Abstract
Using a number of intrafamilial PLTs raised against identical HLA haplotypes it has been possible to construct a model in an informative family defining the HLA-D region as a genetic system. This system consists of at least two regions separated by a recombination between HLA-D and GLO. In relation to the site of recombination, a minimum of one centromeric and three telomeric components can be identified per haplotype.—Fourteen PLTs raised and defined within the family were subsequently tested in a Caucasian population (n=84) and in 13 unrelated, complete families.—It is concluded that the hypothetical model proposed for the HLA-D region as a genetic system of linked loci, coding at the cell surface for associated but distinct components (at least four per haplotype), allows for typing of the components of the HLA-D system of any given haplotype. Serological typing of HLA-D components should, in the near future, provide a more convenient way of establishing component phenotypes than the present use of primed lymphocyte typing reagents. Among the components isolated, some have a high association with the classic alleles defined either by homozygous typing cells or DR serology. Others form the basis of cross-reactivity but their presence does not interfere with standard typing. Others, however, seem by their mere presence to be responsible for false assignments.—The concept of HLA-D as a genetic system clarifies many of the inconsistencies observed with a one-locus system.
Similar content being viewed by others
References
Albertini, R. J. and Bach, F. H.: Quantitative assay of antigenic disparity at the HL-A. The major histocompatibility locus in man. J. Exp. Med. 128: 639–651, 1968
Amos, D. B. and Bach, F. M.: Phenotypic expressions of the major histocompatibility locus in man (HL-A), leucocyte antigens and mixed leucocyte culture reactivity. J. Exp. Med. 128: 623–637, 1968
Bain, B. and Lowenstein, L.: Genetic studies on the mixed leucocyte reaction. Science 145: 1315–1316, 1964
Bijnen, A. B., Schreuder, I., Volkers, W. S., Parlevliet, J., and Van Rood, J. J.: The lymphocyte activating influence of the HLA-region. J. Immunogenet. 4: 1–5, 1977
Bradley, B. A., Edwards, J. M., Dunn, D. C., and Calne, R. Y.: Quantitation of mixed lymphocyte reaction by gene dose phenomenon. Nature 240: 54–56, 1972
Bradley, B. A., Oliver, R. T. D., Mendell, N., and Stevens, A.: Joint report on the primed lymphocyte (PL) exchange. In W. Bodmer (ed.): Histocompatibility Testing 1977, pp. 142–152, Munksgaard, Copenhagen, 1978
Charron, D. J. and McDevitt, H. O.: Analysis of HLA-D region-associated molecules with monoclonal antibodies. Proc. Natl. Acad. Sci. U.S.A. 76: 6567–6571, 1979
Dausset, J., Sasportes, M., and Lebrun, A.: Mixed lymphocyte culture (MLC) between HL-A serologically identical parent-child and between HL-A homo and heterozygous individual. Transplant. Proc. 5: 1511–1515, 1973
Dupont, B., Jersild, C., Hansen, G. S., Nielsen, L. S., Thomsen, M., and Svejgaard, A.: Multiple MLC (LD) determinants on the same HL-A haplotype. Transplant. Proc. 5: 1481–1487, 1973
Dupont, B., Yunis, E. J., Hansen, J. A., Reinsmoen, N., Suciu-Foca, N., Mickelson, E., and Amos, B. D.: Evidence for three genes involved in the expression of the mixed lymphocyte culture reaction. In F. Kissmeyer-Nielsen (ed.): Histocompatibility Testing, 1975, pp. 547–551, Munksgaard, Copenhagen, 1975
Duquesnoy, R., Marrari, M., and Vieira, J.: Definition of MB and MT antigens by 8th International Histocompatibility Workshop B-cell alloamiserum clusters. In P. I. Terasaki (ed.): Histocompatibility Testing 1980. UCLA Press, Los Angeles, in press, 1980
Eijsvoogel, V., Van Rood, J. J., Du Toit, E. D., and Schellendens, P. Th. A.: Position of a locus determining mixed lymphocyte reaction distinct from the known HLA loci. Eur. J. Immunol. 2: 413–418, 1972
Franks, D. and Bradley, B. A.: Statistics in cellular typing. Tissue Antigens 10: 1–15, 1977
Hartzman, R. J.: Summary of the first International Workshop on human primed LD typing. Tissue Antigens 10: 203–211, 1979
Hengartner, H. and Fathman, C. G.: Clones of alloreactive T cells. I. A unique homozygous MLR-stimulating determinant present on B6 stimulators. Immunogenetics 10: 175–184, 1980
Hirschhorn, D., Bach, F. M., Kolodny, R. L., Firschein, I. L., and Hashem, N.: Immune response and mitosis of human peripheral blood lymphocytes in vitro. Science 142: 1185–1187, 1963
Jensen, E. B., Kristensen, T., Jørgensen, J., and Lamm, L. U.: HLA-D typing by homozygous typing cells. A statistical analysis of experimental and biological variations. Tissue Antigens 10: 83–98, 1977
Jørgensen, F., Lamm, L. U., and Kissmeyer-Nielsen, F.: Mixed lymphocyte cultures with inbred individuals: an approach to MLC typing. Tissue Antigens 3: 323–339, 1973
Jørgensen, F., Kristensen, T., Lamm, L. U., and Kissmeyer-Nielsen, F.: MLC (HLA-D) typing. A family study. Tissue Antigens 10: 379–393, 1977
Katagiri, M., Ikeda, H., Maruyama, N., Moriuchi, J., Wakisaka, A., Kimura, S., Aizawa, M., and Itakura, K.: Evidence for two B-cell alloantigen loci in the HLA-D region. Immunogenetics 9: 335–351, 1979
Keuning, J. J., Termijtelen, A., and Blussé Van Oud Albas, A.: Typing for MLC (LD). Transplant. Proc. 7: 35–39, 1975
Lampson, L. A. and Levy, R.: Two populations of Ia-like molecules on a human B cell line. J. Immunol. 125: 293–299, 1980
Longo, D. L. and Schwartz, R. H.: Gene complementation. Neither Ir-GLO gene need be present in the proliferative T cell to generate an immune response to poly (Glu55 Lys36 Phe9)n. J. Exp. Med. 151: 1452–1467, 1980
Markert, M. L. and Cresswell, P.: Polymorphism of human B cell alloantigens: evidence for three loci within the HLA system. Proc. Natl. Acad. Sci. U.S.A. 77: 6101–6104, 1980
Mawas, C. E., Charmot, D., and Sasportes, M.: Secondary response of in vitro primed human lymphocytes to allogeneic cells. I. Role of HL-A antigens and mixed lymphocyte reaction stimulating determinant in secondary in vitro proliferative response. Immunogenetics 2: 449–463, 1975
Mawas, C. E., Charmot, D., Sivy, M., Mercier, P., North, M. L., and Haupmann, G.: A weak human MLR locus mapping at the right of a crossing-over between HLA-D, Bf and GLO. J. Immunogenet. 5: 383–395, 1978
Mawas, C. E., Charmot, D., and Mercier, P.: Split of HLA-D into two regions α and β by a recombination between HLA-D and GLO. I. Study in a family and primed lymphocyte typing for determinants coded by the β region. Tissue Antigens 15: 297–312, 1980
Mempel, W., Grosse-Wilde, H., Albert, E., and Thierfeld, S.: Atypical MLC reaction in HLA typed related and unrelated pairs. Transplant. Proc. 5: 401–408, 1973a
Mempel, W., Grosse-Wilde, H., Baumann, P., Netzel, B., Steinbauer-Rosenthal, I., and Scholz, S.: Population genetics of the MLC response: Typing for MLC determinants using homozygous and heterozygous reference cells. Transplant. Proc. 5: 1529–1534, 1973b
Mendell, N. R., Lee, K. L., Reinsmoen, N., Yunis, E., Amos, D. B., and Emme, L.: Statistical methods for evaluating responses in HLA-D typing. Transplant. Proc. 9: 99–106, 1977
Morling, N., Platz, P., Ryder, L. P., Svejgaard, A., and Thomsen, M.: Data reduction HLA-D typing with the primed lymphocyte typing (PLT) technique. The normalized median response (NMR). Tissue Antigens 15: 123–136, 1980a
Morling, N., Platz, P., Ryder, L. P., Svejgaard, A., and Thomsen, M.: Generation of HLA-D specific primed lymphocyte typing (PLT) cells and cross-reactions of PLT-cells primed with homozygous typing cells. Tissue Antigens 15: 137–151, 1980b
Nunez-Roldan, A., Sasportes, M., and Fradelizi, D.: Analysis of products involved in primary and secondary allogenic proliferation in man. II. Detection of products different from Ia-like, DRw antigens, activating secondary allogenic proliferation in man. Immunogenetics 6: 43–54, 1978
Osoba, D. and Falk, J.: The mixed leucocyte reaction in man. Effects of pools of stimulating cells selected on the basis of cross-reacting HL-A specificities cell. Immunology 10: 117–123, 1974
Park, M. S., Terasaki, P. I., Saito, S., and Opelz, G.: Relation between HLA-Dw and the B-lymphocyte specificities. Scand. J. Immunol. 6: 413–418, 1977
Park, M. S., Terasaki, P. I., Wakata, S., and Aoki, D.: Supertypic groups: MT1, MT2, MT3. In P. I. Terasaki (ed.): Histocompatibility Testing 1980, UCLA Press, Los Angeles, in press, 1980
Piazza, A., and Galfré, G.: A new statistical approach for MLC typing: a clustering technique. In F. Kissmeyer-Nielsen (ed.): Histocompatibility Testing 1975, pp. 552–556, Munksgaard, Copenhagen, 1975
Reinsmoen, N. L., Noreen, H. J., Friend, I. S., Giblett, E. R., Greenberg, L. S., and Kersey, J. M.: Anomalous mixed lymphocyte culture reactivity between HLA-A, B, C, and DR identical siblings. Tissue Antigens 13: 19–34, 1979
Ryder, L. P., Thomson, M., Platz, P., and Svejgaard, A.: Data reduction in LD-typing. In F. Kissmeyer-Nielsen (ed.): Histocompatibility Testing 1975, pp. 557–562, Munksgaard, Copenhagen, 1975
Sasportes, M., Fradelizi, D., Nunez-Roldan, A., Wollman, E., Giannopoulos, Z., and Dausset, J.: Analysis of stimulating products involved in primary and secondary allogenic proliferation in man. I. Preponderant role of the Ia-like DR (Ly-Li) antigens as stimulating products in secondary allogenic response in man. Immunogenetics 6: 29–42, 1978
Schackelford, D. A. and Strominger, J. L.: Demonstration of structural polymorphism among HLA-DR light chains by two-dimensional gel electrophoresis. J. Exp. Med. 151: 144–165, 1980
Shaw, S., Johnson, A. H., and Shearer, G.: Evidence for a new segregant series of B cell antigens which are encoded in the HLA-D region and stimulate secondary allogeneic proliferative and cytotoxic responses. J. Exp. Med. 152: 565–580, 1980
Sheehy, J. M., Sondel, P. M., Bach, M. L., Wank, R., and Bach, F. H.: HLA-D typing: a rapid assay using primed lymphocytes. Science 188: 1308–1310, 1975
Sheehy, J. M.: Primed lymphocyte typing (PLT): Dichotomizing responses into “positives” and “negatives”. Tissue Antigens 11: 87–95, 1978
Tanigaki, N., Tosi, R., Pressman, D., and Ferrara, G. B.: Molecular identification of human Ia antigens coded for by a gene locus closely linked to HLA-DR locus. Immunogenetics 10: 151–167, 1980
Termijtelen, A., Bradley, B. A., and Van Rood, J. J.: A new determinant, defined by PLT, coded for in the HLA region and apparently independent of the HLA-D and DR loci. Tissue Antigens 15: 267–274, 1980
Thorsby, E. and Piazza, A.: Joint report from the Sixth International Histocompatibility Workshop Conference. II. Typing for HLA-D (LD-1 or MLC) determinants. In F. Kissmeyer-Nielsen (ed.): Histocompatibility Testing, pp. 414–458, Munksgaard, Copenhagen, 1975
Tosi, R., Tanigaki, N., Centi, D., Ferrara, G. B., and Pressman, D.: Immunological dissection of human Ia molecules. J. Exp. Med. 148: 1592–1611, 1978
Van den Tweel, J. G., Blusse Van Oud Albas, A., Keuning, J. J., Goulmy, E., Termijtelen, A., Bach, M. L., and Van Rood, J. J.: Typing for MLC (LD) with lymphocytes from cousin marriage offspring as typing cells. Transplant. Proc. 5: 1535–1538, 1973
Van Leeuwen, A., Schmit, H. R. E., and Van Rood, J. J.: Typing for MLC (LD). II. The selection of stimulator cells by MLC inhibition tests using SD identical stimulator cells (MISIS) and fluorescent antibody studies. Transplant. Proc. 5: 1539–1542, 1973
Van Rood, J. J., Van Leeuwen, A., Deuning, J. J., and Blusse Van Oud Albas, A.: The serological recognition of the human MLC determinants using a modified cytotoxicity technique. Tissue Antigens 5: 72–79, 1975a
Van Rood, J. J., Van Leeuwen, A., Parlevliet, J., Termijtelen, A., and Keuning, J. J.: LD typing by serology. IV. Description of a new locus with three alleles. In F. Kissmeyer-Nielsen (ed.): Histocompatibility Testing, pp. 629–636, Munksgaard, Copenhagen, 1975b
Wank, R., Schendel, D. J., Hansen, J. A., Yunis, E. J., and Dupont, B.: Two different HLA restimulating determinants separated by recombination and tirtates. Transplant. Proc. 9: 1771–1775, 1977
Wank, R., Schendel, D. J., Blanco, M. E., and Dupont, B.: Secondary response of primed lymphocytes after selective sensitization to non HLA-D determinants. Scand. J. Immunol. 9: 499–505, 1979
Yunis, E. J. and Amos, D. B.: Three closely linked genetic systems relevant to transplantation. Proc. Natl. Acad. Sci. U.S.A. 68: 3031–3055, 1971
Zier, K. S., Grosse-Wilde, H., Huber, C., Braunsteiner, H., and Albert, E. D.: Restimulation in secondary MLC by a non-D-locus determinant within the MHC. Immunogenetics 6: 459–469, 1978
Zier, K. S., Scholz, S., and Albert, E. D.: Cross-reactivity in PLT: The specificity of primed lymphocytes (PL) depends upon the HLA haplotypes of the priming cell and responder. Transplant. Proc. 11: 723–726, 1979
Zier, K. S., Gänbacher, B., Scholz, S., and Albert, E. D.: Heterogeneity of HLA defined in PLT: a cellular assay detects differences not seen using HLA-DRw serology. Immunogenetics 10: 513–520, 1980
Author information
Authors and Affiliations
Additional information
Research scientists from INSERM.
Research Fellow from the Danish Medical Research Council.
Central Blood Bank — Marseille
Rights and permissions
About this article
Cite this article
Charmot, D., Mawas, C., Kristensen, T. et al. The HLA-D system: At least two loci and four distinct phenotypic traits per haplotype. Introduction to component typing in families and population by primed lymphocyte typing. Immunogenetics 13, 57–84 (1981). https://doi.org/10.1007/BF00524605
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00524605