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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Oct;151(4):1053–1065.

Expression of cytokine mRNA in lentivirus-induced arthritis.

F Lechner 1, H R Vogt 1, H F Seow 1, G Bertoni 1, W P Cheevers 1, U von Bodungen 1, A Zurbriggen 1, E Peterhans 1
PMCID: PMC1858035  PMID: 9327739

Abstract

Infection of goats with the lentivirus caprine arthritis encephalitis virus (CAEV) leads to persistent infection and development of chronic arthritis. We analyzed the expression of cytokines and viral RNA in the joints of goats at early time points after experimental infection with CAEV and in those of animals suffering from chronic arthritis as a result of natural infection. In situ hybridization experiments showed that the pattern of cytokine expression in caprine arthritis was similar to that found in rheumatoid arthritis (RA), with a few cells expressing the lymphocyte-derived cytokines interferon (IFN)-gamma and interleukin (IL)-2 and rather more cells expressing monocyte chemoattractant protein (MCP)-1, IL-6, and tumor necrosis factor (TNF)-alpha. IFN-gamma mRNA expression in experimentally infected joints peaked at day 12 and was mostly detected in areas containing viral RNA. At later time points, no IFN-gamma- or virus-expressing cells were found in inflamed joints but both were again detected in goats with severe arthritis. Interestingly, at the clinical stage of arthritis reflecting the chronic stage of infection, the inflammatory lesion was found to be immunologically compartmentalized. Humoral immune responses and cell-mediated immune responses appeared to concurrently occur in distinct areas of the synovial membrane.

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Selected References

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  1. Adams D. S., Crawford T. B., Klevjer-Anderson P. A pathogenetic study of the early connective tissue lesions of viral caprine arthritis-encephalitis. Am J Pathol. 1980 May;99(2):257–278. [PMC free article] [PubMed] [Google Scholar]
  2. Adams D. S., Oliver R. E., Ameghino E., DeMartini J. C., Verwoerd D. W., Houwers D. J., Waghela S., Gorham J. R., Hyllseth B., Dawson M. Global survey of serological evidence of caprine arthritis-encephalitis virus infection. Vet Rec. 1984 Nov 10;115(19):493–495. doi: 10.1136/vr.115.19.493. [DOI] [PubMed] [Google Scholar]
  3. Akira S., Hirano T., Taga T., Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF). FASEB J. 1990 Aug;4(11):2860–2867. [PubMed] [Google Scholar]
  4. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines--CXC and CC chemokines. Adv Immunol. 1994;55:97–179. [PubMed] [Google Scholar]
  5. Beebe A. M., Dua N., Faith T. G., Moore P. F., Pedersen N. C., Dandekar S. Primary stage of feline immunodeficiency virus infection: viral dissemination and cellular targets. J Virol. 1994 May;68(5):3080–3091. doi: 10.1128/jvi.68.5.3080-3091.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Biberfeld P., Chayt K. J., Marselle L. M., Biberfeld G., Gallo R. C., Harper M. E. HTLV-III expression in infected lymph nodes and relevance to pathogenesis of lymphadenopathy. Am J Pathol. 1986 Dec;125(3):436–442. [PMC free article] [PubMed] [Google Scholar]
  7. Bucht A., Larsson P., Weisbrot L., Thorne C., Pisa P., Smedegård G., Keystone E. C., Grönberg A. Expression of interferon-gamma (IFN-gamma), IL-10, IL-12 and transforming growth factor-beta (TGF-beta) mRNA in synovial fluid cells from patients in the early and late phases of rheumatoid arthritis (RA). Clin Exp Immunol. 1996 Mar;103(3):357–367. doi: 10.1111/j.1365-2249.1996.tb08288.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carr M. W., Roth S. J., Luther E., Rose S. S., Springer T. A. Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652–3656. doi: 10.1073/pnas.91.9.3652. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Chakrabarti L., Isola P., Cumont M. C., Claessens-Maire M. A., Hurtrel M., Montagnier L., Hurtrel B. Early stages of simian immunodeficiency virus infection in lymph nodes. Evidence for high viral load and successive populations of target cells. Am J Pathol. 1994 Jun;144(6):1226–1237. [PMC free article] [PubMed] [Google Scholar]
  10. Chen E., Keystone E. C., Fish E. N. Restricted cytokine expression in rheumatoid arthritis. Arthritis Rheum. 1993 Jul;36(7):901–910. doi: 10.1002/art.1780360706. [DOI] [PubMed] [Google Scholar]
  11. Chensue S. W., Warmington K. S., Ruth J. H., Sanghi P. S., Lincoln P., Kunkel S. L. Role of monocyte chemoattractant protein-1 (MCP-1) in Th1 (mycobacterial) and Th2 (schistosomal) antigen-induced granuloma formation: relationship to local inflammation, Th cell expression, and IL-12 production. J Immunol. 1996 Nov 15;157(10):4602–4608. [PubMed] [Google Scholar]
  12. Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
  13. Cohen S. B., Katsikis P. D., Chu C. Q., Thomssen H., Webb L. M., Maini R. N., Londei M., Feldmann M. High level of interleukin-10 production by the activated T cell population within the rheumatoid synovial membrane. Arthritis Rheum. 1995 Jul;38(7):946–952. doi: 10.1002/art.1780380710. [DOI] [PubMed] [Google Scholar]
  14. Cork L. C., Hadlow W. J., Crawford T. B., Gorham J. R., Piper R. C. Infectious leukoencephalomyelitis of young goats. J Infect Dis. 1974 Feb;129(2):134–141. doi: 10.1093/infdis/129.2.134. [DOI] [PubMed] [Google Scholar]
  15. Cork L. C., Narayan O. The pathogenesis of viral leukoencephalomyelitis-arthritis of goats. I. Persistent viral infection with progressive pathologic changes. Lab Invest. 1980 Jun;42(6):596–602. [PubMed] [Google Scholar]
  16. Crawford T. B., Adams D. S. Caprine arthritis-encephalitis: clinical features and presence of antibody in selected goat populations. J Am Vet Med Assoc. 1981 Apr 1;178(7):713–719. [PubMed] [Google Scholar]
  17. Crawford T. B., Adams D. S., Cheevers W. P., Cork L. C. Chronic arthritis in goats caused by a retrovirus. Science. 1980 Feb 29;207(4434):997–999. doi: 10.1126/science.6153243. [DOI] [PubMed] [Google Scholar]
  18. Deleuran B., Lemche P., Kristensen M., Chu C. Q., Field M., Jensen J., Matsushima K., Stengaard-Pedersen K. Localisation of interleukin 8 in the synovial membrane, cartilage-pannus junction and chondrocytes in rheumatoid arthritis. Scand J Rheumatol. 1994;23(1):2–7. doi: 10.3109/03009749409102126. [DOI] [PubMed] [Google Scholar]
  19. Dutia B. M., Hopkins J., Allington M. P., Bujdoso R., McConnell I. Characterization of monoclonal antibodies specific for alpha- and beta-chains of sheep MHC class II. Immunology. 1990 May;70(1):27–32. [PMC free article] [PubMed] [Google Scholar]
  20. East N. E., Rowe J. D., Madewell B. R., Floyd K. Serologic prevalence of caprine arthritis-encephalitis virus in California goat dairies. J Am Vet Med Assoc. 1987 Jan 15;190(2):182–186. [PubMed] [Google Scholar]
  21. Feldmann M., Brennan F. M., Maini R. N. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397–440. doi: 10.1146/annurev.immunol.14.1.397. [DOI] [PubMed] [Google Scholar]
  22. Firestein G. S., Zvaifler N. J. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum. 1990 Jun;33(6):768–773. doi: 10.1002/art.1780330602. [DOI] [PubMed] [Google Scholar]
  23. Fox C. H., Tenner-Rácz K., Rácz P., Firpo A., Pizzo P. A., Fauci A. S. Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991 Dec;164(6):1051–1057. doi: 10.1093/infdis/164.6.1051. [DOI] [PubMed] [Google Scholar]
  24. Graber H. U., Meyer R. K., Fatzer R., Vandevelde M., Zurbriggen A. In situ hybridization and immunohistochemistry for prion protein (PrP) in bovine spongiform encephalopathy (BSE). Zentralbl Veterinarmed A. 1995 Sep;42(7):453–459. doi: 10.1111/j.1439-0442.1995.tb00399.x. [DOI] [PubMed] [Google Scholar]
  25. Harigai M., Hara M., Yoshimura T., Leonard E. J., Inoue K., Kashiwazaki S. Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol. 1993 Oct;69(1):83–91. doi: 10.1006/clin.1993.1153. [DOI] [PubMed] [Google Scholar]
  26. Hurtrel B., Chakrabarti L., Hurtrel M., Bach J. M., Ganière J. P., Montagnier L. Early events in lymph nodes during infection with SIV and FIV. Res Virol. 1994 May-Aug;145(3-4):221–227. doi: 10.1016/s0923-2516(07)80026-4. [DOI] [PubMed] [Google Scholar]
  27. Jiang Y., Beller D. I., Frendl G., Graves D. T. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J Immunol. 1992 Apr 15;148(8):2423–2428. [PubMed] [Google Scholar]
  28. Johnson G. C., Adams D. S., McGuire T. C. Pronounced production of polyclonal immunoglobulin G1 in the synovial fluid of goats with caprine arthritis-encephalitis virus infection. Infect Immun. 1983 Aug;41(2):805–815. doi: 10.1128/iai.41.2.805-815.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson G. C., Barbet A. F., Klevjer-Anderson P., McGuire T. C. Preferential immune response to virion surface glycoproteins by caprine arthritis-encephalitis virus-infected goats. Infect Immun. 1983 Aug;41(2):657–665. doi: 10.1128/iai.41.2.657-665.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kalden J. R., Gay S. Retroviruses and autoimmune rheumatic diseases. Clin Exp Immunol. 1994 Oct;98(1):1–5. doi: 10.1111/j.1365-2249.1994.tb06597.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Katsikis P. D., Chu C. Q., Brennan F. M., Maini R. N., Feldmann M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med. 1994 May 1;179(5):1517–1527. doi: 10.1084/jem.179.5.1517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
  33. Klevjer-Anderson P., Adams D. S., Anderson L. W., Banks K. L., McGuire T. C. A sequential study of virus expression in retrovirus-induced arthritis of goats. J Gen Virol. 1984 Sep;65(Pt 9):1519–1525. doi: 10.1099/0022-1317-65-9-1519. [DOI] [PubMed] [Google Scholar]
  34. Lechner F., Vogt H. R., Seow H. F., von Bodungen U., Bertoni G., Zurbriggen A., Peterhans E. Expression of TNF alpha in arthritis caused by caprine arthritis encephalitis virus. Vet Immunol Immunopathol. 1996 Nov;54(1-4):281–289. doi: 10.1016/s0165-2427(96)05701-7. [DOI] [PubMed] [Google Scholar]
  35. Legastelois I., Cordier G., Cozon G., Cadoré J. L., Guiguen F., Greenland T., Mornex J. F. Visna-maedi virus-induced expression of interleukin-8 gene in sheep alveolar cells following experimental in vitro and in vivo infection. Res Virol. 1996 Mar-Jun;147(2-3):191–197. doi: 10.1016/0923-2516(96)80234-2. [DOI] [PubMed] [Google Scholar]
  36. Lotz M., Jirik F., Kabouridis P., Tsoukas C., Hirano T., Kishimoto T., Carson D. A. B cell stimulating factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med. 1988 Mar 1;167(3):1253–1258. doi: 10.1084/jem.167.3.1253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McInnes I. B., Leung B. P., Sturrock R. D., Field M., Liew F. Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med. 1997 Feb;3(2):189–195. doi: 10.1038/nm0297-189. [DOI] [PubMed] [Google Scholar]
  38. Miltenburg A. M., van Laar J. M., de Kuiper R., Daha M. R., Breedveld F. C. T cells cloned from human rheumatoid synovial membrane functionally represent the Th1 subset. Scand J Immunol. 1992 May;35(5):603–610. doi: 10.1111/j.1365-3083.1992.tb03260.x. [DOI] [PubMed] [Google Scholar]
  39. Moreland L. W., Koopman W. J. Infection as a cause of arthritis. Curr Opin Rheumatol. 1991 Aug;3(4):639–649. doi: 10.1097/00002281-199108000-00015. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Müller U., Steinhoff U., Reis L. F., Hemmi S., Pavlovic J., Zinkernagel R. M., Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918–1921. doi: 10.1126/science.8009221. [DOI] [PubMed] [Google Scholar]
  42. Orange J. S., Wang B., Terhorst C., Biron C. A. Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med. 1995 Oct 1;182(4):1045–1056. doi: 10.1084/jem.182.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pantaleo G., Menzo S., Vaccarezza M., Graziosi C., Cohen O. J., Demarest J. F., Montefiori D., Orenstein J. M., Fox C., Schrager L. K. Studies in subjects with long-term nonprogressive human immunodeficiency virus infection. N Engl J Med. 1995 Jan 26;332(4):209–216. doi: 10.1056/NEJM199501263320402. [DOI] [PubMed] [Google Scholar]
  44. Perry L. L., Wilkerson M. J., Hullinger G. A., Cheevers W. P. Depressed CD4+ T lymphocyte proliferative response and enhanced antibody response to viral antigen in chronic lentivirus-induced arthritis. J Infect Dis. 1995 Feb;171(2):328–334. doi: 10.1093/infdis/171.2.328. [DOI] [PubMed] [Google Scholar]
  45. Radford A. J., Hodgson A. L., Rothel J. S., Wood P. R. Cloning and sequencing of the ovine gamma-interferon gene. Aust Vet J. 1991 Mar;68(3):82–84. doi: 10.1111/j.1751-0813.1991.tb00755.x. [DOI] [PubMed] [Google Scholar]
  46. Reimann K. A., Tenner-Racz K., Racz P., Montefiori D. C., Yasutomi Y., Lin W., Ransil B. J., Letvin N. L. Immunopathogenic events in acute infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Virol. 1994 Apr;68(4):2362–2370. doi: 10.1128/jvi.68.4.2362-2370.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Rollins B. J., Walz A., Baggiolini M. Recombinant human MCP-1/JE induces chemotaxis, calcium flux, and the respiratory burst in human monocytes. Blood. 1991 Aug 15;78(4):1112–1116. [PubMed] [Google Scholar]
  48. Romagnani S. Human TH1 and TH2 subsets: doubt no more. Immunol Today. 1991 Aug;12(8):256–257. doi: 10.1016/0167-5699(91)90120-I. [DOI] [PubMed] [Google Scholar]
  49. Saltarelli M., Querat G., Konings D. A., Vigne R., Clements J. E. Nucleotide sequence and transcriptional analysis of molecular clones of CAEV which generate infectious virus. Virology. 1990 Nov;179(1):347–364. doi: 10.1016/0042-6822(90)90303-9. [DOI] [PubMed] [Google Scholar]
  50. Schlaak J. F., Pfers I., Meyer Zum Büschenfelde K. H., Märker-Hermann E. Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies. Clin Exp Rheumatol. 1996 Mar-Apr;14(2):155–162. [PubMed] [Google Scholar]
  51. Seow H. F., Rothel J. S., Wood P. R. Cloning and sequencing an ovine interleukin-4-encoding cDNA. Gene. 1993 Feb 28;124(2):291–293. doi: 10.1016/0378-1119(93)90408-u. [DOI] [PubMed] [Google Scholar]
  52. Seow H. F., Yoshimura T., Wood P. R., Colditz I. G. Cloning, sequencing, expression and inflammatory activity in skin of ovine interleukin-8. Immunol Cell Biol. 1994 Oct;72(5):398–405. doi: 10.1038/icb.1994.59. [DOI] [PubMed] [Google Scholar]
  53. Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tong-Starksen S. E., Sepp T., Pagtakhan A. S. Activation of caprine arthritis-encephalitis virus long terminal repeat by gamma interferon. J Virol. 1996 Jan;70(1):595–599. doi: 10.1128/jvi.70.1.595-599.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Ulfgren A. K., Lindblad S., Klareskog L., Andersson J., Andersson U. Detection of cytokine producing cells in the synovial membrane from patients with rheumatoid arthritis. Ann Rheum Dis. 1995 Aug;54(8):654–661. doi: 10.1136/ard.54.8.654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Wilder R. L. Hypothesis for retroviral causation of rheumatoid arthritis. Curr Opin Rheumatol. 1994 May;6(3):295–299. doi: 10.1097/00002281-199405000-00009. [DOI] [PubMed] [Google Scholar]
  57. Wilkerson M. J., Davis W. C., Baszler T. V., Cheevers W. P. Immunopathology of chronic lentivirus-induced arthritis. Am J Pathol. 1995 Jun;146(6):1433–1443. [PMC free article] [PubMed] [Google Scholar]
  58. Wilkerson M. J., Davis W. C., Cheevers W. P. Peripheral blood and synovial fluid mononuclear cell phenotypes in lentivirus induced arthritis. J Rheumatol. 1995 Jan;22(1):8–15. [PubMed] [Google Scholar]
  59. Woodard J. C., Gaskin J. M., Poulos P. W., MacKay R. J., Burridge M. J. Caprine arthritis-encephalitis: clinicopathologic study. Am J Vet Res. 1982 Dec;43(12):2085–2096. [PubMed] [Google Scholar]
  60. Young H. A., Hardy K. J. Role of interferon-gamma in immune cell regulation. J Leukoc Biol. 1995 Oct;58(4):373–381. [PubMed] [Google Scholar]
  61. Zanoni R. G., Vogt H. R., Pohl B., Böttcher J., Bommeli W., Peterhans E. An ELISA based on whole virus for the detection of antibodies to small-ruminant lentiviruses. Zentralbl Veterinarmed B. 1994 Dec;41(10):662–669. doi: 10.1111/j.1439-0450.1994.tb00277.x. [DOI] [PubMed] [Google Scholar]
  62. Zanoni R., Krieg A., Peterhans E. Detection of antibodies to caprine arthritis-encephalitis virus by protein G enzyme-linked immunosorbent assay and immunoblotting. J Clin Microbiol. 1989 Mar;27(3):580–582. doi: 10.1128/jcm.27.3.580-582.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. al-Janadi N., al-Dalaan A., al-Balla S., Raziuddin S. CD4+ T cell inducible immunoregulatory cytokine response in rheumatoid arthritis. J Rheumatol. 1996 May;23(5):809–814. [PubMed] [Google Scholar]

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