Dendritic cells (DCs) are the 'sentinels' of the skin and mucosa, patrolling these tissues for invading bacteriaand viruses. In their immature stage, DCs are uniquely equipped for antigen (Ag) capture, expressing a largevariety of scavenger receptors and other pattern recognition receptors. As they mature and migrate to thelymph nodes, DCs downregulate Ag-capture receptors and upregulate Ag-presenting receptors. Mature DCsare the most efficient Ag-presenting cells (APCs), and the only APCs capable of stimulating naive T cells.The role of dendritic cell subpopulations in chronic periodontitis (CP); however, was largely unknown prior tothese funded studies. Our lab has thus far published 11 papers, with 3 in preparation that can be credited tothis R01, which terms in November of 2005. Our studies have identified an important role for gingivalimmature DC in the recognition and uptake of Porphyromonas gingivalis (Pg) in situ and in vitro, and formaturing DCs in engagement with CD4+ T cells in the gingival lamina propria. The principle DCs in thegingival lamina propria in CP are those that express DC-specific ICAM-3 grabbing non-integrinpositive (DC-SIGN) in CP. DC-SIGN is a member of a family of C-type lectins; it is a type II transmembrane receptor thatis used as an 'escape mechanism' by major human pathogens including HIV-1, Helicobacter pylori,Klepsiella pneumonia, M tuberculosis, Leishmania pifanoi and C albicans. A central feature of pathogensthat target DC-SIGN is that they cause infections that can last a lifetime (i.e. such as CP) and secondly, thatmanipulation of the Th1- versus Th2-balance by these pathogens is central to their persistence. We haveevidence that Pg and its PAMPs may target C-type lectin receptors on DCs and manipulate the Th1-Th2balance; we hypothesize that this is involved in persistence of Pg in the oral mucosa. These proposedcontinued studies will therefore focus on the role of C-type lectins and other pattern recognition receptors(PRR) in uptake/recognition of Pg, its PAMPs and in intracellular routing by MDDCs and how this modulatesthe adaptive immune response, in particular, the induction of T regulatory cells.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Rodriguez-Chavez, Isaac R
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Georgia Regents University
Schools of Dentistry
United States
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Peacock, M E; Arce, R M; Cutler, C W (2016) Periodontal and other oral manifestations of immunodeficiency diseases. Oral Dis :
Arjunan, P; El-Awady, A; Dannebaum, R O et al. (2016) High-throughput sequencing reveals key genes and immune homeostatic pathways activated in myeloid dendritic cells by Porphyromonas gingivalis 381 and its fimbrial mutants. Mol Oral Microbiol 31:78-93
El-Awady, Ahmed R; Miles, Brodie; Scisci, Elizabeth et al. (2015) Porphyromonas gingivalis evasion of autophagy and intracellular killing by human myeloid dendritic cells involves DC-SIGN-TLR2 crosstalk. PLoS Pathog 10:e1004647
El-Awady, Ahmed R; Arce, Roger M; Cutler, Christopher W (2015) Dendritic cells: microbial clearance via autophagy and potential immunobiological consequences for periodontal disease. Periodontol 2000 69:160-80
Muthukuru, Manoj; Cutler, Christopher W (2015) Resistance of MMP9 and TIMP1 to endotoxin tolerance. Pathog Dis 73:
Miles, Brodie; Zakhary, Ibrahim; El-Awady, Ahmed et al. (2014) Secondary lymphoid organ homing phenotype of human myeloid dendritic cells disrupted by an intracellular oral pathogen. Infect Immun 82:101-11
Miles, Brodie; Abdel-Ghaffar, Khaled A; Gamal, Ahmed Y et al. (2014) Blood dendritic cells: ""canary in the coal mine"" to predict chronic inflammatory disease? Front Microbiol 5:6
Miles, Brodie; Scisci, Elizabeth; Carrion, Julio et al. (2013) Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen. J Leukoc Biol 94:281-9
Carrion, Julio; Scisci, Elizabeth; Miles, Brodie et al. (2012) Microbial carriage state of peripheral blood dendritic cells (DCs) in chronic periodontitis influences DC differentiation, atherogenic potential. J Immunol 189:3178-87
Jotwani, Ravi; Moonga, Baljit S; Gupta, Siddharth et al. (2010) Nuclear factor-kappaB p50 subunits in chronic periodontitis and Porphyromonas gingivalis lipopolysaccharide-pulsed dendritic cells. Ann N Y Acad Sci 1192:278-85

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