Immunologic Research

, Volume 32, Issue 1–3, pp 5–13 | Cite as

Initiation of an autoimmune response

Insights from a transgenic model of rheumatoid arthritis
  • Laura Mandik-Nayak
  • Paul M. Allen


K/BxN mice develop an inflammatory joint disease with many features characteristic of rheumatoid arthritis. This model is based on a T-cell receptor transgene, KRN, that has been shown to recognize both the foreign antigen bovine RNase, and the ubiquitously expressed self antigen, glucose-6-phosphate isomerase (GPI). We have used this model to investigate the initial events that occur during the autoimmune response to GPI. We and others have identified key mediators in the inflammatory response: Fc receptors (FcRs) (in particular FcRIII), the alternative pathway of complement, neutrophils, and mast cells. Using micro position emission tomography, we demonstrated that anti-GPI Immunoglobulin G (IgG) localizes specifically to the joints where arthritis occurs and that this localization is dependent on mast cells, neutrophils, FcRs, and immune complexes. The trigger of arthritis in this model is the KRN T-cell inducing the production of anti-GPI Ig. By overexpressing the ligand for the KRN T-cells in major histocompatibility complex class II-expressing cells, we demonstrated that KRN T-cells were able to escape tolerance induction in the thymus owing to insufficient levels of antigen in the thymus antigen-presenting cells. This allows the KRN T-cells to exit to the periphery, where they provide help to anti-GPI B-cells, inducing the production of arthritogenic Ig. To understand the joint specificity of the disease, we followed the anti-GPI B-cell response that naturally arises in K/BxN mice and showed that, although the GPI antigen is ubiquitously expressed, the anti-GPI B-cell response is foucused on the lymph nodes draining the affected joints. Together, these studies have given us a greater understanding of how an autoimmune response is initiated at the level of both the adaptive and innate immune systems and demonstrate the versatility of the K/BxN arthritis model for studying human disease.

Key Words

Autoimmunity Arthritis Autoantibody T-cells B-cells Neutrophils 


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  1. 1.
    Allen PM, Strydom DJ, Unanue ER: Processing of lysozyme by macrophages: identification of the determinant recognized by two T cell hybridomas. Proc Natl Acad Sci USA 1984;81:2489–2493.PubMedCrossRefGoogle Scholar
  2. 2.
    Babbitt BP, Allen PM, Matsueda G, Haber E, Unanue ER: Bilding of immunogenic peptides to Ia histocompatibility molecules. Nature 1985;317:359–361.PubMedCrossRefGoogle Scholar
  3. 3.
    Allen PM, Matsueda GR, Evans RJ, Dunbar JBJ, Marshall GR, Unanue ER: Identification of the T-cell and Ia contact residues of a T-cell antigenic epitope. Nature 1987;327:713–715.PubMedCrossRefGoogle Scholar
  4. 4.
    Grakoui A, Bromley SK, Sumen C, et al: The immunological synapse: a molecular machine controlling T cell activation. Science 1999;285:221–227.PubMedCrossRefGoogle Scholar
  5. 5.
    Lorenz RG, Allen PM: Direct evidence for functional self protein/Ia-molecule complexes in vivo. Proc Natl Acad Sci USA 1988;85:5220–5223.PubMedCrossRefGoogle Scholar
  6. 6.
    Evavold BD, Williams SG, Hsu BL, Buus S, Allen PM: Complete dissection of the Hb(64–76) determinant using Th1, Th2 clones, and T cell hybridomas. J Immunol 1992;148:347–353.PubMedGoogle Scholar
  7. 7.
    Evavold BD, Sloan-Lancaster J, Hsu BL, Allen PM: Separation of T helper 1 clone cytolysis from proliferation and lymphokine production using analog peptides. J Immunol 1993;150:3131–3140.PubMedGoogle Scholar
  8. 8.
    Sloan-Lancaster J, Shaw AS, Rothbard JB, Allen PM: Partial T cell signaling: altered phospho-ξ and lack of Zap 70 recruitment in APL-induced T cell anergy. Cell 1994;79:913–922.PubMedCrossRefGoogle Scholar
  9. 9.
    Kersh GJ, Allen PM: Structural basis for T cell recognition of altered peptide ligands: a single T cell receptor can productively recognize a large continuum of related ligands. J Exp Med 1996;184:1259–1268.PubMedCrossRefGoogle Scholar
  10. 10.
    Chen JS, Lorenz RG, Goldberg J, Allen PM: Identification and characterization of a T cell-inducing epitope of bovine ribonuclease that can be restricted by multiple class II molecules. J Immunol 1991;147:3672–3678.PubMedGoogle Scholar
  11. 11.
    Lorenz RG, Tyler AN, Allen PM: Reconstruction of the immunogenic peptide RNase(43–56) by identification and transfer of the critical residues into an unrelated peptide backbone. J Exp Med 1989;170:203–216.PubMedCrossRefGoogle Scholar
  12. 12.
    Lorenz RG, Tyler AN, Allen PM: T cell recognition of bovine ribonuclease: self/non-self discrimination at the level of binding to the I-A kmolecule. J Immunol 1988;141:4124–4128.PubMedGoogle Scholar
  13. 13.
    Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397–440.PubMedCrossRefGoogle Scholar
  14. 14.
    Peccoud J, Dellabona P, Allen P, Benoist C, Mathis D: Delineation of antigen contact residues on an MHC class II molecule. EMBO J 1990;9:4215–4223.PubMedGoogle Scholar
  15. 15.
    Kouskoff V, Korganow A-S, Duchatelle V, Degott C, Benoist C, Mathis D: Organ-specific disease provoked by systemic autoimmunity. Cell 1996;87:811–822.PubMedCrossRefGoogle Scholar
  16. 16.
    Ji H, Gauguier D, Ohmura K, et al: Genetic influences on the end-stage effector phase of arthritis. J Exp Med 2001;194:321–330.PubMedCrossRefGoogle Scholar
  17. 17.
    Korganow A-S, Ji H, Mangialaio S, et al: From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. Immunity 1999;10:451–461.PubMedCrossRefGoogle Scholar
  18. 18.
    Matsumoto I, Staub A, Benoist C, Mathis D: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science 1999;286:1732–1735.PubMedCrossRefGoogle Scholar
  19. 19.
    Gurney ME, Heinrich SP, Lee MR, Yin H-S: Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. Science 1986;234:566–574.PubMedCrossRefGoogle Scholar
  20. 20.
    Haga A, Niinaka Y, Raz A: Phosphohexose isomerase/autocrine motility factor/neuroleukin/maturation factor is a multifunctional phosphoprotein. Biochim Biophys Acta 2000;1480:235–244.PubMedGoogle Scholar
  21. 21.
    Basu D, Horvath S, Matsumoto I, Fremont DH, Allen PM: Molecular basis for recognition of an arthritic peptide and a foreign epitope on distinct MHC molecules by a single TCR. J Immunol 2000;164:5788–5796.PubMedGoogle Scholar
  22. 22.
    Basu D, Horvath S, O’Mara L, Donermeyer D, Allen PM: Two MHC surface amino acid differences distinguish foreign peptide recognition from autoantigen specificity. J Immunol 2001;166:4005–4011.PubMedGoogle Scholar
  23. 23.
    Ji H, Ohmura K, Mahmood U, et al: Arthritis critically dependent on innate immune system players. Immunity 2002;16:157–168.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB: Mast cells: a cellular link between autoantibodies and imflammatory arthritis. Science 2002;297:1689–1692.PubMedCrossRefGoogle Scholar
  25. 25.
    Solomon S, Kolb C, Mohanty S, et al: Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35). Eur J Immunol 2002;32:644–651.PubMedCrossRefGoogle Scholar
  26. 26.
    Ji H, Pettit AR, Ohmura K, et al: Critical roles for interleukin 1 and tumor necrosis factorα in antibody-induced arthritis. J Exp Med 2002;196:77–85.PubMedCrossRefGoogle Scholar
  27. 27.
    de Bandt M, Grossin M, Weber A-J, et al: Suppression of arthritis and protection from bone destruction by treatment with TNP-470/AGM-1470 in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 2000;43:2056–2063.PubMedCrossRefGoogle Scholar
  28. 28.
    Maccioni M, Zeder-Lutz G, Huang H, et al: Arthritogenic monoclonal antibodies from K/BxN mice. J Exp Med 2002;195:1071–1077.PubMedCrossRefGoogle Scholar
  29. 29.
    Wipke BT, Allen PM: Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J Immunol 2001;167:1601–1608.PubMedGoogle Scholar
  30. 30.
    Wipke BT, Wang Z, Kim J, McCarthy TJ, Allen PM: Dynamic visualization of a joint-specific autoimmune response through positron emission tomography. Nat Immunol 2002;3:366–372.PubMedCrossRefGoogle Scholar
  31. 31.
    Wipke BT, Wang Z, Nagengast W, Reichert DE, Allen PM: Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes. J Immunol 2004;172:7694–7702.PubMedGoogle Scholar
  32. 32.
    Mandik-Nayak L, Wipke BT, Shih FF, Unanue ER, Allen PM: Despite ubiquitous autoantigen expression, arthritogenic autoantibody response initiates in the local lymph node. Proc Natl Acad Sci USA 2002;99:14,368–14,373.CrossRefGoogle Scholar
  33. 33.
    Mangialaio S, Hong J, Korganow A-S, Kouskoff V, Benoist C, Mathis D: The arthritogenic T cell receptor and its ligand in a spontaneous model of arthritis. Arthritis Rheum 1999;42:2517–2523.PubMedCrossRefGoogle Scholar
  34. 34.
    Shih FF, Mandik-Nayak L, Wipke BT, Allen PM: Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells. J Exp Med 2004;199:323–335.PubMedCrossRefGoogle Scholar
  35. 35.
    Williams CB, Engle DL, Kersh GJ, White MJ, Allen PM: A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor-ligand complex. J Exp Med 1999;189:1531–1544.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2005

Authors and Affiliations

  • Laura Mandik-Nayak
    • 1
  • Paul M. Allen
    • 1
  1. 1.Department of Pathology & ImmunologyWashington University School of MedicineSt. Louis

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