In a susceptible host, persistence of periodontal pathogens such as P. gingivalis results in aberrant and prolonged inflammation and subsequent tissue damage of the tooth supporting structures, namely periodontitis. Tissue pathology is largely the consequence of chronic release of factors by activated cells of the immune system. Among the immune cells responding to challenge by bacteria, including P. gingivalis, are antigen presenting cells (APC) of myeloid origin such as monocytes, macrophages and dendritic cells, strategically poised along portals of entry or recruited to sites of infection. After recognition of pathogen associated molecular patterns (PAMPs) via toll like receptors (TLR), innate immune cells initiate responses aiming to contain and/or clear the inciting agent. As coordinators, APC also orchestrate the transition to the adaptive arm of the immune response, including the generation of effector T cell responses. Effector T cells were previously considered to differentiate into either a Th1 or Th2 phenotype, but with the recent recognition of effector T cell plasticity and the Th17 lineage, there has been an emphasis on characterizing the contributing cells involved in chronic mucosal lesions. IL-17 secreting Th17 cells play a protective role in antimicrobial immunity but have also been linked to inflammatory and autoimmune pathologies. Persistence of the Th17 population has been shown to support chronicity of inflammation and to directly mediate tissue destruction, via activation of resident matrix cells such as fibroblasts and osteoclasts, unlike Th1/Th2 cells which can inhibit osteoclast differentiation. Immune-mediated osseous destruction is the hallmark of periodontal disease and, hence, delineating a role for Th1/Th2/Th17 lineages in periodontitis is ongoing, in an effort to further the understanding of disease pathologies and ultimately uncover possible targets to disrupt pathogenesis. To this end, we aimed to study the Th lineage representation within the pathologic lesions of periodontitis and to investigate possible mechanisms by which strains of the periodontal pathogen P. gingivalis which are considered more or less virulent may orchestrate T cell lineage commitment relevant to oral mucosal immunopathology. To delineate immune cell-dependent mechanisms whereby bacterial challenge drives persistent destructive inflammation, we studied involved tissues ex vivo from patients with severe periodontitis. Diseased lesions were populated by abundant Th17 cells, a cell type linked to infection, chronic inflammation/autoimmunity and tissue pathology. To dissect mechanisms by which Th17 cells may be induced in periodontitis we studied the interaction of the periodontal pathogen P. gingivalis with innate immune cells and their potential to differentially drive Th cell responses. We found that P. gingivalis, particularly its virulent strain W83, stimulated myeloid antigen presenting cells to produce cytokines linked to Th17 polarization, such as IL-1 and IL-6, and not Th1 cytokines, favoring a Th17 response. Promotion of Th17 lineage responses was also aided by P. gingivalis proteases, which appeared to differentially degrade pivotal cytokines. In this regard, IL-12 was largely degraded by P. gingivalis, whereas IL-1 was more resistant to proteolysis. Our data unveil multiple pathways by which P. gingivalis may orchestrate chronic inflammation, providing insights into interventional strategies.

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Project End
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Budget End
Support Year
2
Fiscal Year
2011
Total Cost
$180,359
Indirect Cost
Name
National Institute of Dental & Craniofacial Research
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Type
DUNS #
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Dutzan, Nicolas; Abusleme, Loreto; Bridgeman, Hayley et al. (2017) On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Immunity 46:133-147
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Moutsopoulos, Niki M; Kling, Heather M; Angelov, Nikola et al. (2012) Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. J Autoimmun 39:294-303
Ashcroft, Gillian S; Jeong, Moon-Jin; Ashworth, Jason J et al. (2012) Tumor necrosis factor-alpha (TNF-?) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen 20:38-49

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