Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection
Yen-Tung A. Teng, … , Richard P. Ellen, Josef M. Penninger
Yen-Tung A. Teng, … , Richard P. Ellen, Josef M. Penninger
Published September 15, 2000
Citation Information: J Clin Invest. 2000;106(6):R59-R67. https://doi.org/10.1172/JCI10763.
View: Text | PDF
Rapid Publication

Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection

Abstract

Periodontitis, a prime cause of tooth loss in humans, is implicated in the increased risk of systemic diseases such as heart failure, stroke, and bacterial pneumonia. The mechanisms by which periodontitis and antibacterial immunity lead to alveolar bone and tooth loss are poorly understood. To study the human immune response to specific periodontal infections, we transplanted human peripheral blood lymphocytes (HuPBLs) from periodontitis patients into NOD/SCID mice. Oral challenge of HuPBL-NOD/SCID mice with Actinobacillus actinomycetemcomitans, a well-known Gram-negative anaerobic microorganism that causes human periodontitis, activates human CD4+ T cells in the periodontium and triggers local alveolar bone destruction. Human CD4+ T cells, but not CD8+ T cells or B cells, are identified as essential mediators of alveolar bone destruction. Stimulation of CD4+ T cells by A. actinomycetemcomitans induces production of osteoprotegerin ligand (OPG-L), a key modulator of osteoclastogenesis and osteoclast activation. In vivo inhibition of OPG-L function with the decoy receptor OPG diminishes alveolar bone destruction and reduces the number of periodontal osteoclasts after microbial challenge. These data imply that the molecular explanation for alveolar bone destruction observed in periodontal infections is mediated by microorganism-triggered induction of OPG-L expression on CD4+ T cells and the consequent activation of osteoclasts. Inhibition of OPG-L may thus have therapeutic value to prevent alveolar bone and/or tooth loss in human periodontitis.

Authors

Yen-Tung A. Teng, Hai Nguyen, Xuijuan Gao, Young-Yun Kong, Reginald M. Gorczynski, Bhagirath Singh, Richard P. Ellen, Josef M. Penninger

×

Figure 1

(a) Immunocompetence of CD4+ T cells in Aa-HuPBL-NOD/SCID mice.

Options: View larger image (or click on image) Download as PowerPoint
(a) Immunocompetence of CD4+ T cells in Aa-HuPBL-NO...
IL-2 production of periodontal CD4+ T cells (Perio-CD4/T-cells) and splenic CD4+ T cells (Aa-splenic CD4/T-cells) isolated from A. actinomycetemcomitans–immunized HuPBL-NOD/SCID mice is shown. Irradiated (25 Gy) HuPBL-derived autologous monocytes/macrophages (irr-PBL) and CD4+ T cells isolated from non–Aa-immunized HuPBL-NOD/SCID mice (no Aa-splenic CD4/T-cells) were included as the negative controls. Restimulation of Aa-immunized splenic CD4+ T cells with a third-party antigen, P. gingivalis sonicate antigens served as the specificity control (P.g.). Serial dilution of Aa sonicate antigens did not result in significantly different patterns of the IL-2 responses measured. Differences in IL-2 production between the Perio-CD4/T-cell and Aa-splenic CD4/T-cell groups as compared with the irr-PBL, no Aa-splenic CD4/T-cell, and P.g. groups were statistically significant (P < 0.008, paired t test). Values shown are mean IL-2 production of triplicate samples ± SD. One result representative of three independent experiments is shown. (b) Increased alveolar bone loss in Aa-HuPBL-NOD/SCID mice. Groups of mice as indicated were either sham-infected or inoculated with A. actinomycetemcomitans (Aa). Data shown are the relative amounts of alveolar bone loss at the day of the first Aa inoculation (Day 1), by the end of 4 weeks (4th wk), and by the end of 8 weeks (8th wk), expressed as a percentage of the amount of bone loss in the positive control, Aa-infected BALB/c mice (100% = 0.6 ± 0.12 mm per tooth in 8 weeks). Group I, sham-infected NOD/SCID mice (n = 10); group II, sham-infected chimeric NOD/SCID mice engrafted with HuPBL from four LJP patients (n = 12); group III, NOD/SCID mice infected with Aa (n = 16); group IV, Aa-infected chimeric NOD/SCID mice engrafted with HuPBL from four LJP patients (n = 32); group V, Aa-infected chimeric NOD/SCID mice engrafted with HuPBL (N-HuPBL) from two healthy donors (n = 12). Data shown are mean values ± SD pooled from four independent experiments involving HuPBL engraftment from four LJP subjects, each of which gave comparable results. Alveolar bone loss was determined as described in Methods. AThe extent of bone loss in group IV at 8 weeks was significantly increased as compared with all other groups (P < 0.01).