Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1984 Feb;3(2):447–452. doi: 10.1002/j.1460-2075.1984.tb01826.x

Both alpha and beta chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino-terminal domains.

L Schenning, D Larhammar, P Bill, K Wiman, A K Jonsson, L Rask, P A Peterson
PMCID: PMC557364  PMID: 6585297

Abstract

At least three class II antigens, all composed of an alpha and a beta subunit, are encoded in the human major histocompatibility complex, i.e., DR, DC and SB. Two cDNA clones, encoding a DC alpha and a DC beta chain, respectively, were isolated from a cDNA library of the lymphoblastoid cell line Raji (DR3,w6). The two polypeptides predicted from the nucleotide sequences of these clones are each composed of a signal peptide, two extracellular domains, a hydrophobic transmembrane region and a short cytoplasmic tail. Comparison of the DC alpha sequence with two previously published partial sequences shows that the majority of the differences is located in the amino-terminal domain. The differences are not randomly distributed; a cluster of replacements is present in the central portion of the amino-terminal domain. Likewise, the allelic polymorphism of the DC beta chains occurs preferentially in the amino-terminal domain, where three minor clusters of replacements can be discerned. The non-random distribution of the variability of DC alpha and beta chains may be due to phenotypic selection against replacement substitutions in the second domains of the polypeptides.

Full text

PDF
447

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auffray C., Ben-Nun A., Roux-Dosseto M., Germain R. N., Seidman J. G., Strominger J. L. Polymorphism and complexity of the human DC and murine I-A alpha chain genes. EMBO J. 1983;2(1):121–124. doi: 10.1002/j.1460-2075.1983.tb01392.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Auffray C., Korman A. J., Roux-Dosseto M., Bono R., Strominger J. L. cDNA clone for the heavy chain of the human B cell alloantigen DC1: strong sequence homology to the HLA-DR heavy chain. Proc Natl Acad Sci U S A. 1982 Oct;79(20):6337–6341. doi: 10.1073/pnas.79.20.6337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baltimore D. Somatic mutation gains its place among the generators of diversity. Cell. 1981 Nov;26(3 Pt 1):295–296. doi: 10.1016/0092-8674(81)90196-3. [DOI] [PubMed] [Google Scholar]
  4. Benacerraf B. Role of MHC gene products in immune regulation. Science. 1981 Jun 12;212(4500):1229–1238. doi: 10.1126/science.6165083. [DOI] [PubMed] [Google Scholar]
  5. Benoist C. O., Mathis D. J., Kanter M. R., Williams V. E., 2nd, McDevitt H. O. Regions of allelic hypervariability in the murine A alpha immune response gene. Cell. 1983 Aug;34(1):169–177. doi: 10.1016/0092-8674(83)90147-2. [DOI] [PubMed] [Google Scholar]
  6. Böhme J., Owerbach D., Denaro M., Lernmark A., Peterson P. A., Rask L. Human class II major histocompatibility antigen beta-chains are derived from at least three loci. Nature. 1983 Jan 6;301(5895):82–84. doi: 10.1038/301082a0. [DOI] [PubMed] [Google Scholar]
  7. Charron D. J., McDevitt H. O. Analysis of HLA-D region-associated molecules with monoclonal antibody. Proc Natl Acad Sci U S A. 1979 Dec;76(12):6567–6571. doi: 10.1073/pnas.76.12.6567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Choi E., McIntyre K., Germain R. N., Seidman J. G. Murine I-A beta chain polymorphism: nucleotide sequences of three allelic I-A beta genes. Science. 1983 Jul 15;221(4607):283–286. doi: 10.1126/science.6407114. [DOI] [PubMed] [Google Scholar]
  9. Das H. K., Lawrance S. K., Weissman S. M. Structure and nucleotide sequence of the heavy chain gene of HLA-DR. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3543–3547. doi: 10.1073/pnas.80.12.3543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Efstratiadis A., Posakony J. W., Maniatis T., Lawn R. M., O'Connell C., Spritz R. A., DeRiel J. K., Forget B. G., Weissman S. M., Slightom J. L. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653–668. doi: 10.1016/0092-8674(80)90429-8. [DOI] [PubMed] [Google Scholar]
  11. Evans R. L., Faldetta T. J., Humphreys R. E., Pratt D. M., Yunis E. J., Schlossman S. F. Peripheral human T cells sensitized in mixed leukocyte culture synthesize and express Ia-like antigens. J Exp Med. 1978 Nov 1;148(5):1440–1445. doi: 10.1084/jem.148.5.1440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gergen J. P., Stern R. H., Wensink P. C. Filter replicas and permanent collections of recombinant DNA plasmids. Nucleic Acids Res. 1979 Dec 20;7(8):2115–2136. doi: 10.1093/nar/7.8.2115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Götz H., Kratzin H., Thinnes F. P., Yang C., Kruse T., Pauly E., Kölbel S., Egert G., Wernet P., Hilschmann N. Primary structure of human class II histocompatibility antigens 3rd communication. Amino acid sequence comparison between DR and DC subclass antigens derived from a lymphoblastoid B cell line homozygous at the HLA loci (HLA-A3,3; B7,7; Dw2,2; DR2,2: MT1,1; Dc1,1: MB1,1). Hoppe Seylers Z Physiol Chem. 1983 Jun;364(6):749–755. doi: 10.1515/bchm2.1983.364.1.749. [DOI] [PubMed] [Google Scholar]
  14. Hyldig-Nielsen J. J., Schenning L., Hammerling U., Widmark E., Heldin E., Lind P., Servenius B., Lund T., Flavell R., Lee J. S. The complete nucleotide sequence of the I-E alpha d immune response gene. Nucleic Acids Res. 1983 Aug 11;11(15):5055–5071. doi: 10.1093/nar/11.15.5055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Klareskog L., Sandgerg-Trägårdh L., Rask L., Lindblom J. B., Curman B., Peterson P. A. Chemical properties of human Ia antigens. Nature. 1977 Jan 20;265(5591):248–251. doi: 10.1038/265248a0. [DOI] [PubMed] [Google Scholar]
  16. Korman A. J., Auffray C., Schamboeck A., Strominger J. L. The amino acid sequence and gene organization of the heavy chain of the HLA-DR antigen: homology to immunoglobulins. Proc Natl Acad Sci U S A. 1982 Oct;79(19):6013–6017. doi: 10.1073/pnas.79.19.6013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Korman A. J., Knudsen P. J., Kaufman J. F., Strominger J. L. cDNA clones for the heavy chain of HLA-DR antigens obtained after immunopurification of polysomes by monoclonal antibody. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1844–1848. doi: 10.1073/pnas.79.6.1844. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kratzin H., Yang C. Y., Götz H., Pauly E., Kölbel S., Egert G., Thinnes F. P., Wernet P., Altevogt P., Hilschmann N. Primärstruktur menschlicher Histokompatibilitätsantigene der Klasse II. 1. Mitteilung: Aminosäuresequenz der N-terminalen 198 Reste der beta-Kette des HLA-Dw2,2;DR2,2-Alloantigens. Hoppe Seylers Z Physiol Chem. 1981 Dec;362(12):1665–1669. [PubMed] [Google Scholar]
  19. Larhammar D., Gustafsson K., Claesson L., Bill P., Wiman K., Schenning L., Sundelin J., Widmark E., Peterson P. A., Rask L. Alpha chain of HLA-DR transplantation antigens is a member of the same protein superfamily as the immunoglobulins. Cell. 1982 Aug;30(1):153–161. doi: 10.1016/0092-8674(82)90021-6. [DOI] [PubMed] [Google Scholar]
  20. Larhammar D., Hammerling U., Denaro M., Lund T., Flavell R. A., Rask L., Peterson P. A. Structure of the murine immune response I-A beta locus: sequence of the I-A beta gene and an adjacent beta-chain second domain exon. Cell. 1983 Aug;34(1):179–188. doi: 10.1016/0092-8674(83)90148-4. [DOI] [PubMed] [Google Scholar]
  21. Larhammar D., Hyldig-Nielsen J. J., Servenius B., Andersson G., Rask L., Peterson P. A. Exon-intron organization and complete nucleotide sequence of a human major histocompatibility antigen DC beta gene. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7313–7317. doi: 10.1073/pnas.80.23.7313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Larhammar D., Schenning L., Gustafsson K., Wiman K., Claesson L., Rask L., Peterson P. A. Complete amino acid sequence of an HLA-DR antigen-like beta chain as predicted from the nucleotide sequence: similarities with immunoglobulins and HLA-A, -B, and -C antigens. Proc Natl Acad Sci U S A. 1982 Jun;79(12):3687–3691. doi: 10.1073/pnas.79.12.3687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lee J. S., Trowsdale J., Travers P. J., Carey J., Grosveld F., Jenkins J., Bodmer W. F. Sequence of an HLA-DR alpha-chain cDNA clone and intron-exon organization of the corresponding gene. Nature. 1982 Oct 21;299(5885):750–752. doi: 10.1038/299750a0. [DOI] [PubMed] [Google Scholar]
  24. Long E. O., Wake C. T., Gorski J., Mach B. Complete sequence of an HLA-dR beta chain deduced from a cDNA clone and identification of multiple non-allelic DR beta chain genes. EMBO J. 1983;2(3):389–394. doi: 10.1002/j.1460-2075.1983.tb01435.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Malissen M., Hunkapiller T., Hood L. Nucleotide sequence of a light chain gene of the mouse I-A subregion: A beta d. Science. 1983 Aug 19;221(4612):750–754. doi: 10.1126/science.6410508. [DOI] [PubMed] [Google Scholar]
  26. Mathis D. J., Benoist C. O., Williams V. E., 2nd, Kanter M. R., McDevitt H. O. The murine E alpha immune response gene. Cell. 1983 Mar;32(3):745–754. doi: 10.1016/0092-8674(83)90060-0. [DOI] [PubMed] [Google Scholar]
  27. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  28. Rigby P. W., Dieckmann M., Rhodes C., Berg P. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I. J Mol Biol. 1977 Jun 15;113(1):237–251. doi: 10.1016/0022-2836(77)90052-3. [DOI] [PubMed] [Google Scholar]
  29. Saito H., Maki R. A., Clayton L. K., Tonegawa S. Complete primary structures of the E beta chain and gene of the mouse major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5520–5524. doi: 10.1073/pnas.80.18.5520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Shaw S., Johnson A. H., Shearer G. M. Evidence for a new segregant series of B cell antigens that are encoded in the HLA-D region and that stimulate secondary allogenic proliferative and cytotoxic responses. J Exp Med. 1980 Sep 1;152(3):565–580. doi: 10.1084/jem.152.3.565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Silver J., Ferrone S. Structural polymorphism of human DR antigens. Nature. 1979 May 31;279(5712):436–437. doi: 10.1038/279436a0. [DOI] [PubMed] [Google Scholar]
  32. Tanigaki N., Tosi R. The genetic control of human Ia alloantigens: a three-loci model derived from the immunochemical analysis of 'supertypic' specificities. Immunol Rev. 1982;66:5–37. doi: 10.1111/j.1600-065x.1982.tb00432.x. [DOI] [PubMed] [Google Scholar]
  33. Thorsby E., Albrechtsen D., Hirschberg H., Kaakinen A., Solheim B. G. MLC-activating HLA-D determinants: identification, tissue distribution, and significance. Transplant Proc. 1977 Mar;9(1):393–400. [PubMed] [Google Scholar]
  34. Tosi R., Tanigaki N., Centis D., Ferrara G. B., Pressman D. Immunological dissection of human Ia molecules. J Exp Med. 1978 Dec 1;148(6):1592–1611. doi: 10.1084/jem.148.6.1592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wake C. T., Long E. O., Mach B. Allelic polymorphism and complexity of the genes for HLA-DR beta-chains--direct analysis by DNA-DNA hybridization. Nature. 1982 Nov 25;300(5890):372–374. doi: 10.1038/300372a0. [DOI] [PubMed] [Google Scholar]
  36. Watson A. J., DeMars R., Trowbridge I. S., Bach F. H. Detection of a novel human class II HLA antigen. 1983 Jul 28-Aug 3Nature. 304(5924):358–361. doi: 10.1038/304358a0. [DOI] [PubMed] [Google Scholar]
  37. Weiss E., Golden L., Zakut R., Mellor A., Fahrner K., Kvist S., Flavell R. A. The DNA sequence of the H-2kb gene: evidence for gene conversion as a mechanism for the generation of polymorphism in histocompatibilty antigens. EMBO J. 1983;2(3):453–462. doi: 10.1002/j.1460-2075.1983.tb01444.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wiman K., Larhammar D., Claesson L., Gustafsson K., Schenning L., Bill P., Böhme J., Denaro M., Dobberstein B., Hammerling U. Isolation and identification of a cDNA clone corresponding to an HLA-DR antigen beta chain. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1703–1707. doi: 10.1073/pnas.79.6.1703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yang C., Kratzin H., Götz H., Thinnes F. P., Kruse T., Egert G., Pauly E., Kölbel S., Wernet P., Hilschmann N. Primärstruktur menschlicher Histokompatibilitätsantigene der Klasse II. 2. Mitteilung: Aminosäuresequenz der N-terminalen 179 Reste der alpha-Kette des HLA-Dw2/DR2-Alloantigens. Hoppe Seylers Z Physiol Chem. 1982 Jun;363(6):671–676. [PubMed] [Google Scholar]
  40. von Heijne G. Patterns of amino acids near signal-sequence cleavage sites. Eur J Biochem. 1983 Jun 1;133(1):17–21. doi: 10.1111/j.1432-1033.1983.tb07424.x. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES