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. 1998 Apr 15;101(8):1678–1686. doi: 10.1172/JCI1666

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.

Y Zhang 1, A Guerassimov 1, J Y Leroux 1, A Cartman 1, C Webber 1, R Lalic 1, E de Miguel 1, L C Rosenberg 1, A R Poole 1
PMCID: PMC508749  PMID: 9541498

Abstract

Our previous work showed that the proteoglycan aggrecan can induce erosive polyarthritis and spondylitis in BALB/c mice, and that the G1 domain of the proteoglycan aggrecan (G1) is the arthritogenic region. In this study, two T cell epitopes residing on G1 within residues 70-84 (peptide G5) and 150-169 (peptide G9) were identified using synthetic peptides and aggrecan-specific T cell lines. Two G1-specific T cell hybridomas exclusively responded to peptide G5. When the G5-specific T cell line was injected intraperitoneally into BALB/c mice, it induced acute inflammatory arthritis in joints, but only in those that had been injected with the epitope recognized by these T cells. Furthermore, we also demonstrate that the keratan sulfate chain(s) (KS) on G1 possess immunosuppressive properties with respect to T and B cell epitope recognition. T cell lines that recognize both G1 and peptide G5 show an increased response to G1 after KS is removed. Antibodies in hyperimmune sera of mice immunized with G1 show increased epitope recognition (quantitative and qualitative) after KS removal before immunization. These studies reveal that a T cell line specific to an epitope on the G1 domain of aggrecan, also recognizing a corresponding mouse G1 epitope, can induce arthritis by adoptive transfer and homing to the intraarticular epitope, thereby implicating T cells in arthritis development caused by immunity to the G1 domain of aggrecan. Moreover, the presence of KS on G1 can inhibit arthritis development by suppressing T and B cell epitope recognition.

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Selected References

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  1. Banerjee S., Webber C., Poole A. R. The induction of arthritis in mice by the cartilage proteoglycan aggrecan: roles of CD4+ and CD8+ T cells. Cell Immunol. 1992 Oct 15;144(2):347–357. doi: 10.1016/0008-8749(92)90250-s. [DOI] [PubMed] [Google Scholar]
  2. Barry F. P., Rosenberg L. C., Gaw J. U., Gaw J. U., Koob T. J., Neame P. J. N- and O-linked keratan sulfate on the hyaluronan binding region of aggrecan from mature and immature bovine cartilage. J Biol Chem. 1995 Sep 1;270(35):20516–20524. doi: 10.1074/jbc.270.35.20516. [DOI] [PubMed] [Google Scholar]
  3. Ben-Nun A., Wekerle H., Cohen I. R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol. 1981 Mar;11(3):195–199. doi: 10.1002/eji.1830110307. [DOI] [PubMed] [Google Scholar]
  4. Doege K. J., Sasaki M., Kimura T., Yamada Y. Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J Biol Chem. 1991 Jan 15;266(2):894–902. [PubMed] [Google Scholar]
  5. Doege K., Sasaki M., Horigan E., Hassell J. R., Yamada Y. Complete primary structure of the rat cartilage proteoglycan core protein deduced from cDNA clones. J Biol Chem. 1987 Dec 25;262(36):17757–17767. [PubMed] [Google Scholar]
  6. Fosang A. J., Hardingham T. E. 1-C-6 epitope in cartilage proteoglycan G2 domain is masked by keratan sulphate. Biochem J. 1991 Jan 15;273(Pt 2):369–373. doi: 10.1042/bj2730369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fujinami R. S., Oldstone M. B. Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity. Science. 1985 Nov 29;230(4729):1043–1045. doi: 10.1126/science.2414848. [DOI] [PubMed] [Google Scholar]
  8. Glant T. T., Mikecz K., Arzoumanian A., Poole A. R. Proteoglycan-induced arthritis in BALB/c mice. Clinical features and histopathology. Arthritis Rheum. 1987 Feb;30(2):201–212. doi: 10.1002/art.1780300211. [DOI] [PubMed] [Google Scholar]
  9. Glant T. T., Mikecz K., Roughley P. J., Buzás E., Poole A. R. Age-related changes in protein-related epitopes of human articular-cartilage proteoglycans. Biochem J. 1986 May 15;236(1):71–75. doi: 10.1042/bj2360071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goetinck P. F., Stirpe N. S., Tsonis P. A., Carlone D. The tandemly repeated sequences of cartilage link protein contain the sites for interaction with hyaluronic acid. J Cell Biol. 1987 Nov;105(5):2403–2408. doi: 10.1083/jcb.105.5.2403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Golds E. E., Stephen I. B., Esdaile J. M., Strawczynski H., Poole A. R. Lymphocyte transformation to connective tissue antigens in adult and juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus erythematosus, and a nonarthritic control population. Cell Immunol. 1983 Nov;82(1):196–209. doi: 10.1016/0008-8749(83)90153-3. [DOI] [PubMed] [Google Scholar]
  12. Ishioka G. Y., Lamont A. G., Thomson D., Bulbow N., Gaeta F. C., Sette A., Grey H. M. MHC interaction and T cell recognition of carbohydrates and glycopeptides. J Immunol. 1992 Apr 15;148(8):2446–2451. [PubMed] [Google Scholar]
  13. Kalman B., Knobler R. L., Lublin F. D. T cell receptor V beta gene utilization in myelin basic protein specific clones from CXJ1 recombinant inbred mice. J Neuroimmunol. 1993 Mar;43(1-2):191–194. doi: 10.1016/0165-5728(93)90091-c. [DOI] [PubMed] [Google Scholar]
  14. Kappler J. W., Skidmore B., White J., Marrack P. Antigen-inducible, H-2-restricted, interleukin-2-producing T cell hybridomas. Lack of independent antigen and H-2 recognition. J Exp Med. 1981 May 1;153(5):1198–1214. doi: 10.1084/jem.153.5.1198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Leroux J. Y., Guerassimov A., Cartman A., Delaunay N., Webber C., Rosenberg L. C., Banerjee S., Poole A. R. Immunity to the G1 globular domain of the cartilage proteoglycan aggrecan can induce inflammatory erosive polyarthritis and spondylitis in BALB/c mice but immunity to G1 is inhibited by covalently bound keratan sulfate in vitro and in vivo. J Clin Invest. 1996 Feb 1;97(3):621–632. doi: 10.1172/JCI118458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Leroux J. Y., Poole A. R., Webber C., Vipparti V., Choi H. U., Rosenberg L. C., Banerjee S. Characterization of proteoglycan-reactive T cell lines and hybridomas from mice with proteoglycan-induced arthritis. J Immunol. 1992 Apr 1;148(7):2090–2096. [PubMed] [Google Scholar]
  17. Mikecz K., Glant T. T., Baron M., Poole A. R. Isolation of proteoglycan-specific T lymphocytes from patients with ankylosing spondylitis. Cell Immunol. 1988 Mar;112(1):55–63. doi: 10.1016/0008-8749(88)90275-4. [DOI] [PubMed] [Google Scholar]
  18. Mikecz K., Glant T. T., Buzás E., Poole A. R. Proteoglycan-induced polyarthritis and spondylitis adoptively transferred to naive (nonimmunized) BALB/c mice. Arthritis Rheum. 1990 Jun;33(6):866–876. doi: 10.1002/art.1780330614. [DOI] [PubMed] [Google Scholar]
  19. Mikecz K., Glant T. T., Poole A. R. Immunity to cartilage proteoglycans in BALB/c mice with progressive polyarthritis and ankylosing spondylitis induced by injection of human cartilage proteoglycan. Arthritis Rheum. 1987 Mar;30(3):306–318. doi: 10.1002/art.1780300310. [DOI] [PubMed] [Google Scholar]
  20. Mosmann T. R., Cherwinski H., Bond M. W., Giedlin M. A., Coffman R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986 Apr 1;136(7):2348–2357. [PubMed] [Google Scholar]
  21. Neame P. J., Christner J. E., Baker J. R. Cartilage proteoglycan aggregates. The link protein and proteoglycan amino-terminal globular domains have similar structures. J Biol Chem. 1987 Dec 25;262(36):17768–17778. [PubMed] [Google Scholar]
  22. Oike Y., Kimata K., Shinomura T., Nakazawa K., Suzuki S. Structural analysis of chick-embryo cartilage proteoglycan by selective degradation with chondroitin lyases (chondroitinases) and endo-beta-D-galactosidase (keratanase). Biochem J. 1980 Oct 1;191(1):193–207. doi: 10.1042/bj1910193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Rosenberg L. C., Choi H. U., Tang L. H., Johnson T. L., Pal S., Webber C., Reiner A., Poole A. R. Isolation of dermatan sulfate proteoglycans from mature bovine articular cartilages. J Biol Chem. 1985 May 25;260(10):6304–6313. [PubMed] [Google Scholar]
  24. Roughley P. J., White R. J. Age-related changes in the structure of the proteoglycan subunits from human articular cartilage. J Biol Chem. 1980 Jan 10;255(1):217–224. [PubMed] [Google Scholar]
  25. Saxne T., Heinegård D. Synovial fluid analysis of two groups of proteoglycan epitopes distinguishes early and late cartilage lesions. Arthritis Rheum. 1992 Apr;35(4):385–390. doi: 10.1002/art.1780350404. [DOI] [PubMed] [Google Scholar]
  26. Tang L. H., Rosenberg L., Reiner A., Poole A. R. Proteoglycans from bovine nasal cartilage. Properties of a soluble form of link protein. J Biol Chem. 1979 Oct 25;254(20):10523–10531. [PubMed] [Google Scholar]
  27. Walcz E., Deák F., Erhardt P., Coulter S. N., Fülöp C., Horvath P., Doege K. J., Glant T. T. Complete coding sequence, deduced primary structure, chromosomal localization, and structural analysis of murine aggrecan. Genomics. 1994 Jul 15;22(2):364–371. doi: 10.1006/geno.1994.1396. [DOI] [PubMed] [Google Scholar]
  28. Weinberg A. D., Celnik B., Vainiene M., Buenafe A. C., Vandenbark A. A., Offner H. The effect of TCR V beta 8 peptide protection and therapy on T cell populations isolated from the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis. J Neuroimmunol. 1994 Jan;49(1-2):161–170. doi: 10.1016/0165-5728(94)90192-9. [DOI] [PubMed] [Google Scholar]
  29. Witter J., Roughley P. J., Webber C., Roberts N., Keystone E., Poole A. R. The immunologic detection and characterization of cartilage proteoglycan degradation products in synovial fluids of patients with arthritis. Arthritis Rheum. 1987 May;30(5):519–529. doi: 10.1002/art.1780300506. [DOI] [PubMed] [Google Scholar]
  30. Yang B., Yang B. L., Savani R. C., Turley E. A. Identification of a common hyaluronan binding motif in the hyaluronan binding proteins RHAMM, CD44 and link protein. EMBO J. 1994 Jan 15;13(2):286–296. doi: 10.1002/j.1460-2075.1994.tb06261.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Zhang Y., Barkas T., Juillerat M., Schwendimann B., Wekerle H. T cell epitopes in experimental autoimmune myasthenia gravis of the rat: strain-specific epitopes and cross-reaction between two distinct segments of the alpha chain of the nicotinic acetylcholine receptor (Torpedo californica). Eur J Immunol. 1988 Apr;18(4):551–557. doi: 10.1002/eji.1830180410. [DOI] [PubMed] [Google Scholar]

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