Nomenclature for factors of the HLA system*

TERMINOLOGY Nomenclature for factors of the HLA system* A Nomenclature Comnmittee composed of geneticists and immunologists, including specialists in tissue typing, has met after each of the Histocompatibility Workshops beginning with the Third Workshop in 1967. The Committee, in part under the auspices of the World Health Organization and the International Union of Immunological Societies (WHO/IUIS), met after the Sixth Workshop in Aarhus in July 1975. The expanding knowledge of the genetics of the major histocompatibility system of man has necessitated a revision of the terminology for the HLA region Jollowing the principles established in previous reports. This has been done with as few changes as possible. It has been realized for a number of years that in man there is a major histocompatibility system of great complexity, homologous to those of other mammalian species and composed of a series of many closely-linked genes. The original serologi- cally-defined specificities of the HLA system were assigned to two separate series (first or LA, and second or FOUR) corresponding to two linked loci with multiple alleles. These loci have been assigned to chromosome 6, both by family studies and by genetic analysis with somatic cell hybrids. Recent studies, especially in mouse and man, have shown that the genetic region identified by these two loci also contains many other genes controlling cell surface determinants, immune reponse differences, some components of the complement system and, perhaps, other related functions. The purpose of the revised nomenclature is to take account of this increasing complexity. The genetic region encompassing this large series of interrelated loci will be called HLA (the hyphen previously used in the designation of the HLA system is being dropped in order to minimize the increasing number of symbols needed to define loci and specificities belonging to the system). Genetic loci belonging to the system will be designated by one or more letters following the HLA. Individual alleles of each locus, and the corresponding specifici- ties, will be designated by numbers following the locus symbols. Provisionally identified specificities will, as before, carry the additional letter W(w), which will now be inserted between the locus letter(s) and the allele and specificity number. Although many computer outputs contain only capital letters, * This Terminology Note was drafted by the signatories listed on page 265. A French version will be published in a future issue of the Bulletin. nevertheless it is suggested that in writing and printing a lower case " w " should be used. The general notational scheme is therefore as follows: HLA: region or system designation. A, B, C, D, etc.: locus symbols. W (w): symbol to indicate a provisional specificity (may later be dropped when specificity is con- firmed). 1, 2, etc.: number identifying specificities belong- ing to each locus. Detailed examples of this system of notation are given later. The decision as to whether a locus belongs to the HLA system will, as discussed in previous reports, be based at least on genetic mapping data, on evidence as to function and chemical structure, and on popu- lation data showing evidence of significant popula- tion associations (linkage disequilibrium). By these criteria, for example, a human analogue of the mouse Tla locus would most probably be assigned to the HLA system. The loci controlling complement components C2, C4, and properdin factor B (GBG, Bf, etc.), as well as those controlling the Chido and Rogers blood groups, should probably also be as- signed to HLA. In this report, however, we shall confine our attention to the serologically-defined determinants found mainly on lymphocytes, other nucleated cells, and also platelets, and to the deter- minants recently identified by MLC-typing (mixed lymphocyte cultures). The loci previously called LA (or first) and FOUR (or second) will now be designated by the letters A and B, respectively. The complete locus symbols will therefore be HLA-A for the LA (or first), and HLA- 3347 - 261 - BULL. WORLD HEALTH ORGAN., Vol. 52, 1975 262 TERMINOLOGY B for the FOUR (or second) loci. For historical reasons the specificities determined by the alleles of these two loci are numbered jointly, so that apart from W5 and WIO (see below), there is no overlap in numbers between them. For example, specificities 1, 2, 3, 9, 10, 11, etc. belong to the HLA-A locus while 5, 7, 8, 12, 13, etc. belong to the HLA-B locus. This joint numbering scheme will be continued for these first two loci, and in local use the prefixes A and B may be optional. For other loci (C, D, etc.) the numbering of specificities will start in sequence from 1, separately for each locus, so that the prefix locus letter will be an essential part of the notation for a specificity. It is expected that, in most cases, a specificity will first receive a provisional w designa- tion, but may later be upgraded by omitting the w, while keeping the same number. The locus designated by the prefix C corresponds to that previously known as the AJ or third locus, and the locus designated D corresponds to what has variously been called MLR-S1, LD-1, MLC-1, etc. The Committee recognized that many new specifi- cities are being detected on lymphoid subpopula- tions such as B cells, T cells, lymphoblastoid lines, and chronic lymphatic leukaemia cells. Some of these specificities can also be detected on, for exam- ple, macrophages, endothelial cells, and sperm. It is probable that more than one locus is represented, as is the case for the corresponding specificities in the mouse, and as may also prove to be the case for lymphocyte-stimulating activities now provisionally assigned to locus D. Since the knowledge concerning these newer serological specificities is very recent and incomplete, it was felt that the assigment of one or more loci to them was premature. An approach will be made to the Committee, at an appropriate future date, concerning the symbols to be used for the loci in the HLA region controlling or regulating some complement components. The Committee considered the status of the exist- ingW specificities and agreed that a number of them could now be upgraded from their provisional sta- tus. In considering the state of definition of a specificity, the previous criteria were somewhat modified. A specificity formerly designated W was upgraded to full HLA status provided it could be clearly and reproducibly recognized by several gen- erally available antisera, which were represented at one or more workshops. The antigens so considered had all been tested for segregation in informative families and, generally, for their consistent behav- Table 1. New designations for specificities of the H LA-A and H LA-B loci New HLA Old Representative equivalents nomenclature nomenclature where applicable HLA-B14 W14 HLA-B18 W18 H LA-B27 W27 HLA-A28 W28 HLA-A29 W29 HLA-Aw33 W19.6 including Fe55, 10.4, Bar 3 Malay 1 HLA-Aw34 a Malay 2, H L-A1 0-3. F26 HLA-Bw35 W5 HLA-Aw36 a Mo*, LT HLA-Bw37 TY HLA-Bw38 W16.1 W16,W4, Da3l H LA-Bw39 W16.2 W16,W6, W16,382 HLA-Bw4O W1o HLA-Bw4l Sabell, LK, Da34 H LA-Bw42 a MWA HLA-Aw43 a BK a Some of the new specificities are most frequently identified in certain population groups. Examples are Aw36, Bw42, and Aw43, which are most frequently found in certain African groups. HLA-Aw34 (HLA-10 related antigen) is frequently observed in some Orientals and in some Blacks from Africa and America. Table 2. New designations for specificities of the HLA-C and HLA-D loci a New HLA-C Representative New HLA-D nomenclature equivalents nomenclature HLA-Cwl TI -AJ HLA-Dwl HLA-Cw2 T2-Sa532 HLA-Dw2 HLA-Cw3 T3-UPS HLA-Dw3 HLA-Cw4 T4-RH315 HLA-Dw4 HLA-Cw5 T5 HLA-Dw5 HLA-Dw6 a For a more complete listing of Dw equivalents see Table 4. iour in different populations.a Absorptions are, in general, required but it was felt that absorption had less significance than had previously been thought a Bulletin of the World Health Organization, 47: 659-662 (1972). NOMENCLATURE FOR FACTORS OF THE HLA SYSTEM Table 3. Complete listing of recognized HLA specificities a New Previous b New Previous New Previous New Previous HLA-Al HL-Al HLA-15 HL-A5 HLA-Cwl Ti HLA-Dwl LD 101 HLA-A2 HL-A2 HLA-B7 HL-A7 HLA-Cw2 T2 HLA-Dw2 LD 102 HLA-A3 HL-A3 HLA-B8 HL-A8 HLA-Cw3 T3 HLA-Dw3 LD 103 HLA-A9 HL-A9 HLA-B12 HL-A82 HLA-Cw4 T4 HLA-Dw4 LD 104 HLA-A10 HL-A10 HLA-B133 HL-A1 3 HLA-Cw5 T5 HLA-Dw5 LD 105 HLA-A1I HL-A1I HLA-B14 W14 HLA-Dw6 LD 106 HLA-A28 W28 HLA-B18 W18 HLA-A29 W29 HLA-1B27 W27 HLA-Aw19 Li c HLA-Bw15 W15 HLA-Aw23 W23 H LA- Bwl 6 W16 HLA-Aw24 W24 HLA-Bw17 W1 7 H LA-Aw25 W25 HLA-Bw2l W21 HLA-Aw26 W26 HLA-Bw22 W22 HLA-Aw3O W30 HLA-Bw35 W5 HLA-Aw3l W31 HLA-Bw37 TY HLA-Aw32 W32 HLA-Bw38 WI 6.1 H LA-Aw33 Wi 9.6 H LA- Bw39 Wi 6.2 HLA-Aw34 Malay 2 HLA-Bw4O WIO HLA-Aw36 Mo* HLA-Bw4l Sabell HLA-Aw43 BK H LA-Bw42 MWA a The previously reserved specificities W4 (4a) and W6 (4b) remain w4 and w6. These specificities are closely associated with the Blocus. b For a more comprehensive listing of equivalents see Table 1 and the 'table of equivalent nomenclature' in: Dausset, J. & Colombani J., ed. Histocompatibility testing. Copenhagen, Munksgaard, 1972, p. 7. c HLA-Aw19 includes at least HLA-A29, Aw3O, Aw3i, Aw32, Aw33, and Aw34 (7). because of the quantitative difficulties associated with varying degrees of cross-reactivity. Absorption is, however, still considered important and especially useful in the preliminary identification of new speci- ficities. To this aim co-capping and stripping are other important serological tools. The upgraded specificities and newly designated w specificities, together with their previous equivalents, are listed in Table 1. The new provisional Cw and Dw specificities, together with their previous equivalents, are given in Table 2. The specificities W5 and W1O have, for historical reasons, been the only designations that overlap other numbered specificities (HLA-B5 and HLA- AIO). In order to correct this anomaly, it is proposed to renumber the W5 specificity Bw35 and the W1O specificity Bw4O, as indicated in Table 1. The ' local ' HLA-B specificities, TT* (HLA-B12 related), 407*, KSO (= JA), HR, and HS (=SIN 2) are still under consideration for upgrading. A complete listing of all recognized HLA specifici- ties is given in Table 3, together with the most common of the previously used symbols. A more comprehensive list of equivalents for the HLA-D specificities is given in Table 4. Many additional specificities were considered as candidates for w classification. Those not included in Tables 1 and 2 were withheld pending further clarifi- cation by WHO collaborating laboratories. The specificities HLA-Aw32, Aw33, Bw17, Bw2l, B5 (previously HL-A5), Bw35, HR, Bw38, Bw39, TT *, 263 TERMINOLOGY a) u~ co 0x J ,J _J cC V, X) Cl) J c-r- _J 0,00 -J c] _J UC) v- LC) -J N 0 cn EL J -J CD v a a C] a J _* J _J _) CU n C N CO a] )cs Lo CD cD N C. en 0 im CL V_~ N -J co J N c) J 0N- 4 a)o*) U) H-JLL LL r- N J m .0 00 J (UU) co U)U J J U) coJ0 N 00 0 J.J cC-_J .0 N4 0 -J X) C/) cn 2 5: 2 r, m 000 0 0 -J CU) -J 0 -J CO D a aJ a _J _J _J N CD) LO cO 0 0a z CD -D 0-c U) (D EQ0 C co 4- 0 0 U 2 0 0 a) 0 n0 flU a)U _ -0 a0 U)0 DC ._ U)* .0U U)n .C_ L._ 407 *, and KSO (JA) are under consideration for upgrading or further clarification. For these pur- poses the collaborating laboratories will solicit addi- tional antisera from other investigators and will exchange sera and, where practicable, informative cells with other groups. Absorption, family, and population studies will be carried out, following the principles set out in this and previous reports, and revision of status will then be further considered by the Committee. A list of the WHO collaborating laboratories is given in the Annex. Some typical examples of the usage of the new terminology will now be given. An individual carry- ing the specificities Al, A3, B7, B8 might, for example, also carry the specificities Cwl, Cw2. The phenotype would be given as HLA-Al, 3; B7, 8; Cwl, w2. Note that in writing the phenotype, sero- logical specificities controlled by the same locus are separated by commas, while products of different loci are separated by semicolons. This avoids repeti- tion of the locus symbols and also makes it easy to incorporate cross-reacting and subtypic specificities (e.g., HLA-A9, 10, w23, w25; BwI6, w37; C...). The genotype would be written in terms of the two haplotypes as HLA-A1, B8, Cwl/A3, B7, Cw2. Other possible phenotypes would, for example, be HLA-Al, w32; Bw22, w35; Cwl, w3, or HLA-Al, 28; B7, w37; Cwl; Dw2. The presence of only a single specificity for a locus implies a phenotypic blank with respect to the specificities being tested for. A blank in a genotype, established by a family study, could be written, for example, as HLA-A1, Bw35, C-, Dw2/A28, B7, Cwl, D-. When w4 (4a) and w6 (4b) are designated in a pheno- or genotype, they can be inserted after the B locus specificities, e.g., HLA-Ax, y; B7, 12, w4, w6; Cx, y. Following a convention widely accepted in genetics, genetic sym- bols such as for loci, alleles, haplotypes, or geno- types, should be italicized in print and underlined in manuscripts and typed scripts, while antigens, sero- logical specificities, etc. should be written and printed in normal type (e.g., Al is the antigen; Al or Al is the corresponding allele). The loci in the haplotype are written in alphabetical order and so do not represent the relative map position on the chromosome. There may often be no need to include the system prefix, HLA, when it is clear from the context that loci of this system are being referred to. In its revision of nomenclature, the Committee considered and unanimously rejected various alter- native suggestions, including the possibility of desig- 264 x 0 IJ -J Cl) -J t Zz 0 -0?'OJ N cD -J n C 0 C cm ._A a) -o C U) C co 10 -J U) CD UQ) 0 CC) .0 Ch I.- 0C ( 0 - 0 C a 3:U)E 0 0 z z: 0 r- 0 NOMENCLATURE FOR FACTORS OF THE HLA SYSTEM 265 nating the lymphocyte activating determinants and lymphocyte subclass specificities HL-B, HL-C, etc. Attention is drawn to a previous statement on this point, to the effect that the major designations be reserved for other genetic systems not closely linked to or part of the HLA region. The pre-emption of formal symbols such as HLB (or HL-B), HLA-E, etc. before their use has been formally considered by this nomenclature committee, is to be strongly dis- couraged as being detrimental to a clear develop- ment of a systematic classification. We realize that no system of notation can be guaranteed to cope with all future developments. In particular if, as seems likely, the D-locus is split, its specificities may have to be reassigned. We do, however, believe that the system proposed here has considerable flexibility and can be adopted with minimal changes to present usage. * * D. B. Amos, Duke Medical Center, Durham, NC, USA (Chlairman). R. Batchelor, The East Grinstead Research Trust, Blond Laboratories, Queen Victoria Hospital, East Grinstead, England. W. F. Bodmer, University of Oxford, Oxford, England (Rapporteur). R. Ceppellini, Institute for Immunology, Basle, Switzer- land. J. Dausset, Institut de Recherches sur les Maladies du Sang, H6pital Saint-Louis, Paris, France. F. Kissmeyer-Nielsen, The University Hospital, Aarhus, Denmark. P. Morris, Nuffield Department of Surgery, University of Oxford, Oxford, England. Rose Payne, Stanford University School of Medicine, Stanford, CA, USA. J. J. van Rood, University of Leiden, Leiden, Nether- lands. P. I. Terasaki, University of California School of Medi- cine, Los Angeles, CA, USA. Z. Trnka, Institute for Immunology, Basle, Swizerland (Secretary). R. L. Walford, University of California School of Medi- cine, Los Angeles, CA, USA. ACKNOWLEDGEMENTS The contributions of Dr Julia Bodmer, Dr Sergio Curtoni, Dr Alberto Piazza, and Dr Erik Thorsby to this report are gratefully acknowledged. Annex COLLABORATING LABORATORIES FOR LEUCOCYTE ANTIGEN TESTING Department of Microbiology and Immunology, Duke University Medical Center, Durham NC, USA (D. B. Amos & F. E. Ward). Mclndoe Memorial Research Unit, Blond Laboratories, Queen Victoria Hospital, East Grinstead, Sussex, England (R. Batchelor). Genetics Laboratory, Department of Biochemistry, Uni- versity of Oxford, Oxford, England (W. F. Bodmer & J. G. Bodmer). Centro CNR per l'Immunogenetica e l'Istocompatibilith, c/o Istituto di Genetica Medica dell'Universita di Torino, Torino, Italy (R. Ceppellini & S. E. Curtoni). Institut de Recherches sur les Maladies du Sang, Hopital Saint-Louis, Paris, France (J. Dausset & J. Colombani). Central Laboratory, Netherlands Red Cross Blood Transfusion Service, Amsterdam, Netherlands (C. P. Engelfriet & Ella van den Berg-Loonen). Institute of Experimental Biology and Genetics, Czecho- slovak Academy of Sciences, Prague, Czechoslovakia (P. Ivanyi). Histocompatibility Laboratory, Geneva, Switzerland (M. Jeannet). Tissue Typing Laboratory, University Hospital, Aarhus, Denmark (F. Kissmeyer-Nielsen). Department of Medicine (Hematology), Stanford Univer- sity School of Medicine, Palo Alto, CA, USA (Rose Payne). Department of Immunohaematology, University of Leiden, Leiden, Netherlands (J. J. van Rood). Department of Surgery, University of California School of Medicine, Los Angeles, CA, USA (P. I. Terasaki). University of California School of Medicine, Los Angeles, CA, USA (R. L. Walford & G. Smith). 2