Terminology for blood group antigens and genes—historical origins and guidelines in the new millennium

Abstract

In 1901, Landsteiner named the first two blood group antigens A and B, using the first two letters of the al- phabet.1 RBCs not reacting with anti-A and anti-B were called type C.1 In 1902, von Decastello and Sturli2 described RBCs reacting with both anti-A and anti-B but did not give this type a name; they continued calling RBCs that did not react with anti-A and anti-B type C. In a publication in 1910,3 Landsteiner showed serologic results of all four ABO types but did not use the terms O and AB. In 1911, von Dungern and Hirszfeld4 appear to be the first to use the term O to describe RBCs not reacting with anti-A and anti-B and the term AB for RBCs reacting with both anti-A and anti-B. The lack of A and B was indicated by the letter "O", but it is controversial whether this letter should have been printed as a zero (0) or whether the letter O came from the first letter of the German word "ohne" meaning without (i.e., without A or B). The letter O was commonly used in print and speech, and, almost 100 years later, the ISBT Working Party on Terminology for Red Cell Surface Antigens has recommended that we continue to use the letter O.5 Many readers may not realize that there were problems with ABO terminology during the several decades following Landsteiner's discovery. In 1907, Jansky6 proposed using Roman numerals I, II, III, and IV for O, A, B, and AB, respectively. In 1910, Moss7 (in the United States), who had not read Jansky's article, which appeared in an obscure Czech journal, also, independently, suggested using Roman numerals. Unfortunately, Moss suggested IV for group O and I for group AB, a reversal of Jansky's terms. For some years, both numerical terminologies were popular: Moss's nomenclature was popular in the United Kingdom, France, and some parts of the United States, while Jansky's system was popular in other parts of the United States and elsewhere. In 1921, the American Association of Immunology, the Association of Pathologists and Bacteriologists, and the Society of American Bacteriologists made a joint recommendation that, “on the basis of priority,...the Jansky classification be adopted.”8(p130) Because of the continuing confusion, Landsteiner suggested in 19279 the universal use of the symbols A, B, O, and AB, instead of Roman numerals. Nevertheless, it is noteworthy that results of a survey published in 192910 indicated that 71 percent of 552 North American hospitals were still using the Moss terminology, 16.5 percent used the Jansky terminology, 2.9 percent used both, and only 4.7 percent used the Landsteiner terminology. Moss's terminology, often combined with letters (e.g., OIV, AII), persisted into the early 1950s in some areas. After the discovery of the Rh system in 1940,11 the nomenclature problem became acute, again because of two different terminologies, the CcDdEe terms of Fisher and Race12 and Race and Sanger13 and the Rh/Hr terms used by Wiener14 and his followers. Thus, in Europe, it was anti-D, -c, -e, etc., and, in most of the United States it was anti-Rho, -hr′, -hr′′, etc. A fascinating review of the history of this controversy has been published.15 A popular way of naming blood group systems was to use all or part of the name of the first antibody maker, or reactive donor (journals such as TRANSFUSION will allow this now only if there is written permission from the patient or donor). For instance, Lewis, Duffy, Scianna, Dombrock, Colton, Gerbich, Cromer, Knops, and Diego were the names of antibody makers. Lutheran should have been Lutteran, which was the name of the donor of the first reactive Lu(a+) RBCs; the original donor blood sample was incorrectly labeled (Tippett P, oral communication, June 1999). Some blood group names came from part of the name or the initials of the antibody maker, such as Kell from Kelleher; JMH from John Milton Hagen; LKE from Luke; Cs from Cost-Sterling; Bg from Bennett-Goodspeed; and Ch and Rg from Chido and Rodgers. On the basis of agreements reached at an international meeting of prominent scientists,16 superscript lower-case letters began to be used to describe new antigens or alleles (e.g., Lea, Fya). Many other examples can be found.17 The derivation of some of the symbols used for the antigens or alleles is interesting. For instance, the Duffy symbol (Fy) came from the last two letters of the antibody maker's name (Duffy), as the first two letters, D and Du, had already been used. The Ok blood group system was named from the family name (Kobutso) of the antibody (anti-Oka) producer; Ko had already been used, so the first letters of the name were reversed to Ok (Morel P, oral communication, June, 1999). Jk came from the initials of the baby (John Kidd) who had hemolytic disease of the newborn, the child of the antibody maker (Mrs. Kidd), as K had already been used for Kell.18 Some of the miscellaneous derivations of names of blood groups are also fascinating. M and N were named with the second and fifth letters of the word immune, because the antibodies were produced by immunizing rabbits with human RBCs, and it was thought that the first letter, I, might be confused with the number 1.19 Although I was not used by Levine and Landsteiner in 1927, it was used, in 1956, by Wiener et al.20 to describe a high-incidence antigen reacting with a powerful cold agglutinin; the letter I was selected to emphasize the high degree of “individuality” of blood specimens failing to react with the patient's serum at room temperature. In 1948, Morgan and Watkins21 suggested changing the terms “anti-O” and “O substance” to “anti-H” and “H substance” (“...the substance might better be called H-substance in place of O-substance, as this would differentiate it as a hetero-genetic, basic or primary substance common to the great majority of red cells irrespective of their ABO group.”). The name of another high-incidence antigen (U) was derived from “the almost universal distribution of the new blood factor.”22(p1445) Sid (Sda) was the first name of the Head of Maintenance of the Lister Institute in London, whose RBCs were part of an in-house panel and reacted strongly with antibodies that were eventually named anti-Sda (Tippett P, oral communication, June, 1999). The Indian blood group system was named because of its association with antibody producers from India. A similar rationale was used for the Bombay (Oh) blood group, the first examples of which were found in that city in India. The name for the S antigen/antibody came from the city (Sydney) where the first anti-S was discovered (Sanger R, oral communication, June 1999). Xg and XK were named because of their association with the X chromosome; the g in Xg stood for Grand Rapids (Michigan), the site of the discovery, and the K in XK for its more obvious association with the Kell system. Because the first example of En(a–) RBCs reacted like enzyme-treated RBCs, Darnborough et al. suggested that they “may have abnormal red cell envelope structure (hence the choice of the symbol En), which may be due to some enzyme abnormality.”23(p253) A low-incidence determinant on Rh:33 RBCs with depressed C and/or e was named FPTT, because three of the four propositi worked for the French Post and Telegraphic Telecommunications.24 A partial D phenotype associated with FPTT was named DFR, "because F is a mnemonic for FPTT, and since a minimum of three letters is required for synonyms, R was added to F to reflect the initial French connection.”25(p616) A few blood groups were named after the scientists who discovered them. For instance, the Landsteiner-Wiener (LW) system was so named because the original Rh antibody, produced by Landsteiner and Wiener by injecting rabbits and guinea pigs with RBCs from rhesus monkeys, and named Rh (anti-Rho or anti-D) after rhesus monkey, was later found to be different from human Rh antibodies (i.e., anti-D). The original antibody produced in rabbits and guinea pigs was found to be identical to human antibodies (anti-LW) that reacted with almost all RBCs tested, but that reacted much better with D+ than D– RBCs; this antibody was named anti-LW after Landsteiner and Wiener. T was named after Oluf Thomsen of Copenhagen, who, in 1926, called the new antigen “L” (for Latency). L was later termed T, in honor of Thomsen, by his assistant Friedenreich, who showed the relationship of T to bacterial infection.26 The “n” of Tn came from the French word “nouvelle,” for a new T antigen.27 Pr came from protease-sensitive.28 The superscript “T” of IT was used because maximal amounts of the antigen were thought to be present during transition from i to I.29 In 1961 and 1962, Allen and Rosenfield30 and Rosenfield et al.31 suggested a numerical nomenclature for the Kell and Rh systems. The numerical nomenclature was intended to allow investigators to report serologic findings without necessarily including genetic interpretations (D or Rho became Rh1, C or rh′ became Rh2, etc., and D+c+e– became Rh:1,4, –5, etc.). Rosenfield et al.31 allocated Rh1 to Rh25, and other investigators have since allocated Rh26 to Rh52.17,32 The numerical terminology was extended to other systems, (e.g., Lutheran); new antigens were named with numbers instead of the traditional names of antibody makers. Thus, the traditional/conventional/popular terminology for antigens is a mixture of letters (e.g., Lea, Fya, K) and numbers (e.g., Rh29, Lu3, K11), with a few remaining names (e.g., Evans, Crawford).17,32 In 1980, the ISBT set up a Working Party on Terminology for Red Cell Surface Antigens. It should be emphasized that their mandate was to devise a uniform nomenclature that would be both eye- and machine-readable. Their first report, in 1982, stated, “The ISBT Working Party is not trying to change the nomenclature of the blood groups. Numbers assigned to specificities are proposed as standard alternatives to current alphabetical names in those circumstances where numbers are necessary as in some computer systems.”33(p165) The working party suggested using upper-case letters and Arabic numbers for system and antigen codes. New antigens named after the introduction of the terminology use three to six upper-case letters (BOW, JONES, etc.). Each system, collection, or series of antigens is given a number (e.g., ABO system = 001) and each antigen within the system is given a number (e.g., A = 001, B = 002). Thus, in computer code, A is 001001 and B is 001002. Sinistral zeros may be omitted so that A can be expressed as 1.1 and B as 1.2. In the Rh system (004), D = 001, C = 002, E = 003, etc. Thus, for the computer, D, C, and E are 004001, 004002, and 004003, respectively. The system symbol and the antigen number, minus the sinistral zeros, may be used (e.g., RH1, RH2, RH3, respectively). Table 1 shows some of the alternatives. The full report of the ISBT Working Party terms appears elsewhere.5,34,35 Although all terms in Table 1 are acceptable, TRANSFUSION chooses to use traditional terminology in most cases. In 1984 and 1992, Issitt and Crookston36 and Issitt and Moulds37 published in TRANSFUSION advice regarding terminology. These articles provided a basis for the terminology used by TRANSFUSION. In addition, the articles gave advice on the correct use of the English language in connection with immunohematologic terms; examples of common errors were given. This advice is still pertinent and has been reemphasized by Issitt and Anstee in the first chapter of their recently published textbook.17 Table 2 shows acceptable terms for blood group systems and antigens. The headings are the system names. Under each system are listed the antigens. Traditional terms are given first; ISBT terms are given in parentheses.Table 3 shows the ISBT collections of antigens. Once more, TRANSFUSION prefers to use traditional names (e.g., I and i rather than I1 and I2). Tables 4 and 5 show low- and high-incidence antigens by name and/or symbol. TRANSFUSION will usually use the symbol when describing these low- and high-incidence antigens. Table 6 shows RBC antigens that are described in the literature and have traditional names but no ISBT names or symbols. In print, the symbol for a gene or gene cluster is usually italicized (or underlined if italics are not possible). The traditional,17,32 ISBT,5,34,35 or International System for Gene Nomenclature (ISGN)38–40 blood group symbols can be used (e.g., Fy, FY, or DARC, respectively; Jk, JK, or SLC14A1, respectively). Table 7 shows the terminology for blood group genes that has been suggested (e.g., by ISBT) on the basis of serologic findings and that used by the Human Gene Mapping (HGM) Nomenclature Committee (which formulated the ISGN), which relates to known functional aspects of the gene product. For instance, the ISGN uses FUT3 (fucosyl transferase 3) for Le, DARC (Duffy antigen receptor for chemokine) for Fy, SLC14A1 (solute carrier family 14, urea transporter member 1) for Jk, SLC4A1 (solute carrier family 4, anion exchanger member 1) for Di, ACHE (acetylcholinesterase) for Yt, AQP1 (aquaporin) for Co, FUT1 (fuco-syltransferase 1) for H, GYPC (glycophorin C) for Ge, DAF (decay-accelerating factor) for Cromer, CR1 (complement receptor 1) for Kn, CD44 for In, and CD147 for Ok. Such functional terms will continually be changing. For instance, the ISBT gene symbol for the Diego (DI) blood group system has not changed for years, but the ISGN name has changed from DI to EPB3 (erythrocyte surface protein band 3) to AE1 (anion exchanger 1) to the present SLC4A1 (solute carrier family 4, anion exchanger member 1). Although it may be difficult to remember two nomenclatures, there is merit in maintaining each system. For serologists, the ISBT are a of the of blood group and the RBC antigens that are still For the ISGN to the or of a gene product. the of gene is at a investigators should the Nomenclature Committee naming gene names and for the Nomenclature Committee are provided in et it is for investigators to realize that ISGN gene change as more functional TRANSFUSION will continue to use traditional gene terminology (e.g., Fy, when are in the ISGN symbols will be used in addition, in (e.g., Jk Antigens of three blood group systems and are by two genes that are on the Because of the genes and gene of these systems can For the blood group system, the two common gene names and the are listed In the Rh system, both the ISBT and the ISGN have the terms and to describe the genes that of the D and the or or respectively. the gene is not known (e.g., in the of an Rh antigen not at the the term can be used. For the system, the ISBT gene name of is used for both the genes and the two and the and the The ISGN names both genes (i.e., and A gene in this family has not been to its in the RBC The of each gene listed in Table 7 to all the number of which from 1 antigen to antigens are of a Thus, they are expressed by using the gene name and an that the For the ISGN uses the gene by an and a letter or number in italics (e.g., A instead of an is also Unfortunately, ISBT uses numbers (e.g., where ISGN uses letters (e.g., Table some examples of the three terminologies used. Table shows the terminology for serologic and is made up of the and groups. The are of two and is a of by of its four from each of the A is a A is a Table shows the used. are the terms and 1 are used (e.g., a a 1 of the of is by using the (e.g., = A is a of three in a that for an or are also to as (e.g., of also known as are indicated in with the number of (e.g., The that the the of to the of the For of the is to show the at the and the at the The of have the from the to the while its appears it with the on the of Each is by or more in (e.g., and for Table the symbols for the A nomenclature for gene has recently been and this is the terminology that TRANSFUSION will This nomenclature for the common types of and is described using examples from blood group examples are listed in Table The A of the is (e.g., a from a or an should be for The number is listed the change (e.g., or is given. in gene is a C at in the by an A in by numbers by the Thus, the is the of a at of the ABO For of more than the is for a can be is by and the For of the phenotype is the of a T and of the AQP1 In the of in the of in the is (e.g., of a C into the would be as an the C and the as the first of the first by the (in and the number of (e.g., an at and 4 and in the the full is this can be used for this is often not the numbers can be used, with numbers with the of the donor site and numbers from the of the site The can be by the number (e.g., or by the number with a (i.e., the number of the last of the the or the number of the first of the following that For that to the phenotype is can also be as is the first of 7 of This can be or a For Table is letter is X for a the three letter is also The is listed by the number and the This nomenclature the meaning of C, A, and T as or The of the protein is given by the number, and the For the is of for that is and correct terminology is as as using correct English in and The correct for both is the most of the Unfortunately, investigators and are not to correct blood group antigen nomenclature and terminology. that this review of current nomenclature will readers and other realize that nomenclature of the history of RBC antigen discovery, functional for RBC and for on RBC surface antigens. by which are used for may be by a of a and to may a or in the or at which is A of has by which of a of an to of the A set of three that for or that expressed of the by the of of are within and Such are most common in expressed that and in functional gene such as and of and of by which the are to two and of the of a read from to or from to of at the of an and of to to a of a gene that is It is present only in or The or to the of the and the of the A that to phenotype or In the of a gene may be by or Gene of genetic as a of in the of the are so that as the which is made to the second the donor (i.e., on the of the and a of the the of the that the of the donor results in while due to a high degree of results in Gene of genetic (i.e., using a as the The of an that and (i.e., A series of alleles within a on a or of from a of may or The of may be used to and of genes often for genes that early show high of of in which the enzyme used for the (i.e., is added to that has been to The of or of are found the and are not The of are of the gene at the and are not expressed as part of the gene of usually 1 to 4 in is into which is eventually into or that has in the of a gene or genetic are several of and in which by by are and to or are used to the or of In a the is In a the is of the of the that are not of are found at the and the often termed are also found within genes (e.g., and and A without a of and of a in in and are of two 1) to or to and to and to may of may also of made in for use as of that may be read the in the and for on and on the may a structure that In for the of a of using The of the is such that in A of such as have been used to into that is found in number is and the that to The of the for of the and are in A labeled that to produced by the of a or that is into an system (i.e., For may be produced by the of the gene into an that may be into cells which to the of the or that and of For to may or The or to the of the and the of the by which (i.e., is to is by the of with a are on the and of which may from to the because of or in is not but with to of in and S is a of the for the of expressed The by of as the are used to the of and of in the and is by the in which may be in of high and or because the association of by of the of or of is a of the of to that are made in of that to that a structure and protein The to an and with and of an to the of the is by the the of a read from to or from to number of may because of in the number of is by with for a to the number of A is 5 to in genetic that, when into a can of the into a A gene as it in