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. 1995 Apr;63(4):1400–1408. doi: 10.1128/iai.63.4.1400-1408.1995

Borrelia burgdorferi-specific T lymphocytes induce severe destructive Lyme arthritis.

L C Lim 1, D M England 1, B K DuChateau 1, N J Glowacki 1, R F Schell 1
PMCID: PMC173166  PMID: 7890402

Abstract

This is the first documentation that Borrelia burgdorferi-specific T lymphocytes are involved in the pathogenesis of Lyme arthritis. We present direct evidence that T lymphocytes obtained from inbred LSH hamsters vaccinated with a whole-cell preparation of Formalin-inactivated B. burgdorferi sensu stricto isolate C-1-11 in adjuvant conferred on naive recipient hamsters the ability to develop severe destructive arthritis when challenged with B. burgdorferi sensu stricto isolates C-1-11 and 297. By contrast, recipients infused with normal T lymphocytes and challenged with B. burgdorferi sensu stricto isolates C-1-11 and 297 failed to develop severe destructive arthritis. The T lymphocytes transferred were obtained from the lymph nodes of vaccinated and nonvaccinated hamsters by depleting B lymphocytes by using monoclonal antibody 14-4-4s (< 1% B lymphocytes by flow cytometric analysis). The enriched T lymphocytes showed enhanced proliferation to stimulation with concanavalin A and failed to respond to lipopolysaccharide. Moreover, only the enriched T lymphocytes from vaccinated hamsters proliferated on exposure to a whole-cell preparation of B. burgdorferi sensu stricto isolate C-1-11 in the presence of mitomycin-treated syngeneic antigen-presenting cells. These results demonstrate that B. burgdorferi-specific T lymphocytes primed by vaccination with a whole-cell preparation of inactivated B. burgdorferi sensu stricto isolate C-1-11 in adjuvant are involved in the development of severe destructive arthritis. Additional experiments are needed to define the precise mechanism(s) responsible for the development of Lyme arthritis.

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Selected References

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  1. Allen J. B., Malone D. G., Wahl S. M., Calandra G. B., Wilder R. L. Role of the thymus in streptococcal cell wall-induced arthritis and hepatic granuloma formation. Comparative studies of pathology and cell wall distribution in athymic and euthymic rats. J Clin Invest. 1985 Sep;76(3):1042–1056. doi: 10.1172/JCI112057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Asbrink E., Brehmer-Andersson E., Hovmark A. Acrodermatitis chronica atrophicans--a spirochetosis. Clinical and histopathological picture based on 32 patients; course and relationship to erythema chronicum migrans Afzelius. Am J Dermatopathol. 1986 Jun;8(3):209–219. doi: 10.1097/00000372-198606000-00005. [DOI] [PubMed] [Google Scholar]
  3. Brahn E., Trentham D. E. Effect of antithymocyte serum on collagen arthritis in rats: evidence that T cells are involved in its pathogenesis. Cell Immunol. 1984 Jul;86(2):421–428. doi: 10.1016/0008-8749(84)90397-6. [DOI] [PubMed] [Google Scholar]
  4. Callister S. M., Case K. L., Agger W. A., Schell R. F., Johnson R. C., Ellingson J. L. Effects of bovine serum albumin on the ability of Barbour-Stoenner-Kelly medium to detect Borrelia burgdorferi. J Clin Microbiol. 1990 Feb;28(2):363–365. doi: 10.1128/jcm.28.2.363-365.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen I. R., Holoshitz J., van Eden W., Frenkel A. T lymphocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum. 1985 Aug;28(8):841–845. doi: 10.1002/art.1780280802. [DOI] [PubMed] [Google Scholar]
  6. DeJoy S. Q., Ferguson K. M., Sapp T. M., Zabriskie J. B., Oronsky A. L., Kerwar S. S. Streptococcal cell wall arthritis. Passive transfer of disease with a T cell line and crossreactivity of streptococcal cell wall antigens with Mycobacterium tuberculosis. J Exp Med. 1989 Aug 1;170(2):369–382. doi: 10.1084/jem.170.2.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hejka A., Schmitz J. L., England D. M., Callister S. M., Schell R. F. Histopathology of Lyme arthritis in LSH hamsters. Am J Pathol. 1989 May;134(5):1113–1123. [PMC free article] [PubMed] [Google Scholar]
  8. Holmdahl R., Klareskog L., Rubin K., Björk J., Smedegård G., Jonsson R., Andersson M. Role of T lymphocytes in murine collagen induced arthritis. Agents Actions. 1986 Dec;19(5-6):295–305. doi: 10.1007/BF01971231. [DOI] [PubMed] [Google Scholar]
  9. Holmdahl R., Klareskog L., Rubin K., Larsson E., Wigzell H. T lymphocytes in collagen II-induced arthritis in mice. Characterization of arthritogenic collagen II-specific T-cell lines and clones. Scand J Immunol. 1985 Sep;22(3):295–306. doi: 10.1111/j.1365-3083.1985.tb01884.x. [DOI] [PubMed] [Google Scholar]
  10. Holoshitz J., Matitiau A., Cohen I. R. Arthritis induced in rats by cloned T lymphocytes responsive to mycobacteria but not to collagen type II. J Clin Invest. 1984 Jan;73(1):211–215. doi: 10.1172/JCI111193. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Holoshitz J., Naparstek Y., Ben-Nun A., Cohen I. R. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science. 1983 Jan 7;219(4580):56–58. doi: 10.1126/science.6336851. [DOI] [PubMed] [Google Scholar]
  12. Johnson R. C., Kodner C., Russell M., Duray P. H. Experimental infection of the hamster with Borrelia burgdorferi. Ann N Y Acad Sci. 1988;539:258–263. doi: 10.1111/j.1749-6632.1988.tb31859.x. [DOI] [PubMed] [Google Scholar]
  13. Johnson R. C., Kodner C., Russell M. Passive immunization of hamsters against experimental infection with the Lyme disease spirochete. Infect Immun. 1986 Sep;53(3):713–714. doi: 10.1128/iai.53.3.713-714.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jost L. M., Kirkwood J. M., Whiteside T. L. Improved short- and long-term XTT-based colorimetric cellular cytotoxicity assay for melanoma and other tumor cells. J Immunol Methods. 1992 Mar 4;147(2):153–165. doi: 10.1016/s0022-1759(12)80003-2. [DOI] [PubMed] [Google Scholar]
  15. Kayashima K., Koga T., Onoue K. Role of T lymphocytes in adjuvant arthritis. I. Evidence for the regulatory function of thymus-derived cells in the induction of the disease. J Immunol. 1976 Nov;117(5 PT2):1878–1882. [PubMed] [Google Scholar]
  16. Kayashima K., Koga T., Onoue K. Role of T lymphocytes in adjuvant arthritis. II. Different subpopulations of T lymphocytes functioning in the development of the disease. J Immunol. 1978 Apr;120(4):1127–1131. [PubMed] [Google Scholar]
  17. Kenefick K. B., Lim L. C., Alder J. D., Schmitz J. L., Czuprynski C. J., Schell R. F. Induction of interleukin-1 release by high- and low-passage isolates of Borrelia burgdorferi. J Infect Dis. 1993 May;167(5):1086–1092. doi: 10.1093/infdis/167.5.1086. [DOI] [PubMed] [Google Scholar]
  18. Klareskog L., Holmdahl R., Larsson E., Wigzell H. Role of T lymphocytes in collagen II induced arthritis in rats. Clin Exp Immunol. 1983 Jan;51(1):117–125. [PMC free article] [PubMed] [Google Scholar]
  19. Krause A., Brade V., Schoerner C., Solbach W., Kalden J. R., Burmester G. R. T cell proliferation induced by Borrelia burgdorferi in patients with Lyme borreliosis. Autologous serum required for optimum stimulation. Arthritis Rheum. 1991 Apr;34(4):393–402. doi: 10.1002/art.1780340404. [DOI] [PubMed] [Google Scholar]
  20. Krause A., Burmester G. R., Rensing A., Schoerner C., Schaible U. E., Simon M. M., Herzer P., Kramer M. D., Wallich R. Cellular immune reactivity to recombinant OspA and flagellin from Borrelia burgdorferi in patients with Lyme borreliosis. Complexity of humoral and cellular immune responses. J Clin Invest. 1992 Sep;90(3):1077–1084. doi: 10.1172/JCI115923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lahesmaa R., Shanafelt M. C., Allsup A., Soderberg C., Anzola J., Freitas V., Turck C., Steinman L., Peltz G. Preferential usage of T cell antigen receptor V region gene segment V beta 5.1 by Borrelia burgdorferi antigen-reactive T cell clones isolated from a patient with Lyme disease. J Immunol. 1993 May 1;150(9):4125–4135. [PubMed] [Google Scholar]
  22. Lengl-Janssen B., Strauss A. F., Steere A. C., Kamradt T. The T helper cell response in Lyme arthritis: differential recognition of Borrelia burgdorferi outer surface protein A in patients with treatment-resistant or treatment-responsive Lyme arthritis. J Exp Med. 1994 Dec 1;180(6):2069–2078. doi: 10.1084/jem.180.6.2069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lim L. C., England D. M., DuChateau B. K., Glowacki N. J., Creson J. R., Lovrich S. D., Callister S. M., Jobe D. A., Schell R. F. Development of destructive arthritis in vaccinated hamsters challenged with Borrelia burgdorferi. Infect Immun. 1994 Jul;62(7):2825–2833. doi: 10.1128/iai.62.7.2825-2833.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Liu H., Alder J. D., Steiner B. M., Stein-Streilein J., Lim L., Schell R. F. Role of L3T4+ and 38+ T-cell subsets in resistance against infection with Treponema pallidum subsp. pertenue in hamsters. Infect Immun. 1991 Feb;59(2):529–536. doi: 10.1128/iai.59.2.529-536.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Liu H., Steiner B. M., Alder J. D., Baertschy D. K., Schell R. F. Immune T cells sorted by flow cytometry confer protection against infection with Treponema pallidum subsp. pertenue in hamsters. Infect Immun. 1990 Jun;58(6):1685–1690. doi: 10.1128/iai.58.6.1685-1690.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lovrich S. D., Callister S. M., Lim L. C., DuChateau B. K., Schell R. F. Seroprotective groups of Lyme borreliosis spirochetes from North America and Europe. J Infect Dis. 1994 Jul;170(1):115–121. doi: 10.1093/infdis/170.1.115. [DOI] [PubMed] [Google Scholar]
  27. Lovrich S. D., Callister S. M., Lim L. C., Schell R. F. Seroprotective groups among isolates of Borrelia burgdorferi. Infect Immun. 1993 Oct;61(10):4367–4374. doi: 10.1128/iai.61.10.4367-4374.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Neumann A., Schlesier M., Schneider H., Vogt A., Peter H. H. Frequencies of Borrelia burgdorferi-reactive T lymphocytes in Lyme arthritis. Rheumatol Int. 1989;9(3-5):237–241. doi: 10.1007/BF00271888. [DOI] [PubMed] [Google Scholar]
  29. Ozato K., Mayer N., Sachs D. H. Hybridoma cell lines secreting monoclonal antibodies to mouse H-2 and Ia antigens. J Immunol. 1980 Feb;124(2):533–540. [PubMed] [Google Scholar]
  30. Ranges G. E., Sriram S., Cooper S. M. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J Exp Med. 1985 Sep 1;162(3):1105–1110. doi: 10.1084/jem.162.3.1105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Ridge S. C., Zabriske J. B., Oronsky A. L., Kerwar S. S. Streptococcal cell wall arthritis: studies with nude (athymic) inbred Lewis rats. Cell Immunol. 1985 Nov;96(1):231–234. doi: 10.1016/0008-8749(85)90354-5. [DOI] [PubMed] [Google Scholar]
  32. Roehm N. W., Rodgers G. H., Hatfield S. M., Glasebrook A. L. An improved colorimetric assay for cell proliferation and viability utilizing the tetrazolium salt XTT. J Immunol Methods. 1991 Sep 13;142(2):257–265. doi: 10.1016/0022-1759(91)90114-u. [DOI] [PubMed] [Google Scholar]
  33. Schaible U. E., Kramer M. D., Justus C. W., Museteanu C., Simon M. M. Demonstration of antigen-specific T cells and histopathological alterations in mice experimentally inoculated with Borrelia burgdorferi. Infect Immun. 1989 Jan;57(1):41–47. doi: 10.1128/iai.57.1.41-47.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schaible U. E., Wallich R., Kramer M. D., Museteanu C., Simon M. M. A mouse model for Borrelia burgdorferi infection: pathogenesis, immune response and protection. Behring Inst Mitt. 1991 Feb;(88):59–67. [PubMed] [Google Scholar]
  35. Schmitz J. L., Schell R. F., Callister S. M., Lovrich S. D., Day S. P., Coe J. E. Immunoglobulin G2 confers protection against Borrelia burgdorferi infection in LSH hamsters. Infect Immun. 1992 Jul;60(7):2677–2682. doi: 10.1128/iai.60.7.2677-2682.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schmitz J. L., Schell R. F., Hejka A. G., England D. M. Passive immunization prevents induction of Lyme arthritis in LSH hamsters. Infect Immun. 1990 Jan;58(1):144–148. doi: 10.1128/iai.58.1.144-148.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schmitz J. L., Schell R. F., Hejka A., England D. M., Konick L. Induction of lyme arthritis in LSH hamsters. Infect Immun. 1988 Sep;56(9):2336–2342. doi: 10.1128/iai.56.9.2336-2342.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schmitz J. L., Schell R. F., Lovrich S. D., Callister S. M., Coe J. E. Characterization of the protective antibody response to Borrelia burgdorferi in experimentally infected LSH hamsters. Infect Immun. 1991 Jun;59(6):1916–1921. doi: 10.1128/iai.59.6.1916-1921.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Shanafelt M. C., Anzola J., Soderberg C., Yssel H., Turck C. W., Peltz G. Epitopes on the outer surface protein A of Borrelia burgdorferi recognized by antibodies and T cells of patients with Lyme disease. J Immunol. 1992 Jan 1;148(1):218–224. [PubMed] [Google Scholar]
  40. Shanafelt M. C., Hindersson P., Soderberg C., Mensi N., Turck C. W., Webb D., Yssel H., Peltz G. T cell and antibody reactivity with the Borrelia burgdorferi 60-kDa heat shock protein in Lyme arthritis. J Immunol. 1991 Jun 1;146(11):3985–3992. [PubMed] [Google Scholar]
  41. Steere A. C., Schoen R. T., Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987 Nov;107(5):725–731. doi: 10.7326/0003-4819-107-5-725. [DOI] [PubMed] [Google Scholar]
  42. Stevens M. G., Olsen S. C. Comparative analysis of using MTT and XTT in colorimetric assays for quantitating bovine neutrophil bactericidal activity. J Immunol Methods. 1993 Jan 4;157(1-2):225–231. doi: 10.1016/0022-1759(93)90091-k. [DOI] [PubMed] [Google Scholar]
  43. Taurog J. D., Sandberg G. P., Mahowald M. L. The cellular basis of adjuvant arthritis. I. Enhancement of cell-mediated passive transfer by concanavalin A and by immunosuppressive pretreatment of the recipient. Cell Immunol. 1983 Feb 1;75(2):271–282. doi: 10.1016/0008-8749(83)90325-8. [DOI] [PubMed] [Google Scholar]
  44. Wilder R. L., Allen J. B., Hansen C. Thymus-dependent and -independent regulation of Ia antigen expression in situ by cells in the synovium of rats with streptococcal cell wall-induced arthritis. Differences in site and intensity of expression in euthymic, athymic, and cyclosporin A-treated LEW and F344 rats. J Clin Invest. 1987 Apr;79(4):1160–1171. doi: 10.1172/JCI112933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Witte P. L., Stein-Streilein J., Streilein J. W. Description of phenotypically distinct T-lymphocyte subsets which mediate helper/DTH and cytotoxic functions in the Syrian hamster. J Immunol. 1985 May;134(5):2908–2915. [PubMed] [Google Scholar]
  46. Witte P. L., Streilein J. W. Monoclonal antibodies to hamster class II MHC molecules distinguish T and B cells. J Immunol. 1983 May;130(5):2282–2286. [PubMed] [Google Scholar]
  47. Yoshinari N. H., Reinhardt B. N., Steere A. C. T cell responses to polypeptide fractions of Borrelia burgdorferi in patients with Lyme arthritis. Arthritis Rheum. 1991 Jun;34(6):707–713. doi: 10.1002/art.1780340611. [DOI] [PubMed] [Google Scholar]
  48. Yssel H., Nakamoto T., Schneider P., Freitas V., Collins C., Webb D., Mensi N., Soderberg C., Peltz G. Analysis of T lymphocytes cloned from the synovial fluid and blood of a patient with Lyme arthritis. Int Immunol. 1990;2(11):1081–1089. doi: 10.1093/intimm/2.11.1081. [DOI] [PubMed] [Google Scholar]
  49. Yssel H., Shanafelt M. C., Soderberg C., Schneider P. V., Anzola J., Peltz G. Borrelia burgdorferi activates a T helper type 1-like T cell subset in Lyme arthritis. J Exp Med. 1991 Sep 1;174(3):593–601. doi: 10.1084/jem.174.3.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. de Souza M. S., Fikrig E., Smith A. L., Flavell R. A., Barthold S. W. Nonspecific proliferative responses of murine lymphocytes to Borrelia burgdorferi antigens. J Infect Dis. 1992 Mar;165(3):471–478. doi: 10.1093/infdis/165.3.471. [DOI] [PubMed] [Google Scholar]
  51. de Souza M. S., Smith A. L., Beck D. S., Terwilliger G. A., Fikrig E., Barthold S. W. Long-term study of cell-mediated responses to Borrelia burgdorferi in the laboratory mouse. Infect Immun. 1993 May;61(5):1814–1822. doi: 10.1128/iai.61.5.1814-1822.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]

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