Rheumatoid Arthritis: A Polygenic Disease with Multiple Phenotypes

  • Cornelia M Weyand1

    Affiliated with

    Arthritis Res19991(Suppl 1):S03

    DOI: 10.1186/ar17

    Published: 15 November 1999

    Full text

    Rheumatoid arthritis (RA) is recognized as a multigene disorder with a number of genetic polymorphisms contributing to disease pathogenesis. Here, we propose that the diagnostic category of RA includes multiple subtypes of disease and that the different phenotypes of RA correlate to different genotypes. Support for this concept has come from a reappraisal of the clinical heterogeneity of RA and the observation that HLA-DRB1 polymorphisms are useful in describing genetic heterogeneity of RA phenotypes. A series of HLA-DRB1 genes has been identified as RA-associated and, in recent years, emphasis has been put on the sequence similarities of these alleles. An alternative view focuses on the amino acid variations found with different alleles being enriched in distinct subtypes of RA. Rheumatoid factor positive destructive joint disease is predominantly associated with the HLA-DRB1*0401 allele while HLA-DRB1*0404 and B1*0101 predisposes for milder and often seronegative disease. Expression of disease-associated alleles on both haplotypes carries a high risk for extra-articular manifestations. Besides HLA gene polymorphisms, emergence of CD28-deficient CD4 T cells identifies RA patients with extra-articular manifestations. These cells undergo clonal expansion in vivo, produce high amounts of IFN-γ and exhibit autoreactivity. Concordance of monozygotic twins for the expression of CD4+CD28- T cells suggests a role for genetic factors in the generation of these unusual T cells. Evidence for heterogeneity of the synovial component of RA comes from studies describing three distinct patterns of lymphoid organizations in the synovium. Each pattern of lymphoid organization correlates with a unique profile of tissue cytokines, demonstrating that several pathways of immune deviation modulate disease expression in RA. Defining RA variants has major implications on how the disease is studied, treated, and managed. Identifying combinations of RA risk genes that correlate with disease variants could become an important diagnostic tool.

    Authors’ Affiliations

    (1)
    Mayo Clinic

    References

    1. Weyand CM, Hicok KC, Conn DL, Goronzy JJ: The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1992, 117:801–806.PubMed
    2. Weyand CM, McCarthy TG, Goronzy JJ: Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J Clin Invest 1995, 95:2120–2126.View ArticlePubMed
    3. Klimiuk PA, Goronzy JJ, Björnsson J, Beckenbaugh RD, Weyand CM: Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol 1997, 151:1311–1319.PubMed
    4. Martens PB, Goronzy JJ, Schaid D, Weyand CM: Expansion of Unusual CD4+ T Cells in Severe Rheumatoid Arthritis. Arthritis Rheum 1997, 40:1106–1114.View ArticlePubMed
    5. Weyand CM, Goronzy JJ: Pathogenesis of rheumatoid arthritis. Med Clin North Amer 1997, 81:29–55.View Article
    6. Weyand CM, Klimiuk PA, Goronzy JJ: Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol 1998, 20:5–22.View ArticlePubMed
    7. Weyand CM, Schmidt D, Wagner U, Goronzy JJ: The influence of sex on the phenotype of rheumatoid arthritis. Arthritis Rheum 1998, 41:817–822.View ArticlePubMed

    Copyright

    © Current Science Ltd 2000

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