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G(–) Anaerobes–Reactive CD4⁺ T-Cells Trigger RANKL-Mediated Enhanced Alveolar Bone Loss in Diabetic NOD Mice

¹ Eastman Department of Dentistry and Center for Oral Biology, Department of Microbiology and Immunology, School of Medicine and Dentistry, University of Rochester, Rochester, New York
² Department of Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada
³ Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell–mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(–) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans–reactive CD4⁺ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor B ligand (RANKL) expression. When diabetic mice are treated with the RANKL antagonist osteoprotegerin (OPG), there is a significant reversal of alveolar bone loss, as well as reduced RANKL expression in A. actinomycetemcomitans–reactive CD4⁺ T-cells. This study clearly describes the impact of autoimmunity to anaerobic infection in an experimental periodontitis model of type 1 diabetes. Thus, microorganism-reactive CD4⁺ T-cells and the RANKL-OPG axis provide the molecular basis of the advanced periodontal breakdown in diabetes and, therefore, OPG may hold therapeutic potential for treating bone loss in diabetic subjects at high risk.

Abbreviations: CLN, cervical lymph node; FACS, fluorescence-activated cell sorter; FITC, fluorescein isothiocyanate; IL, interleukin; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor B; RANKL, RANK ligand; s-RANKL, soluble RANKL; STZ, streptozocin; TNF, tumor necrosis factor

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