The low grade oral infection chronic periodontitis (CP) has been implicated in coronary artery disease risk, but the mechanisms are unclear. Here, a pathophysiological role for blood dendritic cells (DCs) in systemic dissemination of oral mucosal pathogens to atherosclerotic plaques was investigated in humans. The frequency and microbiome of CD19−BDCA-1+DC-SIGN+ blood myeloid DCs (mDCs) were analyzed in CP subjects with, or without existing acute coronary syndrome (ACS) and in healthy controls (CTL). FACS analysis revealed a significant increase in blood mDCs in the following order: CTL

The oral mucosal pathogen Porphyromonas gingivalis expresses at least two adhesins: the 67-kDa mfa-1 (minor) fimbriae and the 41-kDa fimA (major) fimbriae. In periodontal disease, P. gingivalis associates in situ with dermal dendritic cells (DCs), many of which express DC-SIGN (DC-specific ICAM-3 grabbing nonintegrin; CD209). The cellular receptors present on DCs that are involved in the uptake of minor/major fimbriated P. gingivalis, along with the effector immune response induced, are presently unclear. In this study, stably transfected human DC-SIGN+/− Raji cell lines and monocyte-derived DCs (MoDCs) were pulsed with whole, live, wild-type Pg381 or isogenic major (DPG-3)-, minor (MFI)-, or double fimbriae (MFB)-deficient mutant P. gingivalis strains. The influence of blocking Abs, carbohydrates, full-length glycosylated HIV-1 gp120 envelope protein, and cytochalasin D on the uptake of strains and on the immune responses was determined in vitro. We show that the binding of minor fimbriated P. gingivalis strains to Raji cells and MoDCs is dependent on DC-SIGN, whereas the double fimbriae mutant strain does not bind. Binding to DC-SIGN on MoDCs is followed by the internalization of P. gingivalis into DC-SIGN-rich intracellular compartments, and MoDCs secrete low levels of inflammatory cytokines and remain relatively immature. Blocking DC-SIGN with HIV-1 gp120 prevents the uptake of minor fimbriated strains and deregulates the expression of inflammatory cytokines. Moreover, MoDCs promote a Th2 or Th1 effector response, depending on whether they are pulsed with minor or major fimbriated P. gingivalis strains, respectively, suggesting distinct immunomodulatory roles for the two adhesins of P. gingivalis.

Maintenance of blood DC homeostasis is essential to preventing autoimmunity while controlling chronic infection. However, the ability of bacteremic pathogens to directly regulate blood DC homeostasis has not been defined. One such bacteremic pathogen, Porphyromonas gingivalis, is shown by our group to survive within mDCs under aerobic conditions and therein, metastasize from its oral mucosal niche. This is accompanied by expansion of the blood mDC pool in vivo, independently of canonical DC poietins. We presently know little of how this bacteremic pathogen causes blood DC expansion and the pathophysiological significance. This work shows that optimum differentiation of MoDCs from primary human monocytes, with or without GM-CSF/IL-4, is dependent on infection with P. gingivalis strains expressing the DC-SIGN ligand mfa-1. DC differentiation is lost when DC-SIGN is blocked with its ligand HIV gp120 or knocked out by siRNA gene silencing. Thus, we have identified a novel, noncanonical pathway of DC differentiation. We term these PDDCs and show that PDDCs are bona fide DCs, based on phenotype and phagocytic activity when immature and the ability to up-regulate accessory molecules and stimulate allo-CD4(+) T cell proliferation when matured. The latter is dependent on the P. gingivalis strain used to initially "educate" PDDCs. Moreover, we show that P. gingivalis-infected, conventional MoDCs become resistant to apoptosis and inflammatory pyroptosis, as determined by levels of Annexin V and caspase-8, -3/7, and -1. Taken together, we provide new insights into how a relatively asymptomatic bacteremia may influence immune homeostasis and promote chronic inflammation.

c Several intracellular pathogens, including a key etiological agent of chronic periodontitis, Porphyromonas gingivalis, infect blood myeloid dendritic cells (mDCs). This infection results in pathogen dissemination to distant inflammatory sites (i.e., pathogen trafficking). The alteration in chemokine-chemokine receptor expression that contributes to this pathogen trafficking function, particularly toward sites of neovascularization in humans, is unclear. To investigate this, we utilized human monocytederived DCs (MoDCs) and primary endothelial cells in vitro, combined with ex vivo-isolated blood mDCs and serum from chronic periodontitis subjects and healthy controls. Our results, using conditional fimbria mutants of P. gingivalis, show that P. gingivalis infection of MoDCs induces an angiogenic migratory profile. This profile is enhanced by expression of DC-SIGN on MoDCs and minor mfa-1 fimbriae on P. gingivalis and is evidenced by robust upregulation of CXCR4, but not secondary lymphoid organ (SLO)-homing CCR7. This disruption of SLO-homing capacity in response to respective chemokines closely matches surface expression of CXCR4 and CCR7 and is consistent with directed MoDC migration through an endothelial monolayer. Ex vivo-isolated mDCs from the blood of chronic periodontitis subjects, but not healthy controls, expressed a similar migratory profile; moreover, sera from chronic periodontitis subjects expressed elevated levels of CXCL12. Overall, we conclude that P. gingivalis actively "commandeers" DCs by reprogramming the chemokine receptor profile, thus disrupting SLO homing, while driving migration toward inflammatory vascular sites.

An estimated 80 million US adults have one or more types of cardiovascular diseases. Atherosclerosis is the single most important contributor to cardiovascular diseases; however, only 50% of atherosclerosis patients have currently identified risk factors. Chronic periodontitis, a common inflammatory disease, is linked to an increased cardiovascular risk. Dendritic cells (DCs) are potent antigen presenting cells that infiltrate arterial walls and may destabilize atherosclerotic plaques in cardiovascular disease. While the source of these DCs in atherosclerotic plaques is presently unclear, we propose that dermal DCs from peripheral inflamed sites such as CP tissues are a potential source. This review will examine the role of the opportunistic oral pathogen Porphyromonas gingivalis in invading DCs and stimulating their mobilization and misdirection through the bloodstream. Based on our published observations, combined with some new data, as well as a focused review of the literature we will propose a model for how P. gingivalis may exploit DCs to gain access to systemic circulation and contribute to coronary artery disease. Our published evidence supports a significant role for P. gingivalis in subverting normal DC function, promoting a semimature, highly migratory, and immunosuppressive DC phenotype that contributes to the inflammatory development of atherosclerosis and, eventually, plaque rupture.

A new phylogeny for the Pristimantis lacrimosus species group is presented, its species content reviewed, and three new species described from the eastern slopes of the Ecuadorian Andes. Our phylogeny includes, for the first time, samples of P. aureolineatus, P. bromeliaceus, and P. lacrimosus. The morphology of hyperdistal subarticular tubercles is also assessed among 21 species of Pristimantis. The P. lacrimosus species group is composed of 36 species distributed in the Chocó, Guiana, and Amazon regions of tropical South America with a single species reaching Central America. Ancestral area reconstruction indicates that, despite its high diversity in the Amazon region, the P. lacrimosus group originated in the Pacific basin, Chocó region of Ecuador and Colombia. Pristimantis amaguanaesp. nov. is most closely related to P. bromeliaceus. It differs from P. bromeliaceus by being smaller, having transversal dark bands in the hindlimbs (absent or faint in P. bromeliaceus) and the absence of discoidal fold (present in P. bromeliaceus). Pristimantis nankintssp. nov. and P. romeroaesp. nov. are part of a clade of predominantly light-green frogs that includes P. acuminatus, P. enigmaticus, P. limoncochensis, and P. omeviridis. Pristimantis nankintssp. nov. and P. romeroaesp. nov. can be distinguished from all of them by the presence of a dark dorsolateral stripe that borders a light green band on a green background. Hyperdistal tubercles are present in all examined species of the P. lacrimosus species group and its sister clade. Species with hyperdistal tubercles are characterized by having relatively long terminal phalanges and narrow T-shaped expansion at the end of the terminal phalange. We discuss the phylogenetic distribution of these characters and their potential diagnostic significance.

Background: Glycogen storage diseases (GSDs) are genetic disorders that result from defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types. It also manifests with impaired neutrophil chemotaxis and neutropenic episodes which results in severe destruction of the supporting dental tissues, namely the periodontium. Although GSD Type Ib cannot be cured, associated symptoms and debilitating oral manifestations of the disease can be managed through collaborative medical and dental care where early detection and intervention is of key importance. This objective of the case report was to describe a child with GSD Ib and its associated oral manifestations with microbial, immunological and histological appearances. Case Presentation: An eight-year-old Hispanic male with a history of GSD type Ib presented with extensive intraoral generalized inflammation of the gingiva, ulcerations and bleeding, and intraoral radiographic evidence of bone loss. Tannerella forsythia was readily identifiable from the biofilm samples. Peripheral blood neutrophils were isolated and a deficient host response was observed by impaired neutrophil migration. Histological evaluation of the soft and hard tissues of the periodontally affected primary teeth showed unaffected dentin and cementum. Conclusions: This case illustrates the association between GSD Ib and oral manifestations of the disease. A multi-disciplinary treatment approach was developed in order to establish healthy intraoral conditions for the patient. Review of the literature identified several cases describing GSD and its clinical and radiographic oral manifestations; however, none was identified where also microbial, immunological, and histological appearances were described.

Introduction: To the best of the authors’ knowledge, this is the first case report to describe the use of a perforated resorbable barrier membrane (PRBM) to enhance lateral bone augmentation for implant site development. Case Presentation: A 41‐year‐old female presented to the Advanced Specialty Education Program in Periodontics at Stony Brook University, Stony Brook, New York, for implant consultation regarding a missing maxillary right lateral incisor. The tooth had been lost as a result of trauma 10 years prior to presentation. Clinical examination and radiographs showed significant horizontal ridge deficiency (<5 mm) that supported a staged intervention. Horizontal bone augmentation was performed following guided bone regeneration principles using a mineralized mixed corticocancellous (70:30) allograft followed by a PRBM. A cone beam computed tomography scan was obtained before surgery and 8 months after treatment, from which volumetric width changes were quantified. A bone biopsy was obtained at the time of implant placement to measure new vital bone (NVB) formation, residual graft (RG) particles, and connective tissue (CT) formation. Dimensional width changes were assessed during reentry for implant placement. The lateral bone gain was 5.0 mm, clinically and radiographically. Histologically, the amount of NVB formation, RG particles, and CT infiltration was 38.1%, 38.9%, and 23.1%, respectively. Implant placement was uneventful, with no further need for bone augmentation. Conclusions: Previous studies using similar techniques and regenerative materials have shown an average of 3.5 mm of horizontal bone augmentation. The use of a PRBM appeared to significantly enhance lateral bone augmentation. An ongoing clinical trial is underway to confirm these results.