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Immunologic Research

, Volume 16, Issue 1, pp 121–126 | Cite as

Molecular mechanisms involved in the association of HLA-DR4 and rheumatoid arthritis

  • Isabelle Auger
  • Eric Toussirot
  • Jean Roudier
Article

Abstract

Susceptibility to developing rheumatoid arthritis (RA) maps to a highly conserved amino acid motif located in the third hypervariable region of different HLA-DRB1 chains. This motif, namely QKRAA, QRRAA, or RRRAA, helps the development of RA by an unknown mechanism.

The QKRAA motif predisposes to more severe disease than the QRRAA or RRRAA motifs. The QKRAA motif carries particular properties: it is a strong B- and T-cell epitope, it shapes the T cell repertoire, it is overrepresented in protein databases, and it is a binding motif for bacterial and human 70-kDa heat-shock proteins. In this article, we propose different models to explain how the QKRAA motif might contribute to RA.

Key Words

Rheumatoid arthritis HLA-DR4 Heat-shock proteins 

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References

  1. 1.
    Stastny P: Mixed lymphocytes cultures in rheumatoid arthritis. J Clin Invest 1976;57:1148–1157.PubMedGoogle Scholar
  2. 2.
    Stasny P: Association of the B cell alloantigen DRw4 with rheuma- toid arthritis. N Engl J Med 1978; 298:869–871.CrossRefGoogle Scholar
  3. 3.
    Ollier W, Thomson W: Population genetics of rheumatoid arthritis. Rheum Dis Clin North Am 1992; 18:741–759.PubMedGoogle Scholar
  4. 4.
    Wilkens R, Nepom GT, Marks C, Nettle J, Nepom BS: Association of HLA-Dw l6 with rheumatoid arthritis in Yakima Indians. Arth- ritis Rheum 1991;34:43–17.CrossRefGoogle Scholar
  5. 5.
    Bodmer JG: Nomenclature for factors of the HLA system, 1990. Immunogenetics 1991;33:301–309.CrossRefGoogle Scholar
  6. 6.
    Gregersen PK, Silver J, Winches- ter RJ: The shared epitope hypoth- esis:an approach to understanding the molecular genetics of suscepti- bility to Rheumatoid Arthritis. Arthritis Rheum 1987;30:1205–1213.PubMedCrossRefGoogle Scholar
  7. 7.
    Weyand CM, Mc Carthy TG, Goronzy J: Correlation between dis- ease phenotype and genetic hetero- geneity in rheumatoid arthritis. J Clin Invest 1995;95:2120–2126.PubMedCrossRefGoogle Scholar
  8. 8.
    Roudier J, Rhodes G, Petersen J, Vaughan J, Carson DA: The Ep- stein Barr virus glycoproteingpl 10, a molecular link between HLA- DR4, HLA-DR1 and rheumatoid arthritis. Scand J Immunol 1988; 27:367–371.PubMedCrossRefGoogle Scholar
  9. 9.
    Schaeffer EB, Sette A, Johnson DL, Berkoff MC, Smith JA, Grey JM, Buus S: Relative contribution of determinant selection and holes in the T cell repertoire to T cell response. Proc Natl Acad Sci USA 1989;86:4649–4653.PubMedCrossRefGoogle Scholar
  10. 10.
    Roudier J, Sette A, Lamont A, Albani S, Karras JG, Carson DA: Tolerance to a self peptide from the third hypervariable region of EBS chain. Eur J Immunol 1991; 21:2063–2067.PubMedCrossRefGoogle Scholar
  11. 11.
    Salvat S, Auger I, Rochelle L, Begovich A, Geburher L, Sette A, Roudier J: Tolerance to a self- peptide from the third hypervari- able region of HLA-DRBl*0401 in rheumatoid patients and normal subjects. J Immunol 1994;153: 5321–5329.PubMedGoogle Scholar
  12. 12.
    Roudier J, Petersen J, Rhodes G, Luka J, Carson DA: Susceptibility to rheumatoid arthritis maps to a T cell epitope shared by the HLA- Dw4DRB 1 chain and the Epstein Barr virus glycoprotein gp110. Proc Natl Acad Sci USA 1989;86: 5104–5108.PubMedCrossRefGoogle Scholar
  13. 13.
    Roudier C, Auger I, Roudier J: Molecular mimicry reflected through database screening: seren- dipity or survival strategy. Immunol Today 1996;17:357,358.CrossRefGoogle Scholar
  14. 14.
    Albani S, Tuckwell JE, Esparza L, Carson DA, Roudier J: The suscep- tibility sequence to rheumatoid arthritis is a cross-reactive B cell epitope shared byEscherichia coli heat shock protein dnaJ and histo- compatibility leukocyte antigen DRB1*0401 molecule. J Clin Invest 1992;89:327–331.PubMedGoogle Scholar
  15. 15.
    Auger I, Escola JM, Gorvel JP, Roudier J: HLA-DR4 and HLA- DR10 motifs that carry susceptibility to rheumatoid arthritis bind 70-kD heat shock proteins. Nature Med 1996;3:306–310.Google Scholar
  16. 16.
    Fugger L, Rothbard JB, Sonder- strup-McDevitt G: Specificity of an HLA-DRB1*0401 restricted T cell response to type II col- lagen. Eur J Immunol 1996;26: 928–933.PubMedCrossRefGoogle Scholar
  17. 17.
    Srivastava PK: Heat shock pro- teins in immune response to cancer: the fourth paradigm. Experientia 1994;50:1054–1060.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1997

Authors and Affiliations

  • Isabelle Auger
    • 1
    • 3
  • Eric Toussirot
    • 2
  • Jean Roudier
    • 1
  1. 1.Laboratoire d’Immuno-RhumatologieFacult’e de M’edecineMarseilleFrance
  2. 2.Service de RhumatologieHopital MinjozBesançonFrance
  3. 3.Laboratoire d’Immuno-RhumatologieUniversit’e de la M’editerran’ee Facult’e de M’edecineMarseilleFrance

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