Skip to main content
SpringerLink
Log in

The molecular basis for HLA class II associations with rheumatoid arthritis

  • Special Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

The association of HLA-DR4 with rheumatoid arthritis strongly implicates genes of the major histocompatibility complex (MHC) as contributing to disease susceptibility. Molecular analysis of MHC genes expressed on haplotypes in association with HLA-DR4 reveals that at least six different alleles of the DRβ1 locus and at least three different alleles of the DQβ locus occur on different DR4+ haplotypes. Some of these allelic differences are quite substantial, and others are rather subtle, involving as few as two amino acids. The analysis of individual DR and DQ alleles in rheumatoid arthritis identifies some DR4+ genes strongly associated with disease susceptibility and some DR4+ genes which are not. The Dw4(DR4) and Dw14(DR4) DRβ1 genes appear to represent specific alleles which confer disease risk in RA; other DRβ1 genes, such as Dw10(DR4), may represent DRβ genes altered during evolution which have lost their contribution to RA susceptibility. DQβ 3.1(DQw3) and DQβ 3.2(DQw3) DQβ genes, which are present on DR4+ haplotypes, represent discrete variable alleles not directly implicated in RA, but which account for HLA-DR4 associations with other diseases, such as the association of DQβ 3.2(DQw3) with Type I diabetes.

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

  1. Tiwari J, Terasaki P: HLA and Disease Associations. New York, Springer-Verlag, 1985

    Google Scholar 

  2. Stastny P: Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 298:869–871, 1978

    Google Scholar 

  3. McMichael AJ, Sasazuki T, McDevitt HO, Payne RO: Increased frequency of HLA-Cw3 and HLA-Dw4 in rheumatoid arthritis. Arth Rheum 20:1037–1042, 1977

    Google Scholar 

  4. Thomsen M, Morling M, Snorrason E, Svejgaard A, Sorensen SF: HLA-Dw4 and rheumatoid arthritis. Tissue Antigens 13:56–60, 1979

    Google Scholar 

  5. Young A, Jaraquemada D, Awad J,et al.: Association of HLA-Dw4 (DR4) and DR2/Dw2 with radiologic changes in a prospective study of patients with rheumatoid arthritis. Arth Rheum 27:20–25, 1984

    Google Scholar 

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

    Google Scholar 

  7. Arnett FC, Stevens MB: HLA-DR characterization of a Chippewa Indian subpopulation with high prevalence of rheumatoid arthritis. Hum Immunol 2:155–163, 1981

    Google Scholar 

  8. Payami H, Thomson G, Kahn MA,et al.: Genetics of rheumatoid arthritis. Tissue Antigens 27:57–63, 1986

    Google Scholar 

  9. Khan MA, Kushner I, Weitkamp LR: Genetics of HLA-associated disease; Rheumatoid arthritis. Tissue Antigens 22:182–185, 1983

    Google Scholar 

  10. Nunez G, Moore S, Ball GV, Hurd ER, Stastny P: Study of HLA antigens in ten multiple-case rheumatoid arthritis families. J Rheumatol 11:129–135, 1984

    Google Scholar 

  11. Lawrence JS: Rheumatoid arthritis: Nature or Nurture. Ann Rheum Dis 29:357–379, 1970

    Google Scholar 

  12. Christiansen FT, Kelly H, Dawkins RL: Rheumatoid arthritis.In Histocompatibility Testing, ED Albertet al. (eds). New York, Springer-Verlag, 1984, pp 379–383

    Google Scholar 

  13. Nepom BS, Nepom GT, Mickelson E, Antonelli P, Hansen JA: Electrophoretic analysis of human HLA-DR antigens from HLA-DR4 homozygous cell lines: Correlation between β-chain diversity and HLA-D. Proc Natl Acad Sci USA 80:6962–6966, 1983

    Google Scholar 

  14. Nepom GT, Nepom BS, Antonelli P,et al.: The HLA-DR4 family of haplotypes consists of a series of distinct DR and DS molecules. J Exp Med 159:394–404, 1983

    Google Scholar 

  15. Groner JP, Watson AJ, Bach FH: Dw/LD-related molecular polymorphism of DR4 β-chains. J Exp Med 157:1687–1691, 1983

    Google Scholar 

  16. Maeda H, Hirata R: Molecular identification of HLA-DR4, MT3, and TB21 antigens on HLA-DR4 homozygous B cell lines. J Immunol 132:574, 1984

    Google Scholar 

  17. Suzuki M, Yabe T, Satake M, Juni T, Hamaguchi H: Two-dimensional gel electrophoretic analysis of the MT3 and DR4 molecules from different D typed cells. J Exp Med 160:751, 1984

    Google Scholar 

  18. Hirayama K, Nishimura Y, Tsukamoto K, Sasazuki T: Functional and molecular analysis of three distinct HLA-DR4 β chains responsible for the MLR between HLA-Dw4, Dw15, and DKT2. J Immunol 137:924–933, 1986

    Google Scholar 

  19. Reinsmoen N, Bach F: Five HLA-D clusters associated with HLA-DR4. Hum Immunol 4:249–258, 1982

    Google Scholar 

  20. Grosse-Wilde H, Doxiadis I, Brandt H: Definition of HLA-D with HTC.In Histocompatibility Testing 1984, E Albertet al. (eds). New York, Springer-Verlag, 1984, pp 249–264

    Google Scholar 

  21. Seyfried C, Gregersen P, Nepom B, Nepom GT: Limited peptide variations among HLA-DR4 + DR-β chains account for functional polymorphisms. Mol Immunol (in press), 1987

  22. Gregersen P, Shen M, Song Q, Merryman P, Degar S, Seki T, Maccari T, Goldberg D, Murphy H, Schwenzer J, Wang C, Winchester R, Nepom G, Silver J: Molecular diversity of HLA-DR4 haplotypes. Proc Natl Acad Sci 83:2642–2646, 1986

    Google Scholar 

  23. Cairns JS, Curtsinger CA, Dahl CA, Freeman S, Alter BJ, Bach FH: Sequence polymorphisms of HLA DR β-1 alleles relating to T cell-recognized determinants. Nature 317:116, 1985

    Google Scholar 

  24. Kim SJ, Holbeck SL, Nisperos B, Hansen JA, Maeda H, Nepom GT: Identification of a polymorphic variant associated with HLA-DQw3 and characterized by specific restriction sites within the DQ β-chain gene. Proc Natl Acad Sci USA 82:8139–8143, 1985

    Google Scholar 

  25. Nepom B, Kim SJ, Nepom GT: A deletion mutant defines DQ β variants within DR4 positive DQw3 positive haplotypes. Hum Immunol 17:87–93, 1986

    Google Scholar 

  26. Holbeck S, Nepom GT: Analysis of allelic variation within HLA-DQ β genes using synthetic oligonucleotide probes. Immunogenetics (in press), 1986

  27. Ishikawa N, Kasahara M, Ikeda H,et al.: Demonstration of structural polymorphism among MB3 light chains by two-dimensional gel electrophoresis. J Immunol 134:417, 1985

    Google Scholar 

  28. Bontrop R, Schreuder G, Mikulski E, van Miltenburg R, Giphart M: Polymorphisms within the HLA-DR4 haplotypes. Tissue Antigens 27:22–31, 1986

    Google Scholar 

  29. Maeda H, Hirata R, Thompson A, Mukai R: Molecular characterization of three HLA class II molecules on DR4 and DRw9 haplotypes: Serologic and structural relationships at the polypeptide level. Hum Immunol 15:1–15, 1986

    Google Scholar 

  30. Nepom GT, Seyfried C, Nepom B: Immunogenetics of susceptibility disease. J Pathol Immunopathol 5:37–46, 1986

    Google Scholar 

  31. Nepom B, Palmer J, Kim SJ, Hansen J, Holbeck S, Nepom GT: Specific genomic markers for the HLA-DQ subregion discriminate between DR4+ IDDM and DR4+ JRA. J Exp Med 164:345–350, 1986

    Google Scholar 

  32. Nepom GT, Palmer J, Nepom B: Specific HLA-DQ alleles associated with IDDM.In Immunology of Diabetes, M Jaworskiet al. (eds). New York, Elsevier Press (in press), 1986

    Google Scholar 

  33. Angelini G, dePreval C, Gorski J, Mach B: High resolution analysis of the human HLA-DR polymorphism by hybridization with sequence-specific oligonucleotide probes. Proc Natl Acad Sci 83:4489–4493, 1986

    Google Scholar 

  34. Winchester RJ: The HLA System and Susceptibility to Diseases: An Interpretation,In Clinical Aspects of Autoimmunity, E Tan (ed).New York, Transmedica, 1986, Vol 1, pp 9–16

    Google Scholar 

  35. McDevitt HO: The molecular basis of autoimmunity. Clin Res 34:163–175, 1986

    Google Scholar 

  36. Qvigstad E, Thorsby E, Reinsmoen N, Bach F: Close association between the Dw14(LD40) subtype of HLA-DR4 and a restriction element for antigen-specific T cell clones. Immunogenetics 20:583–588, 1984

    Google Scholar 

  37. Yakura H, Wakisaka A, Aizawa M, Itakura K, Tagawa Y, Sugiura S: HLA-D antigen of Japanese origin (LD.Wa) and its association with Vogt-Koyanagi-Hirada syndrome. Tissue Antigens 8:35–42, 1976

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Virginia Masor Research Center, 1000 Seneca, 98101, Seattle, Washington

    Gerald T. Nepom

  2. Puget Sound Blood Center, 98101, Seattle, Washington

    John A. Hansen

  3. Genetic Systems Corporation, 98101, Seattle, Washington

    Barbara S. Nepom

  4. School of Medicine, University of Washington, 98101, Seattle, Washington

    Barbara S. Nepom

Authors
  1. Gerald T. Nepom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John A. Hansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Barbara S. Nepom
    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

Nepom, G.T., Hansen, J.A. & Nepom, B.S. The molecular basis for HLA class II associations with rheumatoid arthritis. J Clin Immunol 7, 1–7 (1987). https://doi.org/10.1007/BF00915418

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00915418

Key words

Search

Navigation