBT congresses and maintain up to date catalogues of blood group antigens and alleles. We also write guidelines for nomenclature.
Any ISBT member can join the WP; candidates are evaluated on their merits based on publication records and CV.
The red cell membrane contains many anchored surface proteins; many of these are polymorphic and carry the different blood groups. Most blood group antigens are glycoproteins and their specificity is mostly determined either by the oligosaccharide or amino acid sequence. The 30 human blood group system genes have been identified and sequenced and all the polymorphisms are now known. Most blood group polymorphisms result from single nucleotide polymorphisms (SNPs) encoding amino acid substitutions in either a glycosyltransferase or extracellular domain of a red cell membrane protein.
All authenticated antigens fall into one of four classifications: systems, collections, low and high incidence antigens:
- Systems consist of one or more antigens controlled at a single gene locus, or by two or more very closely linked homologous genes with little or no observable recombination between them.
- Collections (200 series) consist of serologically, biochemically, or genetically related antigens, which do not fit the criteria required for system status.
- 700 Seriesor low incidence antigens with an incidence of less than 1% and cannot be included in a system or collection.
- 901 Series or high incidence antigens with an incidence of greater than 90% and cannot be included in a system or collection.
Since their discovery in 1900, a variety of different styles of terminology has been used to denote human blood groups. In 1980 the ISBT established therefore a Working Party (later to become a Committee) to devise and maintain a genetically based numerical terminology for red cell surface antigens. By definition, these antigens must be defined serologically by the use of a specific antibody. All antigens receiving ISBT numbers must have been shown to be inherited characters. The information presented here is an update of one of our publications.
Antigens, phenotypes, genes and genotypes
- Each antigen belonging to a blood group system is identified by a 6-digit number. The first 3 digits represent the system (e.g. 006 for Kell), the second 3 the specificity (e.g. 006003 for Kpa). Alternatively, the system symbol followed by the antigen number may be used (e.g. KEL003 or, more usually, KEL3 as sinistral zeros may be removed).
- Phenotypes are represented by the system symbol, followed by a colon, followed by a list of antigens separated by commas. Those antigens shown to be absent are preceded by a minus sign (e.g. KEL:-1,2,3,4).
- Alleles are designated by the system symbol, followed by an asterisk, and antigen number, all italicised (e.g. KEL*02). · Genotypes have the system symbol, followed by an asterisk, alleles or haplotypes separated by a slash, all italicised (e.g. KEL*02.03/02). Refer to the allele terminology guidelines and tables for more detail.
- For collections, antigen, phenotype, gene, and genotype designations are constructed in the same way.
- For the 700 and 901 series, 700 or 901 replaces the system symbol.
User-friendly and 'everyday' terminology
The numerical terminology was devised primarily for computer storage of information on blood group antigens and to provide a framework for a genetic classification. The numerical terminology is not suitable for everyday communication and many scientists working in the field of human blood groups prefer not to use it in publications. This has led to a variety of alternative names being used for some blood group antigens. In an attempt to introduce some uniformity, a recommended list of alternative names for antigens is provided (see table). In most cases the name or symbol is identical to that originally published, but in a few cases the more commonly used name is provided. In addition, there are recommended formats for describing phenotypes in the alternative terminology.
Criteria for the establishment of new blood group systems
For an antigen to form a new blood group system:
- the antigen must be defined by a human alloantibody
- the antigen must be an inherited character
- the gene encoding it must have been identified and sequenced
- its chromosomal location must be known
- the gene must be different from, and not a closely-linked homologue of, all other genes encoding antigens of existing blood group systems.
Criteria for the inclusion of a new specificity in an established system
All antigens awarded an ISBT number must have been shown to be inherited and at least one of the following four criteria must be met:
- An antithetical relationship between a new antigen and one already assigned to the system.
- Demonstration that expression of the antigen is associated with a variation in the nucleotide sequence of the gene controlling the system.
- Evidence, from a linkage analysis of family data, that the controlling allele is probably a newly recognised form of the pertinent gene, and supporting serological or biochemical information.
- Demonstration that an antigen is located on a protein or glycoprotein that carries other antigens belonging to the system. It must be remembered, however, that this could result from post-translational modification of a gene product, such as glycosylation, which would not support inclusion within the system.
Criteria for establishment of a blood group collection
A collection must contain two or more antigens that are related serologically, biochemically, or genetically, but which do not fit the criteria required for system status.
Criteria for inclusion in the 700 series
- Incidence of <1% in most populations tested.
- Distinction from all other numbered low incidence antigens of the 700 series as well as those of the blood group systems and collections.
- Demonstration of inheritance through at least 2 generations.
Criteria for inclusion in the 901 series
- Incidence of >90% in most populations tested.
- Distinction from all other numbered high incidence specificities.
- Demonstration that the antigen is lacking from the red cells of at least 2 siblings, i.e. that the negative phenotype is genetically determined.
Once a number has been allocated to a specificity, that number cannot be subsequently used for any other specificity. Consequently, if the number of a specificity becomes inappropriate, then that number becomes obsolete. The obsolete numbers are listed here.
Procurement of ISBT Numerical Designations
Symbols for designations of new specificities will consist of 3-6 on-line capital letters and must not duplicate, alphabetically or phonetically, any current or obsolete symbols shown in the tables. Also, symbols used in related fields, such as those used for platelet and leucocyte antigens, must be avoided. Symbols for specificities that may herald new blood group systems, and thus new genes, have the further constraint that they must differ from any symbols given to genes by the HUGO Nomenclature Committee.
Procedures for acquisition of an ISBT number
The initial stipulation is that materials for defining the new specificity be available for either circulation or in-house testing. Proposals should be submitted with supporting data to the members of the Committee listed below, who are authorised to allocate provisional numbers. All decisions must be ratified by the Committee before being finalised. To submit a proposal for the acquisition of an ISBT number, please contact the following Committee members:
- Jill Storry for new blood group system, collections and specificity numbers in a current collection (200 series).
- Nuria Nogues for 700 numbers.
- Catherine Hyland for 901 numbers.
For a specificity number within an established system, see the following contact persons in the table below.
Name Blood Group System
Responsible Committee Member
|016||LW||Christine Lomas Francis|
|021||CROM||Christine Lomas Francis|
|042||EMM||William Joseph Lane|
|Transcription Factors||GATA1, KLF1||Margaret Keller|
As DNA testing for the prediction of blood group phenotypes has become more widely applied, it is important to have an agreed terminology for the multitude of alleles encoding blood group phenotypes. A subgroup of this WP has taken this on and made a decision that two nomenclatures are required:
- A comprehensive database in which all blood group alleles can be identified. This would provide the official allele name and would require that the whole coding region of the gene has been sequenced. This is still to be developed.
- A transfusion medicine-friendly terminology that can be used when only part of the gene has been sequenced or analysed, such as a single nucleotide polymorphism (SNP).
A draft of general guidelines for 'transfusion medicine' terminology was developed by a group consisting of Geoff Daniels, Marion Reid, Jill Storry (WP's chairperson), Connie Westhoff, and Martin Olsson.
Additionally, special guidelines for naming RH alleles were developed in parallel by Connie Westhoff, due to the complexity of RH. These two guidelines were approved by the WP, at the Berlin Congress in 2010. Since the terminology was new and took some time to adopt into routine practice, all comments were discussed in 2012. Currently, guidelines and tables for 27 of the 30 blood groups are listed, as well mutations in GATA1 and KLF1 responsible for blood group phenotypes. Other systems will be added as they are completed.
Information regarding new alleles should be sent to the blood group-responsible committee member on the front page.
Blood Group System
|004||RHD Negative Null|
|004||Weak D and Del|
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- Characterization of a novel high-prevalence antigen in the JMH blood group system 2019 June
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- Knops Alleles and Antigens
- Cell‐free fetal DNA and fetal blood group genotyping: non‐invasive prenatal testingISBT Science Series 06 September 2019
- International Society of Blood Transfusion Working Party on Red Cell Immunogenetics and Blood Group Terminology: Report of the Dubai, Copenhagen and Toronto meetings.Vox Sanguinis, 12 November 2018
- Missense mutations in the C-terminal portion of the B4GALNT2-encoded glycosyltransferase underlying the Sd(a−) phenotypeBiochemistry and Biophysics Reports, Volume 19, September 2019, 100659
- International society of blood transfusion working party on red cell immunogenetics and terminology: report of the Seoul and London meetings.ISBT Sci Series 2016 Aug;11(2):118-122. doi: 10.1111/voxs.12280
- International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Cancun report (2012)Vox Sanguinis (2014) 107, 90–96
- The ISBT 700 series of low-incidence and 901 series of high-incidence blood group antigens.Immunohematology. 2011;27(4):131-5. Review.
- International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology: Berlin report.Vox Sang. 2011 Jul;101(1):