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.
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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

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Figure 4

(a–d) A. actinomycetemcomitans stimulates OPG-L expression on periodontal CD4+ T cells.

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(a–d) A. actinomycetemcomitans stimulates OPG-L exp...
(a) Unstimulated HuPBL-derived CD4+ T cells stained with OPG-FITC; negative control. (b) HuPBL-derived CD4+ T cells restimulated with anti-TCR plus CD28 mAb’s, followed by staining with isotypic control Ab; background control. (c) HuPBL-derived CD4+ T cells restimulated with anti-TCR plus CD28 mAb’s, followed by staining with OPG-FITC; positive control. (d) Periodontal CD4+ T cells derived from Aa-HuPBL-NOD/SCID mice stimulated with A. actinomycetemcomitans sonicate antigens, followed by staining with OPG-FITC. Periodontal CD4+ T cells restimulated with P. gingivalis sonicate antigens did not induce significant membrane OPG-L expression over the background level (data not shown). OPG-L membrane expression was determined by FACS analyses 48 hours later. (e) Reduction of alveolar bone destruction in OPG-Fc treated Aa-HuPBL-NOD/SCID mice. Groups of mice as indicated were infected with A. actinomycetemcomitans followed by in vivo treatment with soluble human OPG-Fc fusion protein. Alveolar bone loss (mean values ± SD) was assessed at 8 weeks and normalized to the positive control, Aa-infected BALB/c mice (100%). Group I, sham-infected NOD/SCID mice (n = 10); group II, Aa-infected HuPBL-NOD/SCID mice not injected with OPG-Fc (n = 16); group III, Aa-infected HuPBL-NOD/SCID mice injected with OPG-Fc (n = 10); group IV, Aa-infected HuPBL-NOD/SCID mice injected with PBS (n = 8). AThe differences in alveolar bone loss between group III and groups II and IV are statistically significant (P < 0.002).