Abstract
Chronic periodontitis is characterized by dense infiltrations of B and T lymphocytes within the gingival connective tissue. Distinct anaerobic gram-negative bacteria as well as autoimmunity to collagen have been reported to play a role in the etiology and the pathogenesis of this disease. Here we describe the cloning and characterization of CD4+ and CD8+ T lymphocytes isolated from inflamed gingival tissue obtained from four patients with chronic periodontitis. Clones were raised with phytohemagglutinin and interleukin-2 and tested for proliferation in response to whole-cell antigens of Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, human collagen type I, and two bacterial heat shock proteins. CD4+ T-cell clones reactive with collagen type I were obtained from all four patients. Eighty percent of these clones had phenotypes resembling the mouse type 2 T helper (Th) phenotype, i.e., they produced high levels of interleukin-4 and low levels of gamma interferon. No collagen-type-I-reactive CD8+ clones were obtained. Bacterial-antigen-reactive CD4+ and/or CD8+ T-cell clones were also obtained from each patient, and the majority of the clones showed a Th0-like cytokine pattern and produced equal amounts of interleukin-4 and gamma interferon. Although most clones were reactive with P. intermedia, it seems that the immune response is not strictly directed against this particular microorganism, as clones reactive with one of the other bacteria were also obtained from two patients. We propose that collagen-specific CD4+ Th2-like T cells contribute to the chronicity of periodontitis but that their modes of activation might be controlled by Th0-like T cells specific for periodontitis-associated bacteria.
Full Text
The Full Text of this article is available as a PDF (610.1 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Anusaksathien O., Dolby A. E. Autoimmunity in periodontal disease. J Oral Pathol Med. 1991 Mar;20(3):101–107. doi: 10.1111/j.1600-0714.1991.tb00901.x. [DOI] [PubMed] [Google Scholar]
- Anusaksathien O., Singh G., Matthews N., Dolby A. E. Autoimmunity to collagen in adult periodontal disease: immunoglobulin classes in sera and tissue. J Periodontal Res. 1992 Jan;27(1):55–61. doi: 10.1111/j.1600-0765.1992.tb02086.x. [DOI] [PubMed] [Google Scholar]
- Ballard J. B., Butler W. T. Proteins of the periodontium. Biochemical studies on the collagen and noncollagenous proteins of human gingivae. J Oral Pathol. 1974;3(4):176–184. doi: 10.1111/j.1600-0714.1974.tb01709.x. [DOI] [PubMed] [Google Scholar]
- Chrétien I., Van Kimmenade A., Pearce M. K., Banchereau J., Abrams J. S. Development of polyclonal and monoclonal antibodies for immunoassay and neutralization of human interleukin-4. J Immunol Methods. 1989 Feb 8;117(1):67–81. doi: 10.1016/0022-1759(89)90120-8. [DOI] [PubMed] [Google Scholar]
- Chung E., Miller E. J. Collagen polymorphism: characterization of molecules with the chain composition (alpha 1 (3)03 in human tissues. Science. 1974 Mar;183(130):1200–1201. doi: 10.1126/science.183.4130.1200. [DOI] [PubMed] [Google Scholar]
- Colasante A., Rosini S., Piattelli A., Artese L., Aiello F. B., Musiani P. Distribution and phenotype of immune cells in normal human gingiva: active immune response versus unresponsiveness. J Oral Pathol Med. 1992 Jan;21(1):12–16. doi: 10.1111/j.1600-0714.1992.tb00961.x. [DOI] [PubMed] [Google Scholar]
- Cole K. L., Seymour G. J., Powell R. N. Phenotypic and functional analysis of T cells extracted from chronically inflamed human periodontal tissues. J Periodontol. 1987 Aug;58(8):569–573. doi: 10.1902/jop.1987.58.8.569. [DOI] [PubMed] [Google Scholar]
- Eastcott J. W., Yamashita K., Taubman M. A., Smith D. J. Characterization of rat T-cell clones with bacterial specificity. Immunology. 1990 Sep;71(1):120–126. [PMC free article] [PubMed] [Google Scholar]
- Firestein G. S., Roeder W. D., Laxer J. A., Townsend K. S., Weaver C. T., Hom J. T., Linton J., Torbett B. E., Glasebrook A. L. A new murine CD4+ T cell subset with an unrestricted cytokine profile. J Immunol. 1989 Jul 15;143(2):518–525. [PubMed] [Google Scholar]
- Fujihashi K., Beagley K. W., Kono Y., Aicher W. K., Yamamoto M., DiFabio S., Xu-Amano J., McGhee J. R., Kiyono H. Gingival mononuclear cells from chronic inflammatory periodontal tissues produce interleukin (IL)-5 and IL-6 but not IL-2 and IL-4. Am J Pathol. 1993 Apr;142(4):1239–1250. [PMC free article] [PubMed] [Google Scholar]
- Genco R. J. Host responses in periodontal diseases: current concepts. J Periodontol. 1992 Apr;63(4 Suppl):338–355. doi: 10.1902/jop.1992.63.4s.338. [DOI] [PubMed] [Google Scholar]
- Harty J. T., Bevan M. J. CD8+ T cells specific for a single nonamer epitope of Listeria monocytogenes are protective in vivo. J Exp Med. 1992 Jun 1;175(6):1531–1538. doi: 10.1084/jem.175.6.1531. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirsch H. Z., Tarkowski A., Miller E. J., Gay S., Koopman W. J., Mestecky J. Autoimmunity to collagen in adult periodontal disease. J Oral Pathol. 1988 Nov;17(9-10):456–459. doi: 10.1111/j.1600-0714.1988.tb01315.x. [DOI] [PubMed] [Google Scholar]
- Jonsson R., Pitts A., Lue C., Gay S., Mestecky J. Immunoglobulin isotype distribution of locally produced autoantibodies to collagen type I in adult periodontitis. Relationship to periodontal treatment. J Clin Periodontol. 1991 Oct;18(9):703–707. doi: 10.1111/j.1600-051x.1991.tb00113.x. [DOI] [PubMed] [Google Scholar]
- Katz J., Michalek S. M., Beagley K. W., Eldridge J. H. Characterization of rat T helper cell clones specific for Bacteroides gingivalis antigen. Infect Immun. 1990 Sep;58(9):2785–2791. doi: 10.1128/iai.58.9.2785-2791.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kemeny D. M., Noble A., Holmes B. J., Diaz-Sanchez D. Immune regulation: a new role for the CD8+ T cell. Immunol Today. 1994 Mar;15(3):107–110. doi: 10.1016/0167-5699(94)90152-X. [DOI] [PubMed] [Google Scholar]
- Listgarten M. A. Nature of periodontal diseases: pathogenic mechanisms. J Periodontal Res. 1987 May;22(3):172–178. doi: 10.1111/j.1600-0765.1987.tb01560.x. [DOI] [PubMed] [Google Scholar]
- Lundqvist C., Baranov V., Teglund S., Hammarström S., Hammarström M. L. Cytokine profile and ultrastructure of intraepithelial gamma delta T cells in chronically inflamed human gingiva suggest a cytotoxic effector function. J Immunol. 1994 Sep 1;153(5):2302–2312. [PubMed] [Google Scholar]
- Lundqvist C., Hammarström M. L. T-cell receptor gamma delta-expressing intraepithelial lymphocytes are present in normal and chronically inflamed human gingiva. Immunology. 1993 May;79(1):38–45. [PMC free article] [PubMed] [Google Scholar]
- Luo A. M., Garza K. M., Hunt D., Tung K. S. Antigen mimicry in autoimmune disease sharing of amino acid residues critical for pathogenic T cell activation. J Clin Invest. 1993 Nov;92(5):2117–2123. doi: 10.1172/JCI116812. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mahanty S., Abrams J. S., King C. L., Limaye A. P., Nutman T. B. Parallel regulation of IL-4 and IL-5 in human helminth infections. J Immunol. 1992 Jun 1;148(11):3567–3571. [PubMed] [Google Scholar]
- Mammo W., Singh G., Dolby A. E. Enhanced cellular immune response to type I collagen in patients with periodontal disease. Int Arch Allergy Appl Immunol. 1982;67(2):149–154. doi: 10.1159/000233006. [DOI] [PubMed] [Google Scholar]
- Manhart S. S., Reinhardt R. A., Payne J. B., Seymour G. J., Gemmell E., Dyer J. K., Petro T. M. Gingival cell IL-2 and IL-4 in early-onset periodontitis. J Periodontol. 1994 Sep;65(9):807–813. doi: 10.1902/jop.1994.65.9.807. [DOI] [PubMed] [Google Scholar]
- Miller S. D., Karpus W. J. The immunopathogenesis and regulation of T-cell-mediated demyelinating diseases. Immunol Today. 1994 Aug;15(8):356–361. doi: 10.1016/0167-5699(94)90173-2. [DOI] [PubMed] [Google Scholar]
- Modlin R. L., Nutman T. B. Type 2 cytokines and negative immune regulation in human infections. Curr Opin Immunol. 1993 Aug;5(4):511–517. doi: 10.1016/0952-7915(93)90031-m. [DOI] [PubMed] [Google Scholar]
- Moretta A., Pantaleo G., Moretta L., Cerottini J. C., Mingari M. C. Direct demonstration of the clonogenic potential of every human peripheral blood T cell. Clonal analysis of HLA-DR expression and cytolytic activity. J Exp Med. 1983 Feb 1;157(2):743–754. doi: 10.1084/jem.157.2.743. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Narayanan A. S., Page R. C. Biochemical characterization of collagens synthesized by fibroblasts derived from normal and diseased human gingiva. J Biol Chem. 1976 Sep 25;251(18):5464–5471. [PubMed] [Google Scholar]
- Opdenakker G., Van Damme J. Cytokine-regulated proteases in autoimmune diseases. Immunol Today. 1994 Mar;15(3):103–107. doi: 10.1016/0167-5699(94)90151-1. [DOI] [PubMed] [Google Scholar]
- Papapanou P. N., Sandros J., Lindberg K., Duncan M. J., Niederman R., Nannmark U. Porphyromonas gingivalis may multiply and advance within stratified human junctional epithelium in vitro. J Periodontal Res. 1994 Sep;29(5):374–375. doi: 10.1111/j.1600-0765.1994.tb01237.x. [DOI] [PubMed] [Google Scholar]
- Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reinhardt R. A., McDonald T. L., Bolton R. W., DuBois L. M., Kaldahl W. B. IgG subclasses in gingival crevicular fluid from active versus stable periodontal sites. J Periodontol. 1989 Jan;60(1):44–50. doi: 10.1902/jop.1989.60.1.44. [DOI] [PubMed] [Google Scholar]
- Robinson D. S., Hamid Q., Ying S., Tsicopoulos A., Barkans J., Bentley A. M., Corrigan C., Durham S. R., Kay A. B. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992 Jan 30;326(5):298–304. doi: 10.1056/NEJM199201303260504. [DOI] [PubMed] [Google Scholar]
- Salgame P., Abrams J. S., Clayberger C., Goldstein H., Convit J., Modlin R. L., Bloom B. R. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science. 1991 Oct 11;254(5029):279–282. doi: 10.1126/science.254.5029.279. [DOI] [PubMed] [Google Scholar]
- Selmaj K., Raine C. S., Cannella B., Brosnan C. F. Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest. 1991 Mar;87(3):949–954. doi: 10.1172/JCI115102. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Seymour G. J., Cole K. L., Powell R. N. Analysis of lymphocyte populations extracted from chronically inflamed human periodontal tissues. I. Identification. J Periodontal Res. 1985 Jan;20(1):47–57. doi: 10.1111/j.1600-0765.1985.tb00410.x. [DOI] [PubMed] [Google Scholar]
- Seymour G. J., Gemmell E., Reinhardt R. A., Eastcott J., Taubman M. A. Immunopathogenesis of chronic inflammatory periodontal disease: cellular and molecular mechanisms. J Periodontal Res. 1993 Nov;28(6 Pt 2):478–486. doi: 10.1111/j.1600-0765.1993.tb02108.x. [DOI] [PubMed] [Google Scholar]
- Spits H., Ijssel H., Terhorst C., de Vries J. E. Establishment of human T lymphocyte clones highly cytotoxic for an EBV-transformed B cell line in serum-free medium: isolation of clones that differ in phenotype and specificity. J Immunol. 1982 Jan;128(1):95–99. [PubMed] [Google Scholar]
- Street N. E., Schumacher J. H., Fong T. A., Bass H., Fiorentino D. F., Leverah J. A., Mosmann T. R. Heterogeneity of mouse helper T cells. Evidence from bulk cultures and limiting dilution cloning for precursors of Th1 and Th2 cells. J Immunol. 1990 Mar 1;144(5):1629–1639. [PubMed] [Google Scholar]
- Sugawara M., Yamashita K., Yoshie H., Hara K. Detection of, and anti-collagen antibody produced by, CD5-positive B cells in inflamed gingival tissues. J Periodontal Res. 1992 Sep;27(5):489–498. doi: 10.1111/j.1600-0765.1992.tb01822.x. [DOI] [PubMed] [Google Scholar]
- Taubman M. A., Yoshie H., Ebersole J. L., Smith D. J., Olson C. L. Host response in experimental periodontal disease. J Dent Res. 1984 Mar;63(3):455–460. doi: 10.1177/00220345840630031801. [DOI] [PubMed] [Google Scholar]
- Van der Meide P. H., Dubbeld M., Schellekens H. Monoclonal antibodies to human immune interferon and their use in a sensitive solid-phase ELISA. J Immunol Methods. 1985 May 23;79(2):293–305. doi: 10.1016/0022-1759(85)90109-7. [DOI] [PubMed] [Google Scholar]
- Verwer R. W., Raber-Durlacher J. E. Efficient and unbiased estimation of volume and area of tissue components and cell number in gingival biopsies. J Periodontal Res. 1993 Sep;28(5):313–323. doi: 10.1111/j.1600-0765.1993.tb01075.x. [DOI] [PubMed] [Google Scholar]
- Walker P. R., Fellowes R., Hecht E. M., Lehner T. Characterization of streptococcal antigen-specific CD8+, MHC class I-restricted, T cell clones that down-regulate in vitro antibody synthesis. J Immunol. 1991 Nov 15;147(10):3370–3380. [PubMed] [Google Scholar]
- Wierenga E. A., Snoek M., Jansen H. M., Bos J. D., van Lier R. A., Kapsenberg M. L. Human atopen-specific types 1 and 2 T helper cell clones. J Immunol. 1991 Nov 1;147(9):2942–2949. [PubMed] [Google Scholar]
- Yamashita K., Eastcott J. W., Taubman M. A., Smith D. J., Cox D. S. Effect of adoptive transfer of cloned Actinobacillus actinomycetemcomitans-specific T helper cells on periodontal disease. Infect Immun. 1991 Apr;59(4):1529–1534. doi: 10.1128/iai.59.4.1529-1534.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yamazaki K., Nakajima T., Gemmell E., Polak B., Seymour G. J., Hara K. IL-4- and IL-6-producing cells in human periodontal disease tissue. J Oral Pathol Med. 1994 Sep;23(8):347–353. doi: 10.1111/j.1600-0714.1994.tb00074.x. [DOI] [PubMed] [Google Scholar]
- van Winkelhoff A. J., Carlee A. W., de Graaff J. Bacteroides endodontalis and other black-pigmented Bacteroides species in odontogenic abscesses. Infect Immun. 1985 Sep;49(3):494–497. doi: 10.1128/iai.49.3.494-497.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]