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Antigen-specific T cells in rheumatoid arthritis

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Abstract

There is considerable evidence of a key role for CD4+ T cells in the pathogenesis of rheumatoid arthritis. Several attractive candidate antigens, mostly joint-specific, have been studied, but information regarding T cell responses to these antigens in patients is limited and occasionally contra-dictory. Novel reagents (such as major histocompatibility complex and peptide tetramers) and sensitive techniques (such as intracellular cytokine staining) will aid in future studies to identify antigen-specific T cells. In addition, a new animal model of inflammatory arthritis has recently pro-vided new perspective to the study of rheumatoid arthritis by drawing attention to systemic self-antigens as targets of autoimmunity and anti-self antibodies as markers of T cell activity and effectors of disease.

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References and Recommended Reading

  1. Marrack P, Kappler J, Kotzin BL: Autoimmune disease: why and where it occurs. Nat Med 2001, 7:899–905.

    Article  PubMed  CAS  Google Scholar 

  2. Notkins AL, Lernmark A: Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest 2001, 108:1247–1252.

    Article  PubMed  CAS  Google Scholar 

  3. Matsumoto I, Staub A, Benoist C, Mathis D: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Sci-ence 1999, 286:1732–1735. This paper provides definitive evidence that GPI is the target antigen in the K/BxN mouse model of arthritis and that anti-GPI antibodies alone are sufficient to cause a destructive arthritis. This mouse model has important implications for the type of autoantigen (systemic) that could stimulate arthritis and for the potential role of autoantibodies in the development of arthritis.

    Article  CAS  Google Scholar 

  4. Wipke BT, Allen PM: Essential role of neutrophils in the initi-ation and progression of a murine model of rheumatoid arthritis. J Immunol 2001, 167:1601–1608. This study elucidates the effector mechanisms by which anti-GPI anti-bodies cause disease in the K/BxN mouse model.

    PubMed  CAS  Google Scholar 

  5. Lehmann PV, Sercarz EE, Forsthuber T, et al.: Determinant spreading and the dynamics of the autoimmune T-cell reper-toire. Immunol Today 1993, 14:203–208.

    Article  PubMed  CAS  Google Scholar 

  6. Nepom GT: Major histocompatibility complex-directed sus-ceptibility to rheumatoid arthritis. Adv Immunol 1998, 68:315–332.

    PubMed  CAS  Google Scholar 

  7. Gregersen PK, Silver J, Winchester RJ: The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987, 30:1205–1213.

    Article  PubMed  CAS  Google Scholar 

  8. Kohem CL, Brezinschek RI, Wisbey H, et al.: Enrichment of dif-ferentiated CD45RBdim, CD27-memory T cells in the periph-eral blood, synovial fluid, and synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum 1996, 39:844–854.

    Article  PubMed  CAS  Google Scholar 

  9. Choy EH, Panayi GS: Cytokine pathways and joint inflamma-tion in rheumatoid arthritis. N Engl J Med 2001, 344:907–916.

    Article  PubMed  CAS  Google Scholar 

  10. Schmidt D, Goronzy JJ, Weyand CM: CD4+ CD7-CD28- T cells are expanded in rheumatoid arthritis and are characterized by autoreactivity. J Clin Invest 1996, 97:2027–2037.

    PubMed  CAS  Google Scholar 

  11. Ali M, Ponchel F, Wilson KE, Francis MJ, et al.: Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy. J Clin Invest 2001, 107:519–528.

    PubMed  CAS  Google Scholar 

  12. O’Garra A, Steinman L, Gijbels K: CD4+ T-cell subsets in autoimmunity. Curr Opin Immunol 1997, 9:872–883.

    Article  PubMed  CAS  Google Scholar 

  13. Feldmann M, Brennan FM, Maini RN: Rheumatoid arthritis. Cell 1996, 85:307–310.

    Article  PubMed  CAS  Google Scholar 

  14. Miossec P: Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum 2003, 48:594–601.

    Article  PubMed  CAS  Google Scholar 

  15. Koetz K, Bryl E, Spickschen K, et al.: T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A 2000, 97:9203–9208.

    Article  PubMed  CAS  Google Scholar 

  16. Altman JD, Moss PA, Goulder PJ, et al.: Phenotypic analysis of antigen-specific T lymphocytes. Science 1996, 274:94–96.

    Article  PubMed  CAS  Google Scholar 

  17. Crawford F, Kozono H, White J, et al.: Detection of antigen-specific T cells with multivalent soluble class II MHC cova-lent peptide complexes. Immunity 1998, 8:675–682.

    Article  PubMed  CAS  Google Scholar 

  18. Meyer AL, Trollmo C, Crawford F, et al.: Direct enumeration of Borrelia-reactive CD4 T cells ex vivo by using MHC class II tetramers. Proc Natl Acad Sci U S A 2000, 97:11433–11438.

    Article  PubMed  CAS  Google Scholar 

  19. Kotzin BL, Falta MT, Crawford F, et al.: Use of soluble peptide-DR4 tetramers to detect synovial T cells specific for cartilage antigens in patients with rheumatoid arthritis. Proc Natl Acad Sci U S A 2000, 97:291–296. This study demonstrates the potential utility of both MHC class II tet-ramers and TCR transfected hybridomas as reagents for the study of antigen-specific T cell responses in RA.

    Article  PubMed  CAS  Google Scholar 

  20. Maino VC, Picker LJ: Identification of functional subsets by flow cytometry: intracellular detection of cytokine expres-sion. Cytometry 1998, 34:207–215.

    Article  PubMed  CAS  Google Scholar 

  21. Hesse MD, Karulin AY, Boehm BO, et al.: A T cell clone’s avid-ity is a function of its activation state. J Immunol 2001, 167:1353–1361.

    PubMed  CAS  Google Scholar 

  22. Zou J, Zhang Y, Thiel A, et al.: Predominant cellular immune response to the cartilage autoantigenic G1 aggrecan in anky-losing spondylitis and rheumatoid arthritis. Rheumatology 2003, 42:1–10.

    Article  CAS  Google Scholar 

  23. Fontenot AP, Canavera SJ, Gharavi L, et al.: Target organ local-ization of memory CD4+ T cells in patients with chronic beryllium disease. J Clin Invest 2002, 110:1473–1482.

    Article  PubMed  CAS  Google Scholar 

  24. Struyk L, Hawes GE, Chatila MK, et al.: T cell receptors in rheu-matoid arthritis. Arthritis Rheum 1995, 38:577–589.

    Article  PubMed  CAS  Google Scholar 

  25. Striebich CC, Falta MT, Wang Y, et al.: Selective accumulation of related CD4+ T cell clones in the synovial fluid of patients with rheumatoid arthritis. J Immunol 1998, 161:4428–4436.

    PubMed  CAS  Google Scholar 

  26. Boen E, Crownover AR, McIlhaney M, et al.: Identification of T cell ligands in a library of peptides covalently attached to HLA-DR4. J Immunol 2000, 165:2040–2047.

    PubMed  CAS  Google Scholar 

  27. Malmstrom V, Michaelsson E, Burkhardt H, et al.: Systemic ver-sus cartilage-specific expression of a type II collagen- specific T-cell epitope determines the level of tolerance and suscepti-bility to arthritis. Proc Natl Acad Sci U S A 1996, 93:4480–4485.

    Article  PubMed  CAS  Google Scholar 

  28. Bäcklund J, Carlsen S, Hℷer T, et al.: Predominant selection of T cells specific for the glycosylated collagen type II epitope (263-270) in humanized transgenic mice and in rheumatoid arthritis. Proc Nat Acad Sci U S A 2002, 99:9960–9965. This study uses mice transgenic for human HLA-DR4, CD4, and CII to show that tolerance for post-translationally modified (glycosylated) CII epitopes may be different than nonmodified epitopes. Additional experiments suggest that RA T cells may predominantly recognize the immunodominant CII epitope in its glycosylated form.

    Article  CAS  Google Scholar 

  29. Rosloniec EF, Brand DD, Myers LK, et al.: Induction of autoim-mune arthritis in HLA-DR4 (DRB1-0401) transgenic mice by immunization with human and bovine type II collagen. J Immunol 1998, 160:2573–2578.

    PubMed  CAS  Google Scholar 

  30. Stuart JM, Dixon FJ: Serum transfer of collagen-induced arthritis in mice. J Exp Med 1983, 158:378–392.

    Article  PubMed  CAS  Google Scholar 

  31. Kim HY, Kim WU, Cho ML, et al.: Enhanced T cell proliferative response to type II collagen and synthetic peptide CII (255- 274) in patients with rheumatoid arthritis. Arthritis Rheum 1999, 42:2085–2093.

    Article  PubMed  CAS  Google Scholar 

  32. Verheijden GF, Rijnders AW, Bos E, et al.: Human cartilage gly-coprotein- 39 as a candidate autoantigen in rheumatoid arthritis. Arthritis Rheum 1997, 40:1115–1125.

    Article  PubMed  CAS  Google Scholar 

  33. Cope AP, Patel SD, Hall F, et al.: T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis-associated and nonassociated HLA-DR4 alleles. Arthritis Rheum 1999, 42:1497–1507.

    Article  PubMed  CAS  Google Scholar 

  34. Hain NA, Stuhlmuller B, Hahn GR, et al.: Biochemical charac-terization and microsequencing of a 205-kDa synovial pro-tein stimulatory for T cells and reactive with rheumatoid factor containing sera. J Immunol 1996, 157:1773–1780.

    PubMed  CAS  Google Scholar 

  35. Blass S, Schumann F, Hain NA, et al.: P205 is a major target of autoreactive T cells in rheumatoid arthritis. Arthritis Rheum 1999, 42:971–980.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang Y, Guerassimov A, Leroux JY, et al.: Arthritis induced by proteoglycan aggrecan G1 domain in BALB/c mice: evidence for t cell involvement and the immunosuppressive influence of keratan sulfate on recognition of T and B cell epitopes. J Clin Invest 1998, 101:1678–1686.

    Article  PubMed  CAS  Google Scholar 

  37. Finnegan A, Mikecz K, Tao P, Glant TT: Proteoglycan (aggre-can)- induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J Immunol 1999, 163:5383–5390.

    PubMed  CAS  Google Scholar 

  38. Guerassimov A, Zhang Y, Banerjee S, et al.: Cellular immunity to the G1 domain of cartilage proteoglycan aggrecan is enhanced in patients with rheumatoid arthritis but only after removal of keratan sulfate. Arthritis Rheum 1998, 41:1019–1025.

    Article  PubMed  CAS  Google Scholar 

  39. Tighe H, Carson D: Rheumatoid factor. In Kelley’s Textbook of Rheumatology, edn 6. Edited by Ruddy S, Harris E, Sledge C. Philadelphia: W.B. Saunders; 2001:151–160.

    Google Scholar 

  40. Blass S, Union A, Raymackers J, et al.: The stress protein BiP is overexpressed and is a major B and T cell target in rheuma-toid arthritis. Arthritis Rheum 2001, 44:761–771.

    Article  PubMed  CAS  Google Scholar 

  41. Corrigall VM, Bodman-Smith MD, Fife MS, et al.: The human endoplasmic reticulum molecular chaperone BiP is an autoan-tigen for rheumatoid arthritis and prevents the induction of experimental arthritis. J Immunol 2001, 166:1492–1498.

    PubMed  CAS  Google Scholar 

  42. Schellekens GA, Visser H, de Jong BA, et al.: The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000, 43:155–163.

    Article  PubMed  CAS  Google Scholar 

  43. Schellekens GA, de Jong BA, van den Hoogen FH, et al.: Citrul-line is an essential constituent of antigenic determinants rec-ognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest 1998, 101:273–281.

    PubMed  CAS  Google Scholar 

  44. Girbal-Neuhauser E, Durieux JJ, Arnaud M, et al.: The epitopes targeted by the rheumatoid arthritis-associated anti-filaggrin autoantibodies are post-translationally generated on various sites of (pro) filaggrin by deimination of arginine residues. J Immunol 1999, 162:585–594.

    PubMed  CAS  Google Scholar 

  45. Masson-Bessiℰe C, Sebbag M, Girbal-Neuhauser E, et al.: The major synovial targets of the rheumatoid arthritis-specific anti-filaggrin autoantibodies are deiminated forms of the alpha- and beta-chains of fibrin. J Immunol 2001, 166:4177–4184. This study characterizes the antigenic targets of anti-filaggrin antibodies, with important implications for the study of relevant Th cell populations.

    Google Scholar 

  46. Fritsch R, Eselböck D, Skriner K, et al.: Characterization of autoreactive T cells to the autoantigens heterogenous nuclear ribonucleoprotein A2 (RA33) and filaggrin in patients with rheumatoid arthritis. J Immunol 2002, 169:1068–1076.

    PubMed  CAS  Google Scholar 

  47. Hong J, Ohmura K, Mahmood U, et al.: Arthritis critically dependent on innate immune system players. Immunity 2002, 16:157–168. Using the K/BxN serum transfer system, this study shows that arthrito-genic anti-GPI antibodies act through Fc receptors and the alternative pathway of complement activation.

    Article  Google Scholar 

  48. Lee DM, Friend DS, Gurish MF, et al.: Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002, 297:1689–1692. This study shows that mast cells are required for anti-GPI antibody transfer of arthritis, and may be a key cell type mediating joint damage.

    Article  PubMed  CAS  Google Scholar 

  49. Hong J, Pettit A, Ohmura K, et al.: Critical roles for interleukin 1 and tumor necrosis factor-alpha in antibody-induced arthritis. J Exp Med 2002, 196:77–85.

    Article  CAS  Google Scholar 

  50. Matsumoto I, Maccioni M, Lee DM, et al.: How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat Immunol 2002, 3:360–365. This study demonstrates that extracellular GPI is present on the artic-ular surface and proposes a mechanism explaining the joint-selectiv-ity of the K/BxN arthritis model.

    Article  PubMed  CAS  Google Scholar 

  51. Schaller M, Burton DR, Ditzel HJ: Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease. Nat Immunol 2001, 2:746–753. This study suggested that GPI could be an autoantigen in patients with RA, but subsequent studies have not been able to confirm this finding.

    Article  PubMed  CAS  Google Scholar 

  52. Matsumoto I, Lee DM, Goldbach-Mansky R, et al.: Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum 2003, 48:944–954. This study represents several follow-up studies showing that responses to GPI are not specific to patients with RA compared with control individuals.

    Article  PubMed  CAS  Google Scholar 

  53. Albert LJ, Inman RD: Molecular mimicry and autoimmunity. N Engl J Med 1999, 341:2068–2074.

    Article  PubMed  CAS  Google Scholar 

  54. Albani S, Carson DA: A multistep molecular mimicry hypoth-esis for the pathogenesis of rheumatoid arthritis. Immunol Today 1996, 17:466–470.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Clinical Immunology (B164), SOM #4627, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, 80262, Denver, CO, USA

    Brian L. Kotzin MD

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  1. Sean R. Bennett PhD
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  2. Michael T. Falta PhD
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  3. Jerry Bill MD
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  4. Brian L. Kotzin MD
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Bennett, S.R., Falta, M.T., Bill, J. et al. Antigen-specific T cells in rheumatoid arthritis. Curr Rheumatol Rep 5, 255–263 (2003). https://doi.org/10.1007/s11926-003-0003-y

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