Nomenclature for factors of the HL-A system*

Terminolog Nomenclature for factors of the HL-A system* After the Third Conference on Histocompatibility Testing, a Nomenclature Committee drawn from among specialists in tissue typing, immunology, and human genetics proposed a nomenclature for leucocyte antigens, which has become accepted internationally. The text of the memorandum drawn up by the Committee was published in the Bulletin of the World Health Organization (1968, 39, 483-486). After the Fifth Workshop on Histocompatibility, the Nomenclature Committee 1 decided that it was necessary to revise the 1968 memorandum. The following is the text of the revised memorandum. Since the first human leucocyte isoantigens were described in the late 1950s, the number of leucocyte and platelet specificities defined by agglutination, complement fixation, and cytotoxicity techniques has been increasing. These factors are found on a variety of tissue cells and the possibility that they are histo- compatibility antigens has been proposed. The defi- nition of antigenic specificities and of genetic rela- tionships among them was greatly facilitated by the introduction of computer analysis. Many leucocyte and platelet factors have been detected. The intricate relationships among them, evident from population and linkage studies, has led to the concept that most of these specificities belong to a single complex system. In this system, the specificities can be arranged in two segregant series and, within each series, each specificity behaves as if determined by one of a mutually exclusive set of alleles. This major system was designated HL-A. The rele- vance of HL-A as an immunogenetic marker was confirmed by family studies combining serology, skin grafting, and lymphocyte culture techniques. The present memorandum concerns the nomencla- ture of specificities within the HL-A system and does not relate to other antigenic systems. The definition of a histocompatibility antigen of the HL-A system passes through four stages. In the first, a new specificity is detected by a laboratory and given that laboratory's designation. Next, if this specificity is confirmed by several of the reference laboratories (see the Annex) it is given a provisional number preceded by the prefix W. In the third stage, when firm agreement has been reached by all the * A French version will be published in a later issue of the Bulletin. 1 See list of signatories on pages 661-662. reference laboratories on the definition of this new specificity, an HL-A number can be designated. Finally, the fourth stage, which has not yet been reached, would allow the chemical confirmation of this HL-A specificity. Since 1968, a number of specificities have been given HL-A numbers. The following ones remain relatively well defined: HL-A1, HL-A2, HL-A3, HL-A7, HL-A8, HL-A11, HL-A12, and HL-A13. Problems have arisen with HL-A9, which appears to represent a cross reactivity between two com- ponents, HL-A1O and HL-A5. The latter also seem to be associated with a number of cross-reacting specificities that are still difficult to disentangle in non-caucasoid populations. Description of nomenclature The use of subscripts, italics, lower-case letters, and similar devices is avoided for ease of composi- tion, communication, and computation. In the 1968 memorandum1 the Committee recommended that a distinct specificity should be designated by a num- ber and that closely related but different specificities should be indicated by adding a figure after a full stop. However, the Committee has now decided that this notation should be abandoned as it implies a biological relationship between factors, which may not be correct. In future a new specificity that is part of a broader HL-A specificity will be given a new number by the Committee. The designation will be reported initially as a W specificity. For example, the two components of HL-A9 will now be desig- nated W23 and W24 (Table 1), but HL-A9 will con- tinue to be defined as the broader specificity. The assignment ofW numbers that do not overlap with existing HL-A numbers allows for the possibility 2946 -659- 660 TERMINOLOGY Table 1. New HL-A designations and representative equivalents designations Representative equivalents W16 U18, Da3l (included in U18), Gel2, Sa533, Te64, Ao81 W21 Da24, ET, ?M3, ?Te6l W23 HL-A9.1, Da27 (9'), Lc-12 W24 HL-A9.2, Da32 (9"), BIM W25 H L-A1 0.1, To3l, Da29 (10") W26 H L-A1 0.2, To4O, Da28 (10') W29 Wi 9.1, Ao77, Btl 5, Da22, Ge33, Te63 W30 W19.3, Da25' (Da26), Lc-21, Te66 W31 Wi 9.4, LAW, Da25' (Da33), Lc-26.1 W32 WI 9.5, Ao28, To3O, Ge32, Te59 that, when an antigen to which a W number has been provisionally assigned becomes eligible for an HL-A number, it can keep the same number. Table 1 shows the specificities to which W numbers have been assigned and their equivalent terms. These assignments arose out of the Fifth International Histocompatibility Workshop. At present it is not possible to state to what degree these newer factors are important in matching donors and recipients of organ transplants. It seems likely that the definition offamilies ofcross-reacting specificities will be impor- tant in this respect, but knowledge of the compo- nents ofthese cross-reacting groups is still incomplete. The HL-A phenotype of an individual will be represented by the system symbol followed by the numbers corresponding to the defined factors, separ- ated by a comma-e.g., HL-A1, 2, 7, 8. Where one of the factors has a W designation, the phenotype will be expressed as before, but the W prefix will appear before the factor-e.g., HL-A1, W23, 7, W16. The genotype must be derived from family segre- gation analysis (or another means of genetic analysis) that identifies the two sets of factors controlled by the two homologous chromosomes. These sets, or haplotypes, are indicated by the factors that are inherited in coupling, separated by a comma. Thus, for the examples given above, the haplotypes could be HL-A1, 8 and HL-A2, 7, and HL-A1, W16 and HL-A, W23, 7, respectively. The genotype is indi- 1 Bull. Wld Hlth Org., 1968, 39, 483-486. cated by the two haplotypes separated by an oblique stroke (solidus)-e.g., HL-A, 8/2, 7. A series of serological factors, such as the HL-A specificities, are grouped into a system if the recom- bination fractions between their corresponding gene- tic determinants are small. The effective limit on these recombination fractions is set by the resolution of human pedigree studies and so is unlikely to be much less than 1 %. A frequent, but not inevitable, consequence of such close linkage is association among the factors at the population level. Such asso- ciation may vary from one population to another. The recognition ofa new factor belonging to a system such as HL-A depends, therefore, not only on a population correlation analysis with established HL-A factors, but also on family studies. The fami- lies studied must be directly informative with respect to recombination involving the postulated new fac- tor. The Committee recommended that, in order to be assigned to the HL-A system, a new factor should show no recombination among a total of at least 20 genetically informative children from at least 3 families. This makes interdependence between the new factor and the HL-A system unlikely, although it does not exclude comparatively loose linkage- for example, with a recombination fraction of about 10% at a probability level of 0.1. Further family studies showing recombination between HL-A fac- tors at a level below 1 %, or chemical evidence lead- ing to an understanding of gene-antigen relation- ships, may justify subdividing the HL-A system into small genetic units in future. Allocation of numbers The following procedures are recommended for obtaining international designations for HL-A fac- tors. Until certification is obtained, a local designa- tion is appropriate; numbers preceded by the sym- bols HL-A or W should not be used. Preliminary testing in laboratory of origin. The investigator should screen, on his own cell panel, sera suspected of defining new specificities, comparing them with antisera defining known HL-A specifici- ties. In addition, panels including individuals from different race groups can be very helpful and their use where appropriate is recommended. The follow- ing steps are recommended: 1. The investigator should attempt to obtain more than one serum defining the supposed new specificity. 2. The reagents should be available in quantities of at least 200 ml. (Smaller quantities of high-titred NOMENCLATURE FOR FACTORS OF TE HL-A SYSTEM 661 serum may contain an equivalent amount of anti- body.) 3. The reagents should give a reproducibility of at least 95% by a recognized technique designated by the investigator. 4. They should be monospecific or oligospecific on the basis of absorptions with at least 10 selected positive cells when retested on the immunizing donor or on at least 10 highly reactive cells. The use of cells that are known to have a blank allele of the appropriate series, as well as of cells that are known to be homozygous, will provide a more precise defini- tion of a new specificity. Certification 1. The sera should be tested on members of 3 or more genetically informative families containing at least 20 children and should show no recombination with HL-A factors. 2. When these criteria have been fulfilled, the evidence should be submitted to a WHO collaborat- ing laboratory. The laboratory may supply the inves- tigator with cells, fresh or frozen, from its own panel of characterized donors. Details of the pro- cedure will be agreed upon by the investigator and the laboratory concerned. 3. Ultimately, the reagent must be shown to be operationally monospecific by absorption with, in general, cells from not fewer than 30 positive sub- jects if the frequency of reaction is greater than 15 %, or from not fewer than 15 positive donors if the frequency is less than 15%. 4. If the specificity is confirmed as apparently new, verification should be obtained from a second colla- borating laboratory. 5. All relevant data will then be considered by the Committee and, if the designation does not cor- respond to a previously designated factor, it will be given a W number. Two sera can be considered to define the same specificity only if they give identical results when tested on a panel containing approximately 100 cells of which at least 10 should react positively and 10 negatively. Any discrepancies that exist on first testing should disappear on repeated testing or following absorption. * * F. H. Allen, New York Blood Center, New York, N.Y., USA D. B. Amos, Duke Medical Center, Durham, N.C., USA (Chairman) J. R. Batchelor, Queen Victoria Hospital, East Grin- stead, Sussex, England W. F. Bodmer, University of Oxford, Oxford, England R. Ceppellini, Institute of Medical Genetics, University of Turin, Italy J. Dausset, Institut de Recherches sur les Maladies du Sang, Hopital St-Louis, Paris, France F. Kissmeyer-Nielsen, Aarhus Community Hospital, Aarhus, Denmark P. J. Morris, University of Melbourne, Victoria, Australia (Rapporteur) Rose Payne, Stanford University School of Medicine, Palo Alto, Calif., USA J. J. van Rood, University of Leiden, Leiden, Nether- lands P. I. Terasaki, University of California School of Medi- cine, Los Angeles, Calif., USA Z. Trnka, Basle Institute for Immunology, Basle, Switzerland (Secretary) R. L. Walford, University of California School of Medicine, Los Angeles, Calif., USA Annex COLLABORATING LABORATORIES FOR LEUCOCYTE ANTIGEN TESTING Professor D. B. Amos and Dr F. E. Ward, Department of Microbiology and Immunology, Duke University Medical Center, Durham, N.C., USA Professor J. R. Batchelor, Mclndoe Memorial Research Unit, Blond Laboratories, Queen Victoria Hospital, East Grinstead, Sussex, England Professor W. F. Bodmer and Dr J. G. Bodmer, Genetics Laboratory, Department of Biochemistry, University of Oxford, Oxford, England Professor R. Ceppellini, Centro Immunogenetica ed Isto- compatibilitA-CNR, c/o Institute of Medical Genetics, University of Turin, Turin, Italy Professor J. Dausset and Dr J. Colombani, Institute for Research on Blood Diseases, Hopital Saint-Louis, Paris, France Dr P. Ivanyi, Institute of Experimental Biology and Genetics, Czechoslovak Academy of Sciences, Prague, Czechoslovakia Dr M. Jeannet, Chief Medical Officer, Histocompatibility Laboratory, Geneva, Switzerland Dr F. Kissmeyer-Nielsen, Blood Bank and Blood Group- ing Labmratory, Aarhus Community Hospital, Aar- hus, Denmark 662 TERMINOLOGY Dr P. J.IMorris, Tissue Transplantation Laboratories, Department of Surgery, University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia Dr Rose Payne, Dr C. Grumet, and Dr H. Perkins, Department of Medicine (Hematology), Stanford Uni- versity School of Medicine, Palo Alto, Calif., USA Dr J. J. van Rood, Department of Immunohaematology, University of Leiden, Leiden, Netherlands Dr P. I. Terasaki, Department of Surgery, University of California School of Medicine, Los Angeles, Calif., USA Dr R. L. Walford and Dr G. Smith, University of Cali- fornia School of Medicine, Los Angeles, Calif., USA Dr C. P. Engelfriet and Dr J. J. van Loghem, Central Laboratory of the Netherlands Red Cross Blood Trans- fusion Service, Amsterdam, Netherlands