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Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes

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Abstract

Rheumatoid arthritis (RA) is now 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-DRB 1 polymorphisms are useful in describing genetic heterogeneity of RA phenotypes. A series of HLA-DRB 1 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 in RA-associated HLA-DRB 1 alleles 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-DRB 1*0404 and B1*0101 predispose for milder and often seronegative disease. Expression of disease-associated alleles on both haplotypes carries a high risk for extra-articular manifestations. In particular, patients homozygous for HLA-DRB1*0401 frequently develop rheumatoid vasculitis on follow-up. Besides HLA gene polymorphisms, abnormalities in the generation and function of CD4 T cells and in inflammatory pathways established in synovial lesions can be used to dissect patient subsets with different variants of RA. 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 organization in the synovium. Based upon the topography of tissue-infiltrating mononuclear cells, diffuse, follicular, and granulomatous variants of rheumatoid synovitis can be distinguished. 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. A dissection of RA variants would have major implications on how the disease is studied, treated, and managed. Identifying combinations of RA risk genes that correlate with disease variants could, therefore, become an important diagnostic tool.

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References

  1. Abril A, Schaid D, Goronzy JJ, Weyand CM (1998) Genetic factors influence the emergence of CD28 deficient CD4+ T cells and may represent novel disease risk genes for rheumatoid arthritis. Arthritis Rheum 40:762

    Google Scholar 

  2. Albani S, Carson DA (1996) A multistep molecular mimicry hypothesis for the pathogenesis of rheumatoid arthritis. Immunol Today 17:466

    Google Scholar 

  3. Albani S, Keystone EC, Nelson JL, Ollier WE, La Cava A, Montemayor AC, Weber DA, Montecucco C, Martini A, Carson DA (1995) Positive selection in autoimmunity: abnormal immune responses to a bacterial dnaJ antigenic determinant in patients with early rheumatoid arthritis. Nat Med 1:448

    Google Scholar 

  4. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries IF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315

    Google Scholar 

  5. Brown JH, Jardetzky TS, Gorga JC, Stem LJ, Urban RG, Strominger JL, Wiley DC (1993) Three-dimensional structure of the human class II histocompatibility antigen HLA-DRL Nature 364:33

    Google Scholar 

  6. Chapman A, Stewart SJ, Nepom GT, Green WE, Crowe D, Thomas JW, Miller GG (1996) Cd11b+Cd28CD4+ human T cells: activation requirements and association with HLA-DR alleles. J Immunol 157:4771

    Google Scholar 

  7. Cornelis F, Hardwick L, Flipo RM, Martinez M, Lasbleiz S, Prud'Homme JF, Tran TH, Walsh S, Delaye A, Nicod A, Loste MN, Lepage V, Gibson K, Pile K, Djoulah S, Danze PM, Liote F, Charron D, Weissenbach J, Kuntz D, Bardin T, Wordsworth BP (1997) Association of rheumatoid arthritis with an amino acid allelic variation of the T cell receptor. Arthritis Rheum 40:1387

    Google Scholar 

  8. DerSimonian H, Sugita M, Glass DN, Maier AL, Weinblatt ME, Reme T, Brenner MB (1993) Clonal V alpha 12.1+ T cell expansions in the peripheral blood of rheumatoid arthritis patients. J Exp Med 177:1623

    Google Scholar 

  9. Dessen A, Lawrence CM, Cupo S, Zaller DM, Wiley DC (1997) X-ray crystal structure of HLA-DR4 (DRA*0101, DRB1*0401) complexed with a peptide from human collagen II. Immunity 7:473

    Google Scholar 

  10. Finkelman FD (1995) Relationships among antigen presentation, cytokines, immune deviation, and autoimmune disease. J Exp Med 182:279

    Google Scholar 

  11. Fitzgerald JE, Ricalton NS, Meyer AC, West SG, Kaplan H, Behrendt C, Kotzin BL (1995) Analysis of clonal CD8+ T cell expansions in normal individuals and patients with rheumatoid arthritis. J Immunol 154:3538

    Google Scholar 

  12. Fu XT, Bono CP, Woulfe SL, Swearingen C, Summers NL, Sinigaglia F, Sette A, Schwartz BD, Karr RW (1995) Pocket 4 of the HLA-DR(alpha,beta 1*0401) molecule is a major determinant of T cells recognition of peptide. J Exp Med 181:915

    Google Scholar 

  13. Gao X, Gazit E, Livneh A, Stastny P (1991) Rheumatoid arthritis in Israeli Jews: shared sequences in the third hypervariable region of DRB1 alleles are associated with susceptibility. J Rheumatol 18:801

    Google Scholar 

  14. Gonzalez-Quintial R, Baccala R, Pope RM, Theofilopoulos AN (1996) Identification of clonally expanded T cells in rheumatoid arthritis using a sequence enrichment nuclease assay. J Clin Invest 97:1335

    Google Scholar 

  15. Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM (1994) Dominant clonotypes in the repertoire of peripheral CD4+ T cells in rheumatoid arthritis. J Clin Invest 94:2068

    Google Scholar 

  16. Goronzy JJ, Weyand CM (1994) Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol 6:290

    Google Scholar 

  17. Goronzy JJ, Weyand CM (1995) T cells in rheumatoid arthritis. Paradigms and facts. Rheum Dis Clin North Am 21:655

    Google Scholar 

  18. Goronzy JJ, Zeal A, Weyand CM (1998) T cell receptor repertoire in rheumatoid arthritis. Int Rev Immunol (in press)

  19. Gough A, Faint J, Salmon M, Hassell A, Wordsworth P, Pilling D, Birley A, Emery P (1994) Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 37:1166

    Google Scholar 

  20. Gregersen PK, Silver J, Winchester RJ (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 30:1205

    Google Scholar 

  21. Hall FC, Brown MA, Weeks DE, Walsh S, Nicod A, Butcher S, Andrews LJ, Wordsworth BP (1997) A linkage study across the T cell receptor A and T cell receptor B loci in families with rheumatoid arthritis. Arthritis Rheum 40:1798

    Google Scholar 

  22. Hammer J, Gallazzi F, Bono E, Karr RW, Guenot J, Valsasnini P, Nagy ZA, Sinigaglia F (1995) Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association. J Exp Med 181:1847

    Google Scholar 

  23. Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM (1989) Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169:59

    Google Scholar 

  24. Hingorani R, Monteiro J, Furie R, Chartash E, Navarrete C, Pergolizzi R, Gregersen PK (1996) Oligoclonality of V beta 3 TCR chains in the CD8+ T cell population of rheumatoid arthritis patients. J Immunol 156:852

    Google Scholar 

  25. Hiraiwa A, Yamanaka K, Kwok WW, Mickelson EM, Masewicz S, Hansen JA, Radka SF, Nepom GT (1990) Structural requirements for recognition of the HLA-Dw14 class II epitope: a key HLA determinant associated with rheumatoid arthritis. Proc Natl Acad Sci USA 87:8051

    Google Scholar 

  26. Isomaki P, Luukkainen R, Saario R, Toivanen P, Punnonen J (1996) Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum 39:386

    Google Scholar 

  27. Klimiuk PA, Goronzy JJ, Björnsson J, Beckenbaugh RD, Weyand CM (1997) Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol 151:1311

    Google Scholar 

  28. Kurosaka M, Ziff M (1983) Immunoelectron microscopic study of the distribution of T cell subsets in rheumatoid synovium. J Exp Med 158:1191

    Google Scholar 

  29. Lanchbury JS, Jaeger EE, Sansom DM, Hall MA, Wordsworth P, Stedeford J, Bell JI, Panayi GS (1991) Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA-DQw7 association with Felty's syndrome. Hum Immunol 32:56

    Google Scholar 

  30. Lim A, Toubert A, Pannetier C, Dougados M, Charron D, Kourilsky P, Even J (1996) Spread of clonal T-cell expansions in rheumatoid arthritis patients. Hum Immunol 48:77

    Google Scholar 

  31. Lynn AH, Kwoh CK, Venglish CM, Aston CE, Chakravarti A (1995) Genetic epidemiology of rheumatoid arthritis. Am J Hum Genet 57:150

    Google Scholar 

  32. Martens PB, Goronzy JJ, Schaid D, Weyand CM (1997) Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum 40:1106

    Google Scholar 

  33. McDaniel DO, Alarcon GS, Pratt PW, Reveille JD (1995) Most African-American patients with rheumatoid arthritis do not have the rheumatoid antigenic determinant (epitope). Ann Intern Med 123:181

    Google Scholar 

  34. Merrill JT, Shen C, Schreibman D, Coffey D, Zakharenko O, Fisher R, Lahita RG, Salmon J, Cronstein BN (1997) Adenosine Al receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis. Arthritis Rheum 40:1308

    Google Scholar 

  35. Namekawa T, Wagner UG, Goronzy JJ, Weyand CM (1998) Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum (in press)

  36. Nepom GT, Erlich H (1991) MHC class-II molecules and autoimmunity. Annu Rev Immunol 9:493

    Google Scholar 

  37. Olsen NJ, Callahan LF, Brooks RH, Nance EP, Kaye JJ, Stastny P, Pincus T (1988) Associations of HLA-DR4 with rheumatoid factor and radiographic severity in rheumatoid arthritis. Am J Med 84:257

    Google Scholar 

  38. Park W, Weyand CM, Schmidt D, Goronzy JJ (1997) Co-stimulatory pathways controlling activation and peripheral tolerance of human CD4+Cd28 T cells. Eur J Immunol 27:1082

    Google Scholar 

  39. Penzotti JE, Nepom GT, Lybrand TP (1997) Use of T cell receptor/HLA-DRB1*04 molecular modeling to predict site- specific interactions for the DR shared epitope associated with rheumatoid arthritis. Arthritis Rheum 40:1316

    Google Scholar 

  40. Rigby AS, Voelm L, Silman AJ (1993) Epistatic modeling in rheumatoid arthritis: an application of the Risch theory. Genet Epidemiol 10:311

    Google Scholar 

  41. Risch N, Merikangas K (1996) The future of genetic studies of complex human diseases. Science 273:1516

    Google Scholar 

  42. Rittner HL, Zettl A, Jendro MC, Bartz-Bazzanella P, Goronzy JJ, Weyand CM (1997) Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis. Mol Med 3:452

    Google Scholar 

  43. Roudier J, Petersen J, Rhodes GH, Luka J, Carson DA (1989) Susceptibility to rheumatoid arthritis maps to a T-cell epitope shared by the HLA-Dw4 DR beta-1 chain and the Epstein-Barr virus glycoprotein gp110. Proc Natl Acad Sci USA 86:5104

    Google Scholar 

  44. Salvat S, Auger I, Rochelle L, Begovich A, Geburher L, Sette A, Roudier J (1994) Tolerance to a selfpeptide from the third hypervariable region of HLA DRB1*0401 in rheumatoid arthritis patients and normal subjects. J Immunol 153:5321

    Google Scholar 

  45. Schmidt D, Goronzy JJ, Weyand CM (1996) CD4+ CD7 CD28 T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 97:2027

    Google Scholar 

  46. Schmidt D, Martens PB, Weyand CM, Goronzy JJ (1996) The repertoire of CD4+ CD28 T cells in rheumatoid arthritis. Mol Med 2:608

    Google Scholar 

  47. Schroder AE, Greiner A, Seyfert C, Berek C (1996) Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci USA 93:221

    Google Scholar 

  48. Simon AK, Seipelt E, Sieper J (1994) Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 91:8562

    Google Scholar 

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

    Google Scholar 

  50. Stern LJ, Brown JH, Jardetzky TS, Gorga JC, Urban RG, Strominger JL, Wiley DC (1994) Crystal structure of the human class II MHC protein HLA-DR1 complexed with an influenza virus peptide. Nature 368: 215

    Google Scholar 

  51. Taneja V, David CS (1998) HLA transgenic mice as humanized mouse models of disease and immunity. J Clin Invest 101:921

    Google Scholar 

  52. Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, McDermott M, Sinha AA, Timmerman L, Steinman L (1988) A molecular basis for MHC class II-associated autoimmunity. Science 240:1003

    Google Scholar 

  53. Vallejo AN, Nestel A, Weyand CM, Goronzy JJ (1998) Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene specific nuclear factor binding activity. J Biol Chem 273:8119

    Google Scholar 

  54. Van Roon JA, Van Roy JL, Gmelig-Meyling FH, Lafeber FP, Bijlsma JW (1996) Prevention and reversal of cartilage degradation in rheumatoid arthritis by interleukin-10 and interleukin-4. Arthritis Rheum 39:829

    Google Scholar 

  55. Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM (1996) Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum 39:904

    Google Scholar 

  56. Wagner UG, Kurtin P, Walmer A, Brackertz M, Berry D, Goronzy JJ, Weyand CM (1998) The role of CD8+ T cells in the formation of germinal centers in rheumatoid synovitis. J Immunol (in press)

  57. Wakeland E, Morel L, Achey K, Yui M, Longmate J (1997) Speed congeries: a classic technique in the fast lane (relatively speaking). Immunol Today 18:472

    Google Scholar 

  58. Walmsley M, Katsikis PD, Abney E, Parry S, Williams RO, Maini RN, Feldmann M (1996) Interleukin-10 inhibition of the progression of established collagen-induced arthritis. Arthritis Rheum 39:495

    Google Scholar 

  59. Walser-Kuntz DR, Weyand CM, Weaver AJ, O'Fallon WM, Goronzy JJ (1995) Mechanisms underlying the formation of the T cell receptor repertoire in rheumatoid arthritis. Immunity 2:597

    Google Scholar 

  60. Weyand CM, Brandes JC, Schmidt D, Goronzy JJ (1998) Functional properties of CD4+CD28T cells in the aging immune system. Mech Ageing Dev (in press)

  61. Weyand CM, Goronzy JJ (1995) Inherited and noninherited risk factors in rheumatoid arthritis. Curr Opin Rheumatol 7:206

    Google Scholar 

  62. Weyand CM, Goronzy JJ (1997) Pathogenesis of rheumatoid arthritis. Med Clin North Am 81:29

    Google Scholar 

  63. Weyand CM, Hicok KC, Conn DL, Goronzy JJ (1992) The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis [see comments]. Ann Intern Med 117:801

    Google Scholar 

  64. Weyand CM, Hunder NN, Hicok KC, Hunder GG, Goronzy JJ (1994) HLA-DRB1 alleles in polymyalgia rheumatoca, giant cell arthritis, and rheumatoid arthritis. Arthritis Rheum 37:514

    Google Scholar 

  65. Weyand CM, McCarthy TG, Goronzy JJ (1995) Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. J Clin Invest 95:2120

    Google Scholar 

  66. Weyand CM, Xie C, Goronzy JJ (1992) Homozygosity for the HLA-DRB 1 allele selects for extraarticular manifestations in rheumatoid arthritis. J Clin Invest 89:2033

    Google Scholar 

  67. Wicker LS, Todd JA, Peterson LB (1995) Genetic control of autoimmune diabetes in the NOD mouse. Anon Rev Immunol 13:179

    Google Scholar 

  68. Willkens RF, Nepom GT, Marks CR, Nettles JW, Nepom BS (1991) Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the “shared epitope” hypothesis. Arthritis Rheum 34:43

    Google Scholar 

  69. Winchester R (1994) The molecular basis of susceptibility to rheumatoid arthritis. Adv Immunol 56:389

    Google Scholar 

  70. Yamamura M, Uyemura K, Deans RJ, Weinberg K, Rea TH, Bloom BR, Medlin RL (1991) Defining protective responses to pathogens: cytokine profiles in leprosy lesions. Science 254:277

    Google Scholar 

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Weyand, C.M., Klimiuk, P.A. & Goronzy, J.J. Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol 20, 5–22 (1998). https://doi.org/10.1007/BF00831996

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