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Epitopes Are the Functional Units of HLA Class II Molecules and Form the Molecular Basis for Disease Susceptibility

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Book cover HLA Class II Antigens

Abstract

The incidence of many autoimmune diseases has for many years been known to be associated with certain HLA class II types. For example, 70% of rheumatoid arthritis (RA) patients type as DR4, compared with only 28% of the normal population. Similarly, 59% of multiple sclerosis (MS) patients express DR2, against only 26% of the normal population. Other autoimmune diseases, such as myasthenia gravis and juvenile diabetes, have also been shown to be associated with certain HLA class II types (Table 1). These associations are presumed to reflect the effect of particular class II gene products on an individual’s ability to respond immunologically to an exogenous pathogen, or alternatively on his ability to regulate his response to endogenous autoantigens. This ability to respond would in turn play an important role in the etiology or pathogenesis of the disease. However, the most puzzling feature of these analyses is the lack of absolute association of the disease with a particular class II type, i.e., why many individuals with other class II types and therefore different class II gene products also develop the disease. For example, 30% of individuals with RA do not express DR4, and 41% of individuals with MS do not express DR2.

This work was supported by grants from the National Institutes of Health

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References

  1. Owerbach D, Lernmark A, Platz P, Ryder LP, Rask L, Peterson PA, Ludvigssdon J (1983) HLA-D region β–chain DNA endonuclease fragments differ between HLA-DR identical healthy and insulin-dependent diabetic individuals. Nature 303:815–817

    Article  PubMed  CAS  Google Scholar 

  2. Nepom BS, Nepom GT, Mickelson E, Schaller JG, Antonelli P, Hansen J A (1984) Specific HLA-DR4-associated histocompatibility molecules characterize patients with seropositive juvenile rheumatoid arthritis. J Clin Invest 74:287–291

    Article  PubMed  CAS  Google Scholar 

  3. Servenius B, Gustafsson K, Widmark E, Emmoth E, Andersson G, Larhammar D, Rask L, Peterson PA (1984) Molecular map of the human HLA-SB (HLA-DP) region and sequence of an SBα (DPα) pseudogene. EMBO J 3:3209–3214

    PubMed  CAS  Google Scholar 

  4. Gorski J, Rollini P, Long E, Mach B (1984) Molecular organization of the HLA-SB region of the human major histocompatibility complex and evidence for two SB β chain genes. Proc Natl Acad Sci USA 81:3934–3938

    Article  PubMed  CAS  Google Scholar 

  5. Spielman RS, Lee J, Bodmer WF, Bodmer JG, Trowsdale J (1984) Six HLA-D region α–chain genes on human chromosome 6: polymorphisms and associations of DCα–related sequences with DR types. Proc Natl Acad Sci USA 81:3461–3465

    Article  PubMed  CAS  Google Scholar 

  6. Auffray C, Kuo J, DeMars R, Strominger JL (1983) A minimum of four human class II α chain genes are endoded in the HLA region of chromosome 6. Nature 304:174–177

    Article  PubMed  CAS  Google Scholar 

  7. Long EO, Wake CT, Gorski J, Mach B (1983) Complete sequence of an HLA-DRβ chain gene. EMBO J 2:389–394

    PubMed  CAS  Google Scholar 

  8. Allison JP, Walker LE, Russell WA, Pellegrino MA, Ferrone S, Reisfeld RA, Frelinger J A, Silver J (1978) Murine Ia and human DR antigens: homology of amino terminal sequences. Proc Natl Acad Sci USA 74:5135–5139

    Google Scholar 

  9. Goyert SM, Shively JE, Silver J (1982) Biochemical characterization of a second family of human Ia molecules, HLA-DS, equivalent to murine I-A subregion molecules. J Exp Med 156:550–556

    Article  PubMed  CAS  Google Scholar 

  10. Schenning L, Larhammar D, Bill P, Wiman K, Jonsson AK, Peterson PA (1984) Both α and β chains of HLA-DC class II histocompatibility antigens display extensive polymorphism in their amino terminal domains. EMBO J 3:447–452

    PubMed  CAS  Google Scholar 

  11. Larhammar D, Schenning L, Gustafsson K, Wiman K, Claesson L, Rask L, Peterson P (1982) Complete amino acid sequence of an HLA DR antigen like β chain as predicted from the nucleotide sequence similarities with immunoglobulins and HLA-A, B, and C antigens. Proc Natl Acad Sci USA 79:3687–3691

    Article  PubMed  CAS  Google Scholar 

  12. Auffray C, Korman AJ, Roux-Dosseto M, Bono R, Strominger JL (1982) 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 USA 79:6337–6341

    Article  PubMed  CAS  Google Scholar 

  13. Roux-Dosetto M, Auffray C, Lillie JW, Boss JM, Cohen D, DeMars R, Mawas C, Seidman JG, Strominger JL (1983) Genetic mapping of a human class II antigen β chain cDNA clone to the SB region of the HLA complex. Proc Natl Acad Sci USA 80:6036–6040

    Article  Google Scholar 

  14. Gustafsson K, Emmoth E, Widmark E, Bohine J, Peterson PA, Rask L (1984) Isolation of a cDNA clone coding for an SB β–chain. Nature 309:76–78

    Article  PubMed  CAS  Google Scholar 

  15. Karr RW, Kannpell CC, Zangara RJ, Goyert SM, Silver J, Schwartz BD (1983) An HLA-DR5 homozygous cell line expresses two DS (I-A–like) molecules. J Exp Med 158:1374–1379

    Article  PubMed  CAS  Google Scholar 

  16. Karr RW, Alber C, Goyert SM, Silver J, Duquesnoy RJ (1984) The complexity of HLA-DS molecules: a homozygous cell line expresses multiple HLA-DS alpha chains. J Exp Med 159:1512–1531

    Article  PubMed  CAS  Google Scholar 

  17. Koch N, Hammerling KN, Tada GJ, Kimura S, Hammerling U (1982) Cross blocking studies with monoclonal antibodies against I-A molecules of haplotypes b, d, and k. Eur J Immunol 12:909–914

    Article  PubMed  CAS  Google Scholar 

  18. Pierres M, Devaux C, Dosseto M, Marchetto S (1981) Clonal analysis of B and T-cell responses to Ia antigens I Topology of epitope regions on IAk and IEk molecules analyzed with 35 monoclonal alloantibodies. Immunogenetics 14:481–495

    Article  PubMed  CAS  Google Scholar 

  19. Goyert SM, Shively JE, Silver J (1982) Biochemical characterization of a second family of human Ia molecules HLA-DS equivalent to murine IA subregion molecules. J Exp Med 156:550–566

    Article  PubMed  CAS  Google Scholar 

  20. Cohen D, LeGall I, Marcadet A, Font MP, Lalquel JM, Daussett J (1984) Clusters of HLA class IIβ restriction fragments describe allelic series. Proc Natl Acad Sci USA 81:7870–7874

    Article  PubMed  CAS  Google Scholar 

  21. Park MS, Terasaki PI, Nakata S, Aoki D (1980) MT1, MT2, and MT3 – alternate allelic candidates for DRw supratypic antigens. In: Terasaki PI (ed) Histocompatibility testing 1980. UCLA Tissue Typing Laboratory, Los Angeles, pp 858–859

    Google Scholar 

  22. Markert ML, Cresswell P (1982) Human B cell alloantigens: expressions of MB and MT determinants. J Immunol 128:2004–2008

    PubMed  CAS  Google Scholar 

  23. Karr RW, Kannapell CC, Stein JA, Gebel HM, Mann DL, Dusquesnoy RJ, Fuller TC, Rodey GE, Schwartz BD (1982) Molecular relationships of the human B cell alloantigens, MT2, MT3, MT4, and DR5. J Immunol 128:1809–1818

    PubMed  CAS  Google Scholar 

  24. Tanigaki N, Tosi R, Sagana K, Minowada J, Ferrara GB (1983) The distribution of DR5, MT2, and MB3 specificities on human Ia subsets. Immunogenetics 17:371–386

    Article  PubMed  CAS  Google Scholar 

  25. Hurley CK, Giles RC, Nunez G, DeMars R, Nadler L, Winchester R, Stastny P, Capra JD (1984) Molecular localization of human class IIMT2 and MT3 determinants. J Exp Med 160:472–493

    Article  PubMed  CAS  Google Scholar 

  26. Moriuchi J, Moriuchi T, Silver J (1985) Nucleotide sequence of an HLA-DQ α chain derived from a DRw9 cell line: genetic and evolutionary implications. Proc Natl Acad Sci USA 82:3420–3424

    Article  PubMed  CAS  Google Scholar 

  27. Duquesnoy RJ, Marrari M, Annen K (1979) Identification of an HLA-DR-associated system of B-cell alloantigens. Transplant Proc 11:1757–1761

    PubMed  CAS  Google Scholar 

  28. Goyert SM, Silver J (1983) Further characterization of HLA-DS molecules: implication for studies assessing the role of human Ia molecules in cell interactions and disease susceptibility. Proc Natl Acad Sci USA 80:5719–5723

    Article  PubMed  CAS  Google Scholar 

  29. Giles RC, Nunez G, Hurley CK, Nunez-Roldan A, Winchester R, Stastny R, Capra JD (1983) Structural analysis of a human I-A homologue using a monoclonal antibody that recognizes an MB3-like specificity. J Exp Med 157:1461–1470

    Article  PubMed  CAS  Google Scholar 

  30. McKenzie IFC, Morgan GM, Sandrin MS, Michaelides MM, Melvold RW, Kohn HI (1979) B6C-H-2(bml2), a new H-2 mutation in the I region in the mouse. J Exp Med 150:1323–1338

    Article  PubMed  CAS  Google Scholar 

  31. McKean DJ, Melvold RW, David CS (1981) Tryptic peptide comparison of Ia antigen α βpolypeptide from the I-A mutant B6-C-H-2(bml2) and its congenic parental strain B6. Immunogenetics 14:41–51

    Article  PubMed  CAS  Google Scholar 

  32. Mclntyre K, Seidman J (1984) Nucleotide sequence of mutant I-Aβ (bml2) gene is evidence for genetic exchange between mouse immune response genes. Nature 308:551–554

    Article  Google Scholar 

  33. Denaro M, Hammerling U, Rask L, Peterson PA (1984) The Eβ gene may have acted as the donor gene in a gene conversion-like even generating the Aβ (bml2) mutant. EMBO J 3(9):2029–2032

    PubMed  CAS  Google Scholar 

  34. Mengle-Gaw L, Conner S, McDevitt HO, Fathman CG (1984) Gene conversion between murine class II major histocompatibility complex loci. J Exp Med 160: 1184–1194

    Article  PubMed  CAS  Google Scholar 

  35. Slightom J, Blechl AE, Smithies O (1980) Human fetal Gγ and Aγ–globin genes: complete nucleotide sequences suggest that DNA can be exchanged between the duplicated genes. Cell 21:627–638

    Article  PubMed  CAS  Google Scholar 

  36. Bothwell A, Paskind M, Reth M, Imanishi-Kari T, Rajewsky K, Baltimore D (1981) Multiple differences between the nucleic acid sequences of the IgG2a and IgG2ab alleles of the mouse. Cell 24:625–637

    Article  PubMed  CAS  Google Scholar 

  37. Mellor AL, Weiss EH, Ramachandran K, Flavell RA (1984) A potential donor gene for the bml conversion event in the C57BL mouse. Nature 306:792–795

    Article  CAS  Google Scholar 

  38. Michaelides M, Sandrin M, Morgan G, McKenzie IFC, Ashman R, Melvold RW (1981) Ir gene function in an I-A subregion mutant B6C-H-2(bml2). J Exp Med 153:464–469

    Article  PubMed  CAS  Google Scholar 

  39. Lin CC, Rosenthal AS, Passmore HC, Hansen TH (1981) Selective loss of an antigenspecific Ir gene function in the 1–1 mutant B6.C-H-2(bml2) is an antigenpresenting cell defect. Proc Natl Acad Sci USA 78:6406–6410

    Article  PubMed  CAS  Google Scholar 

  40. Hochman PS, Huber BT (1984) A class II gene conversion event defines an antigenspecific Ir gene epitope. J Exp Med 160:1925–1930

    Article  PubMed  CAS  Google Scholar 

  41. Stastny P (1978) Association of the B cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298:869–871

    Article  PubMed  CAS  Google Scholar 

  42. Svejgaard A, Platz P, Ryder LP (1983) HLA and disease 1982. A survey. Immunol Rev 70:0105–2896

    Article  Google Scholar 

  43. Duquesnoy RJ, Marrari M, Hackbarth S, Zeevi A (1984) Serological and cellular definition of a new HLA-DR associated determinant, MCI, and its association with rheumatoid arthritis. Hum Immunol 10:165–176

    Article  PubMed  CAS  Google Scholar 

  44. Lee SH, Gregersen PK, Shen HH, Silver J, Winchester RJ (1985) Strong association of rheumatoid arthritis with a polymorphic Ia epitope defined by monoclonal antibody. Comparison with the allodeterminant DR4. Rheumatol Int (in press)

    Google Scholar 

  45. 45. Kajimura Y, Toyoda H, Shively JE, Goyert S, Silver, and Itakura K (1983) Characterization of a cDNA clone coding for the heavy chain of HLA-DR antigens. DNA 2:175–178

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. J. Silver
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  2. S. M. Goyert
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Editor information

Editors and Affiliations

  1. Blood Bank and Immunohematological Laboratory, Rikshospitalet, National Hospital, Pilestredet 32, N-0027, Oslo 1, Norway

    Bjarte G. Solheim (Director) (Director)

  2. Karolinska Institute, Department of Clinical Immunology, Huddinge Hospital, S-14186, Huddinge, Sweden

    Erna Møller

  3. Dept. of Microbiology and Immunology, New York Medical College, Valhalla, NY, 10595, USA

    Soldano Ferrone

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© 1986 Springer-Verlag Berlin Heidelberg

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Silver, J., Goyert, S.M. (1986). Epitopes Are the Functional Units of HLA Class II Molecules and Form the Molecular Basis for Disease Susceptibility. In: Solheim, B.G., Møller, E., Ferrone, S. (eds) HLA Class II Antigens. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-70367-6_3

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  • DOI: https://doi.org/10.1007/978-3-642-70367-6_3

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-70369-0

  • Online ISBN: 978-3-642-70367-6

  • eBook Packages: Springer Book Archive

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