DESCRIPTION (provided by applicant): Dendritic cells (DCs) serve many important functions in the immune response, including the capture of microbes in the periphery, trafficking through the lymphatics to the secondary lymphoid organs, and antigen presentation to naive T cells. The trafficking ability of DCs to lymph nodes is tightly regulated by many factors including the DC maturation state. Human pathogens such as HIV-1, Mycobacterium tuberculosis, Helicobacter pylori and Porphyromonas gingivalis are able to infect DCs and disrupt DC maturation, leading to immunosuppression. This may also misdirect DC traffic, resulting in reverse transmigration of DCs from tissues directly into the bloodstream, in a process called pathogen trafficking. The inflammatory factors involved in pathogen trafficking of DCs to systemic sites through the blood are unclear. The development of atherosclerosis (ATH) is characterized by invasion of the arterial wall with activated DCs and other leukocytes. These DCs express specific atherogenic biomarkers that can promote plaque rupture, thrombus formation, and increase risk of heart attack and stroke. We presently understand very little about the pathogenic factors that mobilize DCs into the blood, that stimulate them to become atherogenic and invade ATH plaques. Chronic periodontitis (CP), initiated by P. gingivalis (Pg) and other bacterial species, is a significant risk factor for ATH, approaching that of smoking and elevated triglycerides. Most evidence points to infection with Pg and serologic exposure to Pg as being important risk factors for ATH. Published work from our group has identified an important role for the HIV-1 receptor DC-SIGN in the histopathology of CP and in infection of DCs by Pg. DC-SIGN is a C-type lectin endocytic receptor that appears to maintain DCs in an semi-mature immunosuppressive/migratory state and also binds to ICAM-2 on endothelial cells. We now have new evidence in several patient cohorts, in sufficient numbers for statistical inference, indicating that DC-SIGN+ and BDCA- 1+ DCs undergo mobilization in CP patients in response to S&RP and in acute coronary syndrome patients, relative to healthy controls. We have also confirmed the specificity of our Pg 16s rDNA probes by gene sequencing and have shown increased levels by nested qRt-PCR. The short term objectives of these studies are to further establish proof- of- concept for pathogen trafficking DCs. The long term objectives are to corroborate pathogen trafficking DCs in situ in atherosclerotic plaques from a cohort of coronary artery disease patients with CP. We propose to ultimately develop immunotherapeutic strategies for the prevention of pathogen trafficking DCs in patients at high risk for developing coronary artery disease.
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