Nomenclature for factors of the HLA system, 1977*

BeotWd( 461- (198 l Bulletin of the World Health Organization, 56 (3): 461-465 (1978) Nomenclature for factors of the HLA system, 1977 * This article gives the decisions of the WHO nomenclature committee on leukocyte antigens, in particular concerning (a) the upgrading of certain HLA-A and HLA-B specificities to full HLA status, (b) the designation of new provisional specificities of the HLA-B, HLA-C, and HLA-D loci, and (c) the establishment of a nomenclature for the new specificities identified by serological techniques on B lymphocytes. The WHO nomenclature committee on leuko- cyte antigens met under the auspices of the World Health Organization and the International Union of Immunological Societies, after the 7th Workshop on Histocompatibility Testing in Oxford in Septem- ber 1977, with the aim of updating the nomenclature for specificities of the HLA-A, HLA-B, HLA-C, and HLA-D loci and establishing a nomenclature for the new specificities identified by serological techniques on B lymphocytes. Previous reports in the Bulletin of the World Health Organization (1, 2, 3) have established a revised nomenclature for the HLA region. Taking into account advances in knowledge of the genetics of the major histocompatibility system of man it was agreed that HLA should be the name given to the whole region, while the terms HLA-A, HLA-B, HLA-C, and HLA-D should refer to the individual loci within it. Numbers following the locus symbols would identify individual specificities (e.g., HLA-A1), while the letter w following the locus symbol and preceding the number would indicate a provisionally identified specificity (e.g., HLA-Bw35). The main aims of this report are: (1) to upgrade certain HLA-A and HLA-B locus specificities to full HLA status. *This terminology note was prepared by the WHO nomenclature committee on leukocyte antigens. The names of the members of the committee are listed on pages 464-465. The article has also been published in Zeitschrlft fur Immu- nit:tsforschung, 153: 373-379 (1977). A French version of this article will appear in a future issue of the Bulletin. Table 1. New designations for specificities of the HLA-A and HLA-B loci that have been upgraded to full HLA status New Previous HLA-A25 HLA-Aw25 HLA-A26 HLA-Aw26 HLA-B15 HLA-Bwl5 HLA-B17 HLA-Bwl7 HLA-B37 HLA-Bw37 HLA-B40 HLA-Bw4O (2) to designate new provisional specificities of the HLA-B, HLA-C and HLA-D loci. (3) to establish a nomenclature for the new specificities identified by serological techniques on B lymphocytes. Specificities for HLA-A, HLA-B, and HLA-C loci The newly upgraded specificities are listed in Table 1. In deciding which specificities should be upgraded, in addition to clarity and reproductibility of definition, general availability of the appropriate antisera was taken into account. Although the specificities Cwl, Cw2, Cw3, and Cw4 are now considered to be sufficiently well defined to satisfy the qualifications for upgrading to full HLA status, it has been decided not to change the nomenclature, at least for the time being, to avoid any possible confusion with the nomenclature 3711 - 461- HLA SYSTEM: NOMENCLATURE Table 2. New designations for provisional specificities of the HLA-B and HLA-C loci New Representative equivalents HLA-Bw4 w4,4a HLA-Bw6 w6,4b HLA-Bw44 B12 (not TT*) HLA-Bw45 T1T HLA-Bw46 HS, SIN2 HLA-Bw47 407i, M066, CAS, Bw4OC HLA-Bw48 KSO, JA, Bw4O.3 HLA-Bw49 Bw21.1, SL-ET H LA- Bw5O Bw21.2, ET' HLA-Bw5l B5.1 HLA-Bw52 B5.2 HLA-Bw53 HR HLA-Bw54 Bw22j, SAP1 HLA-Cw6 17 for the complement components C2 and C4, coded for, at least in part, by genes in the HLA region. Steps are being taken to consult with the IUIS Com- plement Nomenclature Sub-committee as to the symbols to be used for these complement loci. New provisional designations for specificities of the HLA-B and HLA-C loci are listed in Table 2. These designations conform to the previously established principles-namely, that the specificities of the HLA-A and HLA-B loci are numbered jointly, so that there is no overlap in numbers between them, that numbers are retained for a specificity that may be split (e.g., HLA-A9, split into HLA-Aw23 and HLA-Aw24), and that num- bers once used are never reassigned. It is recom- mended, however, that when both " broad " cross- reacting specificities and "narrow " or subtypic specificities are included in a phenotype designation, the broad specificities may be listed in parentheses at the end of the set of specificities for each locus, e.g., HLA-Al, 26 (10); B27, w50 (w21, w4, w6). The listing of broad specificities in this way, in addition to the narrow subtypic specificities, is optional. When, however, only the broad specificity is identified this is listed in the usual way, e.g., HLA-Al, 10; B27, w21. HLA-Bw4 (previously w4 or 4a) and HLA-Bw6 (previously w6 or 4b) are now specifically associated with the B locus because of chemical evidence for their presence on the same molecules that carry the other HLA-B locus specificities. These two speci- ficities often help considerably in distinguishing splits in B locus specificities. For example, in the case of HLA-Bw21 splits, HLA-Bw49 (previously Bw21.1 or SL-ET) is HLA-Bw4 associated while HLA-Bw5O (previously Bw2l.2 or ET*) is HLA- Bw6 associated. In certain cases, e.g., HLA-Bw53 (previously HR), a provisional specificity has been assigned even though all sera also contain antibodies against other specificities, in this case HLA-B5 and/or HLA- Bw35. HLA-Bw45 (previously TT*) is most frequently found in certain African groups and is, for example, quite rare in European Caucasoid populations. This means that in practice, in European Caucasoids, HLA-B12 individuals are nearly always HLA-Bw44. When, however, sera identifying HLA-Bw45 have been used and an individual has been shown to be negative for this specificity, this person should be designated HLA-Bw44 or HLA-Bw44 (12) and not just HLA-B12. In some cases it may be helpful to include a broad specificity in the genotype, following the same rules recommended above for the phenotype. For example, in the absence of sera identifying HLA-Bw45 but given typing for Bw4 and Bw6, a genotype HLA-A1, B8(w6)/A2, B12(w4) would clearly indicate that the HLA-A2, B12(w4) haplotype was probably HLA-A2, Bw44. As is the case for a number of the previously established HLA specificities, certain of the newly designated provisional specificities are found pre- dominantly in particular population groups, as already mentioned for Bw45. For example, HLA- Bw53 (previously HR) is found mainly in Negroes from Africa and America, HLA-Bw54 (previously Bw22J, etc.) and HLA-Bw46 (previously HS, SIN2) in Orientals and HLA-Bw48 (previously KSO, etc.) in Eskimos, American Indians, and possibly other oriental related populations. The following suggested specificities were discus- sed, but were considered not yet sufficiently well defined to be assigned a provisional w designation: 9.3, 5.3, 5.4, 14.1, 14.2, 15.1, 15.2, 15A, 17 long, 17 short, 22.1, 22.2, DA30, 35A, 35C, 40.1, 40.2, DB, IM2, BU, T6. HLA-D specificities There has been a significant advance in the defini- tion of certain of the HLA-D locus specificities, notably HLA-Dwl, HLA-Dw2, and HLA-Dw3. Nevertheless, the practical difficulties of cell typing do not yet justify the upgrading of any of these specificities to full HLA status. New designations for provisional specificities of the HLA-D locus are given in Table 3. The new specificity HLA-Dwll 462 HLA SYSTEM: NOMENCLATURE Table 3. New designations for provisional specificities of the HLA-D locus New Previous or representativeequivalent HLA-Dw7 LD1 07 HLA-Dw8 LD108 HLA-Dw9 TB9, OH H LA-Dwl0 LD1 6 HLA-Dw1 LD17 (previously LD17) appears to be more or less included in HLA-Dw7 and may turn out to be a " split " of this latter specificity. Other suggested specificities discussed but not yet considered ready for provisional w designation, pending further cell exchanges evaluated by appro- priate statistical procedures, were RE and the Japanese specificities HO and YT or AW. Further exchanges are also needed before other suggested MLC loci, possibly distinct from HLA-D, can be considered. At the 6th and 7th Workshops on Histocompatibility Testing a group of reference laboratories for cellular typing was established, on an informal basis, and these laboratories are con- tinuing to collaborate in cell exchanges in order to clarify the definition of these and other proposed specifities (4). Specificities identified by serological techniques on B lymphocytes The 7th Workshop consolidated a major advance in the definition of the new specificities identified by serological techniques on B lymphocytes, mainly using a microlymphocytotoxicity assay on purified peripheral blood B lymphocytes. These specificities, which appear to be the counterpart of at least some of the so called Ia determinants of the mouse major histocompatibility system, H-2, are in general closely associated with the already defined specificities of the HLA-D locus. In order to reflect this relation- ship, while at the same time reserving judgement on whether these serologically detected determinants are on the products of the HLA-D locus, it has been decided to use for them the designation DR (for D related), followed, as usual, by the letter w to indicate that the designation is still provisional. This nomenclature for the first seven DRw specifici- ties, using numbers that correspond to the relevant associated Dw specificity, is given in Table 4, together with their 7th Workshop equivalents. The Table 4. Nomenclature for the new specificities estab- lished by serological assays on B lymphocytes New nomenclature 7th Workshop nomenclature a DRwl WIAI DRw2 WIA2 DRw3 WIA3 DRw4 WIA4 DRw5 WIA5 DRw6 WIA6 DRw7 WIA7 a Other equivalent nomenclatures and further details concerning the definition of these specificities can be found in Bodmer et al. (4). specificities DRwl, DRw2, DRw3, and DRw7 are clearly defined, each by several sera. DRw4 has been defined in two ways. First. by sera that show some evidence of cross-reaction with DRw5 but do not consistently react with any other specificity; second, by sera that contain activity against DRw4 and DRw7, and so can be used to define DRw4 only in the absence of DRw7, again reflecting cross- reaction, in this case between DRw4 and DRw7. The specificity DRw6 is the least well defined, as the available sera react in addition either with DRw3 and possibly DRw5, or with DRw2 and often also DRwl. These cross-reaction patterns, which seem to be a common feature of the DRw specificities, may reflect the existence of supertypic specificities for, for example, the combinations DRwl, DRw2, and DRw6, or DRw4, DRw5, and possibly DRw7. Allowing for these problems of cross-reaction, the evidence so far is consistent with the hypothesis that these seven specificities are controlled genetically by a single multiple allelic series, as in the case of the HLA-A, B, C, and D loci. In the 7th Workshop, an effort was made to define an HLA-Dw8 associated specificity (Workshop designation WIA8) but this was considered to be not yet sufficiently well established to be assigned a provisional w designation. There were, in addition, a number of suggestions for other specificities, mainly identified as " tails " in the 7th Workshop sera, and these also need further evaluation before they can be considered for a w designation. Some evidence has been obtained, both before and during the Workshop, for the existence of one or more determinants coded for by a locus in the neighbourhood of HLA-A, but once again further work is needed before this can be considered for a new locus symbol. It is probable that, in due course, serological tests on B 463 HLA SYSTEM: NOMENCLATURE Table 5. Complete listing of recognized HLA specificities a HLA-A H LA-Al H LA-A2 HLA-A3 HLA-A9 H LA-A1 0 H LA-Al 1 H LA-Awl 9 HLA-Aw23 HLA-Aw24 H LA-A25 H LA-A26 H LA-A28 H LA-A29 H LA-Aw3O H LA-Aw3l HLA-Aw32 HLA-Aw33 HLA-Aw34 H LA-Aw36 HLA-Aw43 HLA-B HLA-B5 HLA-B7 HLA-B8 HLA-B12 HLA-B13 HLA-1B14 HLA-B15 HLA-Bwl6 HLA-B17 HLA-B18 HLA-Bw2l HLA-Bw22 HLA-B27 HLA-Bw35 HLA-B37 HLA-Bw38 HLA-Bw39 HLA-B40 HLA-Bw4l HLA-C H LA-Bw42 HLA-Bw44 HLA-Bw45 HLA-Bw46 H LA-Bw47 HLA-Bw48 HLA-Bw49 H LA-Bw5O HLA-Bw5l H LA-Bw52 H LA-Bw53 H LA-Bw54 HLA-Cwl HLA-Cw2 HLA-Cw3 HLA-Cw4 HLA-Cw5 HLA-Cw6 HLA-D HLA-Dwl HLA-Dw2 HLA-Dw3 HLA-Dw4 HLA-Dw5 HLA-Dw6 HLA-Dw7 HLA-Dw8 HLA-Dw9 HLA-DwlO HLA-Dwl 1 HLA-DR HLA-DRw1 HLA-DRw2 HLA-DRw3 HLA-DRw4 HLA-DRw5 HLA-DRw6 HLA-DRw7 HLA-Bw4 HLA-Bw6 a The following specificities arose as clear-cut splits of other specifities: HLA-A9 into HLA-Aw23 HLA-Aw24 HLA-A10 into HLA-A25 HLA-A26 HLA-B5 into HLA-Bw5l HLA-Bw52 HLA-B12 into HLA-Bw44 HLA-Bw45 HLA-Bwl6 into HLA-Bw38 HLA-Bw39 HLA-Bw2l into HLA-Bw49 HLA-Bw5 Historically HLA-Awl9 has included HLA-A29, HLA-Aw3O, HLA-Aw3l, HLA-Aw32, and HLA-Aw33. lymphocytes and other techniques including, for example, the primed lymphocyte test (PLT) and cell- mediated lymphocytotoxicity (CML) may define other loci in and outside the HLA region. Though evidence has been obtained that suggests a relatively close relation between determinants identified using the PLT test and the DRw and similar specificities, the results of the 7th Workshop exchange did not warrant the designation ofany separate nomenclature for these. The committee adheres to the view that it should confine its attention to the cell surface determinants, identified by serological and cellular techniques, that are coded for by genes in the HLA region. This does not exclude the possibility that it may in the future have to broaden its horizon beyond the HLA region. However, the committee reaffirms its recom- mendation that the pre-emption of formal symbols, such as HLB, HL-B or HLA-E, that are clearly re- lated to the symbols used in the nomenclature for factors of the HLA system, is to be strongly dis- couraged before their use has been considered by the committee. The members of the committee accept that their laboratories should play a major role in the ex- changes of sera, cells, and information that are needed to continue to clarify the definition of new and proposed factors of the HLA system. This cooperation provides a network of reference labo- ratories that can, together with the workshops, continue to aid the clear development of knowledge of the HLA system. * * E. Albert, University Polyclinic for Children, Munich, Federal Republic of Germany. D. B. Amos, Duke Medical Center, Durham, NC, USA (Chairman) W. F. Bodmer, Genetics Laboratory, University of Oxford, Oxford, England (Rapporteur) R. Ceppellini, Institute for Immunology, Basle, Switzerland, and CNR Centre for the Study of Immunogenetics and Histocompatibility, Turin, Italy J. Dausset, Institut de Recherches sur les Maladies du Sang, Hopital Saint-Louis, Paris, France. F. Kissmeyer-Nielsen, The University Hospital, Aarhus, Denmark. 464 HLA SYSTEM: NOMENCLATURE 465 W. Mayr, Institut for Blood Group Serology, University of Vienna, Vienna, Austria. R. Payne, Stanford University School of Medicine, Stanford, CA, USA. J. J. van Rood, University of Leiden, Netherlands. P. I. Terasaki, University of California School of Medicine, Los Angeles, CA, USA. Z. Trnka, Institute for Immunology, Basle, Swit- zerland, representing Immunology, Division of Noncommunicable Diseases, World Health Organ- ization, and the IUIS Nomenclature Committee (Secretary). R. L. Walford, University of California School of Medicine, Los Angeles, CA, USA. ACKNOWLEDGEMENTS The contributions of Julia Bodmer and Hilliard Festenstein, who acted as co-opted members of the committee for the meeting that led to the preparation of this report, are gratefully acknowledged. REFERENCES 1. Bulletin of the World Health Organization, 39: 483 (1968). 2. Bulletin of the World Health Organization, 47: 659 (1972). 3. Bulletin of the World Health Organization, 52: 261 (1975). 4. BODMER, W. F. ET AL., ED. Histocompatibility testing. Copenhagen, Munksgaard, 1977.