Role of periodontal pathogenic bacteria in RANKL-mediated bone destruction in periodontal disease

Accumulated lines of evidence suggest that hyperimmune responses to periodontal bacteria result in the destruction of periodontal connective tissue and alveolar bone. The etiological roles of periodontal bacteria in the onset and progression of periodontal disease (PD) are well documented. However, the mechanism underlying the engagement of periodontal bacteria in RANKL-mediated alveolar bone resorption remains unclear. Therefore, this review article addresses three critical subjects. First, we discuss earlier studies of immune intervention, ultimately leading to the identification of bacteria-reactive lymphocytes as the cellular source of osteoclast-induction factor lymphokine (now called RANKL) in the context of periodontal bone resorption. Next, we consider (1) the effects of periodontal bacteria on RANKL production from a variety of adaptive immune effector cells, as well as fibroblasts, in inflamed periodontal tissue and (2) the bifunctional roles (upregulation vs. downregulation) of LPS produced from periodontal bacteria in a RANKL-induced osteoclast-signal pathway. Future studies in these two areas could lead to new therapeutic approaches for the management of PD by down-modulating RANKL production and/or RANKL-mediated osteoclastogenesis in the context of host immune responses against periodontal pathogenic bacteria

Toll-like receptor agonists Porphyromonas gingivalis LPS and CpG differentially regulate IL-10 competency and frequencies of mouse B10 cells

IL-10 expressing regulatory B cells (B10) play a key role in immune system balance by limiting excessive inflammatory responses. Effects of toll-like receptor signaling and co-stimulatory molecules on B10 activity during innate and adaptive immune responses are not fully understood. Objective This study is to determine the effects of P. gingivalis LPS and CpG on B10 cell expansion and IL-10 competency in vitro. Material and Methods Spleen B cells were isolated from C57BL/6J mice with or without formalin-fixed P. gingivalis immunization. B cells were cultured for 48 hours under the following conditions: CD40L, CD40L+LPS, CD40L+CpG, and CD40L+LPS+CpG in the presence or absence of fixed P. gingivalis. Percentages of CD1dhiCD5+ B cells were measured by flow cytometry. IL-10 mRNA expression and secreted IL-10 were measured by real-time quantitative PCR and by ELISA respectively. Results P. gingivalis LPS plus CD40L significantly increased CD1dhiCD5+ B cell percentages and secreted IL-10 levels in both immunized and non-immunized mice B cells in the presence or absence of P. gingivalis, compared with control group. Secreted IL-10 levels were significantly increased in CD40L+LPS treated group compared with CD40L treatment group in the absence of P. gingivalis. CpG plus CD40L significantly decreased CD1dhiCD5+ B cell percentages, but greatly elevated secreted IL-10 levels in immunized and non-immunized mice B cells in the absence of P. gingivalis, compared with CD40L treatment group. Conclusions P. gingivalis LPS and CpG differentially enhance IL-10 secretion and expansion of mouse B10 cells during innate and adaptive immune responses

Porphyromonas gingivalis suppresses adaptive immunity in periodontitis, atherosclerosis and Alzheimer’s disease

Porphyromonas gingivalis, a keystone pathogen in chronic periodontitis, has been found to associate with remote body organ inflammatory pathologies including atherosclerosis and Alzheimer’s disease (AD). Although P. gingivalis has a plethora of virulence factors, much of its pathogenicity is surprisingly related to the overall immunosuppression of the host. This review focuses on P. gingivalis aiding suppression of the host’s adaptive immune system involving manipulation of cellular immunological responses specifically T- and B-cells in periodontitis and related conditions. In periodontitis this bacterium inhibits the synthesis of IL-2 and increases humoral responses. This reduces inflammatory responses related to T- and B-cell activation, and subsequent IFN-ɤ secretion by a subset of T cells. The T cells further suppresses upregulation of programmed cell death-1 (PD-1)-receptor on CD+-cells and its ligand PD-L1 on CD11b+- subset of T-cells. IL-2 down-regulates immune response-regulated genes, induces a cytokine pattern in which the Th17 lineage is favored thereby modulating the Th17/ T-regulatory cell (Treg) imbalance. The suppression of IFN-ɤ stimulated release of interferon-inducible protein-10 (IP-10) chemokine ligands [ITAC (CXCL11) and Mig (CXCL9)] by P. gingivalis capsular serotypes, triggers distinct T-cell responses, and contributes to local immune evasion by release of its outer membrane vesicles. In atherosclerosis P. gingivalis reduces Tregs and transforming growth factor beta-1 (TGF-1) and causes imbalance in the Th17 lineage of the Treg population. In Alzheimer’s disease P. gingivalis may affect the blood-brain barrier permeability, and inhibit local IFN-ɤ response by preventing entry of immune cells into the brain. The scarcity of adaptive immune cells in Alzheimer’s disease neuropathology implies P. gingivalis infection of the brain likely causes impaired clearance of insoluble amyloid and induces immunosuppression. By the effective manipulation of the armory of adaptive immune suppression through a plethora of virulence factors P. gingivalis may act as a keystone organism in periodontitis and in related systemic diseases and other remote body inflammatory pathologies

Attitudes Towards Economic Risk and the Gender Pay Gap

This paper examines the links between gender differences in attitudes towards economic risk and the gender pay gap. Consistent with the literature on the socio-economic determinants of attitudes towards economic risk, it shows that females are much more risk averse than males. It then extends this research to show that workers with more favorable attitudes towards risk are associated with higher earnings, and that gender differences in attitudes towards economic risk can account for a small, though important, part of the standardized gender pay gap

Systematic Parameterization, Storage, and Representation of Volumetric DICOM Data

Tomographic medical imaging systems produce hundreds to thousands of slices, enabling three-dimensional (3D) analysis. Radiologists process these images through various tools and techniques in order to generate 3D renderings for various applications, such as surgical planning, medical education, and volumetric measurements. To save and store these visualizations, current systems use snapshots or video exporting, which prevents further optimizations and requires the storage of significant additional data. The Grayscale Softcopy Presentation State extension of the Digital Imaging and Communications in Medicine (DICOM) standard resolves this issue for two-dimensional (2D) data by introducing an extensive set of parameters, namely 2D Presentation States (2DPR), that describe how an image should be displayed. 2DPR allows storing these parameters instead of storing parameter applied images, which cause unnecessary duplication of the image data. Since there is currently no corresponding extension for 3D data, in this study, a DICOM-compliant object called 3D presentation states (3DPR) is proposed for the parameterization and storage of 3D medical volumes. To accomplish this, the 3D medical visualization process is divided into four tasks, namely pre-processing, segmentation, post-processing, and rendering. The important parameters of each task are determined. Special focus is given to the compression of segmented data, parameterization of the rendering process, and DICOM-compliant implementation of the 3DPR object. The use of 3DPR was tested in a radiology department on three clinical cases, which require multiple segmentations and visualizations during the workflow of radiologists. The results show that 3DPR can effectively simplify the workload of physicians by directly regenerating 3D renderings without repeating intermediate tasks, increase efficiency by preserving all user interactions, and provide efficient storage as well as transfer of visualized data. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40846-015-0097-5) contains supplementary material, which is available to authorized users

A novel method of sampling gingival crevicular fluid from a mouse model of periodontitis

Using a mouse model of silk ligature-induced periodontal disease (PD), we report a novel method of sampling mouse gingival crevicular fluid (GCF) to evaluate the time-dependent secretion patterns of bone resorption-related cytokines. GCF is a serum transudate containing host-derived biomarkers which can represent cellular response in the periodontium. As such, human clinical evaluations of PD status rely on sampling this critical secretion. At the same time, a method of sampling GCF from mice is absent, hindering the translational value of mouse models of PD. Therefore, we herein report a novel method of sampling GCF from a mouse model of periodontitis, involving a series of easy steps. First, the original ligature used for induction of PD was removed, and a fresh ligature for sampling GCF was placed in the gingival crevice for ten minutes. Immediately afterwards, the volume of GCF collected in the sampling ligature was measured using a high precision weighing balance. The sampling ligature containing GCF was then immersed in a solution of PBS-Tween 20 and subjected to ELISA. This enabled us to monitor the volume of GCF and detect time-dependent changes in the expression of such cytokines as IL-1b, TNF-α, IL-6, RANKL, and OPG associated with the levels of alveolar bone loss, as reflected in GCF collected from a mouse model of PD. Therefore, this novel GCF sampling method can be used to measure various cytokines in GCF relative to the dynamic changes in periodontal bone loss induced in a mouse model of PD. Correspondence: Toshihisa Kawai, DDS, PhD, Department of Immunology and Infectious diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, Tel: 617-892-8317, Fax: 617-892-8437, [email protected]. # Contributed equally to this work HHS Public Access Author manuscript J Immunol Methods. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: J Immunol Methods. 2016 November ; 438: 21–25. doi:10.1016/j.jim.2016.08.008. Author Manuscript Author Manuscript Author Manuscript Autho

Aggregatibacter actinomycetemcomitans Omp29 Is Associated with Bacterial Entry to Gingival Epithelial Cells by F-Actin Rearrangement

The onset and progressive pathogenesis of periodontal disease is thought to be initiated by the entry of Aggregatibacter actinomycetemcomitans (Aa) into periodontal tissue, especially gingival epithelium. Nonetheless, the mechanism underlying such bacterial entry remains to be clarified. Therefore, this study aimed to investigate the possible role of Aa outer membrane protein 29 kD (Omp29), a homologue of E. coli OmpA, in promoting bacterial entry into gingival epithelial cells. To accomplish this, Omp29 expression vector was incorporated in an OmpA-deficient mutant of E. coli. Omp29+/OmpA− E. coli demonstrated 22-fold higher entry into human gingival epithelial line cells (OBA9) than Omp29−/OmpA− E. coli. While the entry of Aa and Omp29+/OmpA− E. coli into OBA9 cells were inhibited by anti-Omp29 antibody, their adherence to OBA9 cells was not inhibited. Stimulation of OBA9 cells with purified Omp29 increased the phosphorylation of focal adhesion kinase (FAK), a pivotal cell-signaling molecule that can up-regulate actin rearrangement. Furthermore, Omp29 increased the formation of F-actin in OBA9 cells. The internalization of Omp29-coated beads and the entry of Aa into OBA9 were partially inhibited by treatment with PI3-kinase inhibitor (Wortmannin) and Rho GTPases inhibitor (EDIN), both known to convey FAK-signaling to actin-rearrangement. These results suggest that Omp29 is associated with the entry of Aa into gingival epithelial cells by up-regulating F-actin rearrangement via the FAK signaling pathway

Upstream Solutions: Does the Supplemental Security Income Program Reduce Disability in the Elderly?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72843/1/j.1468-0009.2007.00512.x.pd