Dendritic cells (DCs) are the """"""""sentinels"""""""" of the skin and mucosa, patrolling these tissues for invading bacteria and viruses. In their immature stage, DCs are uniquely equipped for antigen (Ag) capture, expressing a large variety of scavenger receptors and other pattern recognition receptors. As they mature and migrate to the lymph nodes, DCs downregulate Ag-capture receptors and upregulate Ag-presenting receptors. Mature DCs are 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 to these funded studies. Our lab has thus far published 11 papers, with 3 in preparation that can be credited to this R01, which terms in November of 2005. Our studies have identified an important role for gingival immature DC in the recognition and uptake of Porphyromonas gingivalis (Pg) in situ and in vitro, and for maturing DCs in engagement with CD4+ T cells in the gingival lamina propria. The principle DCs in the gingival 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 that is 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 pathogens that target DC-SIGN is that they cause infections that can last a lifetime (i.e. such as CP) and secondly, that manipulation of the Th1- versus Th2-balance by these pathogens is central to their persistence. We have evidence that Pg and its PAMPs may target C-type lectin receptors on DCs and manipulate the Th1-Th2 balance;we hypothesize that this is involved in persistence of Pg in the oral mucosa. These proposed continued 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 modulates the adaptive immune response, in particular, the induction of T regulatory cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014328-10
Application #
7743442
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2001-02-01
Project End
2010-08-31
Budget Start
2009-12-01
Budget End
2010-08-31
Support Year
10
Fiscal Year
2010
Total Cost
$357,351
Indirect Cost
Name
State University New York Stony Brook
Department
Dentistry
Type
Schools of Dentistry
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
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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