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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