Skip to main content
SpringerLink
Log in

Sequencing of HLA-D in responders and nonresponders to short ragweed allergen, Amb a V

  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

We investigated the molecular basis for the striking association between HLA-DR2,Dw2 and human immune responsiveness to the Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a V by sequencing the second exons of the DRB and DQBI genes of 17 selected ragweed-allergic Caucasoid subjects. We also studied the DQA1 allelic polymorphic regions (APRs) in these patients by dot-blotting using sequence-specific oligonucleotides (SSOs). The deduced amino acid sequences of the respective class II β and α polypeptides were compared, with particular emphasis on residues in the APRs that are implicated in antigen binding. No evidence for “new” HLA-DRB or DQB sequences unique to Amb a V responders were found on sequencing seven Dw2+ subjects. This suggests that the presence of a particular Dw2-associated class II molecule usually provides a necessary, but not always sufficient condition for responsiveness to Amb a V. The HLA phenotypes of three subjects suggest that they possess novel recombinant haplotypes containing either DRB1 * 1501 and DRB5 * 0101 (Dr2.2-associated) or DQB1 * 0602 (DQ1.2-associated) sequences. In these subjects, responsiveness to Amb a V was associated with the DR2.2 but not the DQ1.2 sequences, suggesting that DRαβI or DRαβV class II molecules are involved in antigen presentation. We investigated whether there may be shared HLA-D-encoded responder sequences present in all responders, including some exceptional DR2− Amb a V responders. The 13 subjects producing antibody (Ab) responses to Amb a V [either from natural exposure and/or after ragweed immunotherapy (Rx)] possessed DRB1 * 1501, 1601, 1602, 0103, 0402, 0404, 0801 or 1101 sequences, which share the majority of their aa residues in the APRs 2–4. Some of these shared residues might be important for the binding of a common Amb a V agretope prior to presentation of the class II Amb a V complex to the T-cell receptor (Tcr). An alternative postulate is that the recognition of two different Amb a V agretopes may be determined by the βI polypeptides of molecules having the DR2 and DQw3 specificities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Allen, P. M., Babbitt, B. P., and Unanue, E. R.: T-cell recognition of lysosymes; the biochemical basis of presentation. Immunol Rev 98: 172–200, 1987

    Google Scholar 

  • Andersson, G. D., Larhammar, D., Widmark, E., Servenius, B., Peterson, P. A., and Rask, L.: Class II genes of the human histocompatibility complex: organisation and evolutionary relationship of the DRβ genes. J Biol Chem 262: 8748–8758, 1987

    Google Scholar 

  • Ansari, A. A., Freidhoff, L. R., Meyers, D. A., Bias, W. B., and Marsh, D. G.: Human immune responsiveness to Lolium perenne grass pollen allergen Lol p III (Rye III) is associated with HLA-DR3 and DR5. Hum Immunol 25: 59–72, 1989

    Google Scholar 

  • Baur, M. P., Neugebauer, N., and Albert, E. D.: Reference tables of two-locus haplotype frequencies for all MHC marker loci. In E. D. Albert, M. P. Baur, and W. R. Mayr (eds.): Histocompatibility Testing, 1984, pp. 677–713, Springer, Berlin, 1984

    Google Scholar 

  • Bell, J., Denney, D., Foster, L., Belt, T., Todd, J., and McDevitt, H. O.: Allelic variation in the DR subregion of the human major histocompatibility complex. Proc Natl Acad Sci USA 84: 6234–6238, 1987

    Google Scholar 

  • Bidwell, J. L., Bidwell, E. A., Sansom, D. M., Klouda, P. T., and Bradley, B. A.: The origin of HLA-D “Br”: exon 2 nucleotide sequence implicates possible gene conversion of DR1 by DR4-Dw10, DR5, or DRw6-Dw18. Hum Immunol 26: 191–197, 1989

    Google Scholar 

  • Bodmer, J. G., Marsh, S. G. E., and Albert, E.: Nomenclature for factors of the HLA system, 1989. Immunol Today 11: 3–10, 1990

    Google Scholar 

  • Brown, J. H., Jardetzky, T., Saper, M., Samraoui, B., Bjorkman, P. J., and Wiley, D. C.: A hypothetical model for the foreign antigen binding site of class II histocompatibility molecules. Nature 332: 845–850, 1988

    Article  CAS  PubMed  Google Scholar 

  • Bugawan, T. L., Saiki, R. K., Levenson, C. H., Watson, R. M., and Erlich, H. A.: The use of non-radioactive oligonucleotide probes to analyse enzymatically amplified DNA for prenatal diagnosis and forensic HLA typing. Biotechnology 6: 943–951, 1988

    Google Scholar 

  • Buus, S., Sette, A., and Grey, H.: The interaction between protein derived immunogenic peptides and Ia. Immunol Rev 98: 115–141, 1987

    Google Scholar 

  • Coulter, K. M., Yang, W. H., Dorval, G., Drouin, M. A., Osterland, C. K., and Goodfriend, L.: Specific IgE antibody response to ragweed allergens Ra5S and Ra5G is associated with distinct HLA-DRβ genes. Mol Immunol 24: 1207–1214, 1987

    Google Scholar 

  • Erlich, H. A., Scharf, S. J., Long, C. M., and Horn, G. T.: Analysis is isotypic and allotypic sequence variation in the HLA-DRβ region using the in vitro enzymatic amplification of specific DNA segments. In B. Dupont (ed.): Immunobiology of HLA, Vol 2, pp. 181–185, Springer, New York, 1989

    Google Scholar 

  • Freidhoff, L. R., Kautzky, E. E., Meyers, D. A., Ansari, A. A., Bias, W. B., and Marsh, D. G.: Associations of HLA-DR3 with human immune response to Lol p I and Lol p II allergens in allergic subjects. Tissue Antigens 83: 211–219, 1988

    Google Scholar 

  • Gregersen, P. K., Shen, M., Song, Q. L., Merryman, P., Deger, S., Seki, T., Maccaari, J., Goldberg, D., Murphy, H., Schwenzer, J., Nepom, G., and Silver, J.: Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci USA 83: 2642–2646, 1986

    Google Scholar 

  • Gregersen, P. K., Todd, J., Erlich, H. A., Long, E., Servenius, B., Choi, E., Kao, H. T., and Lee, J. S.: First domain sequence diversity of DR and DQ subregion alleles. In B. Dupont (ed.): Immunobiology of HLA, Vol 1, pp. 1027–1031, Springer, New York, 1989

    Google Scholar 

  • Guillet, J. G., Lay, M.-Z., Briner, T. J., Buus, S., Sette, A., Grey, H. M., Smith, J. A., and Gefter, M. L.: Immunological self, nonself discrimination. Science 235: 865–870, 1987

    Google Scholar 

  • Heber-Katz, E., Hansburg, D., and Schwartz, R. H.: The la molecule of the antigen presenting cell plays a critical role in immune response gene regulation of T cell activation. J Cell Mol Immunol 1: 3–11, 1983

    Google Scholar 

  • Horn, G., Bugawan, T., Long, C. M., and Erlich, H. A.: Allelic variation of the HLA-DQ loci: relationship to serology and to insulin-dependent diabetes susceptibility. Proc Natl Acad Sci USA 85: 6012–6017, 1988

    Google Scholar 

  • Huang, S. K. and Marsh, D. G.: Class II MHC restriction of human T-cell responses to ragweed pollen allergens. Amb V. (Abstract.) J Allergy Clin Immunol 85: 199, 1990

    Google Scholar 

  • Jonsson, A. K., Hylding-Nielsen, J. J., Servenius, B., Larhammer, D., Anderson, G., Jorgensen, F., and Rask, L.: Class II genes of the human major histocompatibility complex: comparisons of the DQ and DX α and β genes. J Biol Chem 262: 8767–8777, 1987

    Google Scholar 

  • Kappes, D. and Strominger, J. L.: Human class II major histocompatibility complex genes and proteins. Annu Rev Biochem 57: 991–1028, 1988

    Google Scholar 

  • Kawai, J., Ando, A., Sato, T., Nakasatsuji, T., Tsuji, K., and Inoko, H.: Analysis of gene structure and antigen determinants of DR2 antigens using DR gene transfer into mouse L cells. J Immunol 142:312–317, 1989

    Google Scholar 

  • Lapkoff, C. B. and Goodfriend, L.: Isolation of a low molecular weight ragweed pollen allergen: Ra5. Int Arch Allergy Appl Immunol 46: 215–229, 1974

    Google Scholar 

  • Lee, B. S. M., Bell, J. I., Rust, N. A., and McDevitt, H. O.: Structural and functional variability among DQβ alleles of DR2 subtypes. Immunogenetics 26: 85–91, 1987a

    Google Scholar 

  • Lee, B. S. M., Rust, N. A., McMichael, A. J., and McDevitt, H. O.: HLA-DR2 subtypes form an additional supertypic family of DRβ alleles. Proc Natl Acad Sci USA 84: 4591–4595, 1987b

    Google Scholar 

  • Liu, C.-P., Bach, F. H., and Wu, S.: Molecular studies of a rare DR2/LD-5a/DQw3 HLA class II haplotype. Multiple genetic mechanisms in the generation of polymorphic HLA class II genes. J Immunol 140: 3631–3639, 1988

    Google Scholar 

  • Marsh, D. G.: Allergens and the genetics of allergy. In M. Sela (ed.): The Antigens, Vol III, pp. 271–359, Academic, New York, 1975

    Google Scholar 

  • Marsh, D. G.: Defining human immune response fingerprints toward ultra-pure allergens: immunochemical and genetic aspects of responsiveness toward the Amb V (Ra5) homologues. J Allergy Clin Immunol 78 [Suppl]: 242–248, 1986

    Google Scholar 

  • Marsh, D. G., Hsu, S. H., Roebber, M., Kautzky, E. E., Freidhoff, L. R., Meyers, D. A., Pollard, M. K., and Bias, W. B.: HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. I. Response resulting primarily from natural antigenic exposure. J Exp Med 155: 1439–1451, 1982a

    Google Scholar 

  • Marsh, D. G., Meyers, D. A., Freidhoff, L. R., Kautzky, E. E., Roebber, M., Norman, P. S., Hsu, S. H., and Bias, W. B.: HLA-Dw2: a genetic marker for human immune response to short ragweed pollen allergen Ra5. II. Response after ragweed immunotherapy. J Exp Med 155: 1452–1463, 1982b

    Google Scholar 

  • Marsh, D. G., Goodfriend, L., King, T. P., Løwenstein, H., and Platts-Mills, T. A. E.: Allergen nomenclature. Bull WHO 64: 767–770, 1986

    Google Scholar 

  • Marsh, D. G., Freidhoff, L. R., Ehrlich-Kautzky, E., Bias, W. B., and Roebber, M.: Immune responsiveness to Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a VI (Ra6) is associated with HLA-DR5 in allergic humans. Immunogenetics 26: 230–236, 1987a

    Google Scholar 

  • Marsh, D. G., Freidhoff, L. R., Golden, D. B., Kautzky, E. E., Roebber, M., Meyers, D. A., and Holland, C. L.: Genetic studies of immune response to the Amb a V homologues. (Abstract.) Fed Proc 46: 1047, 1987b

    Google Scholar 

  • Marsh, D. G., Zwollo, P., and Ansari, A. A.: Toward a total human immune response fingerprint: the allergy model. In A. S. El Shami and T. G. Merrett (eds.): Allergy and Molecular Biology, pp. 65–82, Pergamon, Oxford, 1988

    Google Scholar 

  • Mole, L. E., Goodfriend, L., Lapkoff, C. B., Kehoe, J. M., and Capra, J. D.: The amino-acid sequence of allergen Ra5. Biochemistry 14: 1216–1220, 1975

    Google Scholar 

  • O'Hehir, R. E., Young, D. B., Kay, A. B., and Lamb, J. R.: Cloned human T lymphocytes reactive with Dermatophagoides farinae (house dust mite): a comparison of T- and B-cell antigen recognition. Immunology 62: 635–647, 1987

    Google Scholar 

  • O'Hehir, R. E., Frew, A. J., Kay, A. B., and Lamb, J. R.: MHC class II restriction specificity of cloned human T lymphocytes reactive with Dermatophagoides farinae (house dust mite). Immunology 64: 627–631, 1988

    Google Scholar 

  • Roebber, M., Klapper, D. G., Goodfriend, L., Bias, W. B., Hsu, S. H., and Marsh, D. G.: Immunochemical and genetic studies of Amb t V (Ra5G), an Ra5 homologue from giant ragweed pollen. J Immunol 134: 3062–3069, 1985

    Google Scholar 

  • Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., and Arnheim, N.: Enzymatic amplification of β-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230: 1350–1354, 1985

    CAS  PubMed  Google Scholar 

  • Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S., Higuchi, R., Horn, G. T., Mulis, K. B., and Erlich, H. A.: Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239: 487–490, 1988

    CAS  PubMed  Google Scholar 

  • Scharf, S. J., Friedmann, A., Brautbar, C., Szafer, F., Steinman, L., Horn, G., Gyllensten, U., and Erlich, H. A.: HLA class II allelic variation and susceptibility to pemphigus vulgaris. Proc Natl Acad Sci USA 85: 3504–3508, 1988

    Google Scholar 

  • Tieber, V. L., Abruzzini, L. F., Didier, D. K., Schwartz, B. D., and Rotwein, P.: Complete characterization and sequence of an HLA class II DRβ chain cDNA from the DR5 haplotype. J Biol Chem 261: 2738–2742, 1987

    Google Scholar 

  • Todd, J. A., Bell, J. I., and McDevitt, H. O.: HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329: 599–604, 1987

    Google Scholar 

  • Wilkinson, D., de Vries, R. R. P., Madrigal, J. A., Lock, C. B., Morgenstern, J. A., and Altman, D. M.: Analysis of HLA-DR glycoproteins by DNA-mediated gene transfer. Definition of DR2β gene products and antigen presentation to T cell clones from leprosy patients. J Exp Med 167: 1442–1458, 1988

    Google Scholar 

  • Zwollo, P., Ansari, A. A., and Marsh, D. G.: Association of class II DNA-restriction fragments with responsiveness to Ambrosia artemisiifolia (short ragweed) pollen allergen Amb a V. J Allergy Clin Immunol 83: 45–54, 1989

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Clinical Immunology, Johns Hopkins Asthma and Allergy Center, 21224, Baltimore, MD, USA

    Patty Zwollo, Eva Ehrlich-Kautzky, Aftab A. Ansari & David G. Marsh

  2. Department of Human Genetics, Cetus Corporation, 94608, Emeryville, CA, USA

    Stephen J. Scharf & Henry A. Erlich

Authors
  1. Patty Zwollo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Ehrlich-Kautzky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stephen J. Scharf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aftab A. Ansari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Henry A. Erlich
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David G. Marsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zwollo, P., Ehrlich-Kautzky, E., Scharf, S.J. et al. Sequencing of HLA-D in responders and nonresponders to short ragweed allergen, Amb a V . Immunogenetics 33, 141–151 (1991). https://doi.org/10.1007/BF00210828

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00210828

Keywords

Search

Navigation