Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss.

Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.

Optimizing esthetic zone periodontal regeneration in a 1-2-wall infrabony defect using recombinant human platelet-derived growth factor BB and ß-tricalcium phosphate: A case report.

OBJECTIVE: Periodontitis is an inflammatory condition induced by subgingival bacterial dysbiosis, resulting in inflammatory-mediated destruction of tooth-supporting structures, potentially leading to the formation of infrabony defects. This case report describes the treatment of a patient who presented with a combination 1-2-wall defect on tooth 21. To maintain the residual periodontal attachment and minimize esthetic consequences, a regenerative approach was performed using recombinant human platelet-derived growth factor-BB (rh-PDGF-BB) and ß-tricalcium phosphate (ß-TCP). MATERIALS AND METHODS: At the time of postscaling/root planing reevaluation, a 34-year-old Asian male initially diagnosed with molar/incisor pattern stage III grade C periodontitis exhibited a 6-mm residual probing depth on the mesiopalatal aspect of tooth 21. Periodontal regenerative surgery was performed using rh-PDGF-BB with ß-TCP, without the use of a membrane. RESULTS: At the 1-year follow-up, a significant reduction in probing depth and radiographic evidence of bone fill were observed. Additionally, re-entry surgery for implant placement at site tooth 23 confirmed bone fill in the defect on tooth 21. CONCLUSION: These results demonstrate the efficacy of rh-PDGF-BB with ß-TCP in enhancing periodontal regeneration and support its use as a treatment option when treating poorly contained infrabony defects in the esthetic zone.

Aggregatibacter actinomycetemcomitans Cytolethal Distending Toxin Induces Cellugyrin-(Synaptogyrin 2) Dependent Cellular Senescence in Oral Keratinocytes.

Recently, we reported that oral-epithelial cells (OE) are unique in their response to Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) in that cell cycle arrest (G2/M) occurs without leading to apoptosis. We now demonstrate that Cdt-induced cell cycle arrest in OE has a duration of at least 7 days with no change in viability. Moreover, toxin-treated OE develops a new phenotype consistent with cellular senescence; this includes increased senescence-associated ß-galactosidase (SA-ß-gal) activity and accumulation of the lipopigment, lipofuscin. Moreover, the cells exhibit a secretory profile associated with cellular senescence known as the senescence-associated secretory phenotype (SASP), which includes IL-6, IL-8 and RANKL. Another unique feature of Cdt-induced OE senescence is disruption of barrier function, as shown by loss of transepithelial electrical resistance and confocal microscopic assessment of primary gingival keratinocyte structure. Finally, we demonstrate that Cdt-induced senescence is dependent upon the host cell protein cellugyrin, a homologue of the synaptic vesicle protein synaptogyrin. Collectively, these observations point to a novel pathogenic outcome in oral epithelium that we propose contributes to both A. actinomycetemcomitans infection and periodontal disease progression.

A Periodontal Perspective on the Successful Treatment of Recurrent Benign Gingival Lesions Affecting the Anterior Dentition: Two Case Reports.

Recurrent benign gingival lesions occurring in the anterior dentition are clinical dilemmas. While complete removal of such lesions is required to prevent recurrence, this can result in a poor esthetic outcome. Relative to this conundrum, this report discusses the diagnosis, psychologic management, and clinical treatment of two patients with recurring lesions on the facial gingiva of the mandibular and maxillary incisors, respectively. Patient A, a 55-year-old woman, presented with a recurrent peripheral ossifying fibroma (POF); Patient B, a 76-year-old man, presented with a recurrent pyogenic granuloma (PG). Both patients underwent multiple procedures and were ultimately treated without lesion recurrence. The efficacious surgical treatment of recurrent gingival lesions like POF and PG requires an aggressive approach involving lesion removal of the lesion as well as a 1.0- to 2.0-mm margin of normal tissue, underlying alveolar bone, and associated periodontal ligament (PDL). The rationale for this approach stresses the potential periodontal and esthetic ramifications that were considered. In summary, when recurrent benign gingival lesions are localized to the anterior part of the mouth, the approach to their surgical removal should be modified to minimize the extent of gingival recession and other potential esthetic issues.

A randomized, double-blind pilot study of analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen following dental implant placement surgery.

Introduction: Post-surgical pain following dental implant placement surgery is typically managed with non-opioid analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. However, the comparative analgesic efficacy of over-the-counter doses of non-steroidal anti-inflammatory drugs and acetaminophen in implant patients is unknown. Therefore, we compared the analgesic and anti-inflammatory effects of naproxen sodium and acetaminophen after surgical placement of one or two dental implants. Methods: Adult patients were treated with naproxen sodium (440 mg loading dose +220 mg q8h, n = 15) or acetaminophen (1,000 mg q6h-max daily dose 3,000 mg, n = 15) for 3 days after implant placement in a randomized, double-blind design. Pain was assessed on a 0-10 scale every 20 min for 6 h after study medication treatment. Tramadol (50 mg) was available as a rescue medication. Plasma and gingival crevicular fluid (GCF) were collected prior to the surgery and 0, 1, 2, 4, 6, 24, and 72 h after surgery for quantification of interleukin (IL)-6, IL-8, and IL-1ß levels. Results: Pain scores were significantly lower in patients treated with naproxen sodium compared to those treated with acetaminophen. Inflammatory mediator levels in plasma and gingival crevicular fluid increased after surgery and returned to near baseline levels by 72 h. Plasma IL-6 levels were significantly lower 6 h after surgery in patients treated with naproxen sodium compared to acetaminophen. No differences in inflammatory mediator concentrations in gingival crevicular fluid were observed between the treatment groups. The number of implants placed and body mass index (BMI) influenced inflammatory mediator concentrations in plasma and gingival crevicular fluid, respectively. Discussion: Naproxen sodium was more effective than acetaminophen in reducing post-operative pain and systemic inflammation following surgical placement of one or two dental implants. Further studies are needed to determine whether these findings are applicable to more complex implant cases and how they affect clinical outcomes following implant placement. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04694300.

Addition of cariogenic pathogens to complex oral microflora drives significant changes in biofilm compositions and functionalities.

BACKGROUND: Dental caries is a microbe and sugar-mediated biofilm-dependent oral disease. Of particular significance, a virulent type of dental caries, known as severe early childhood caries (S-ECC), is characterized by the synergistic polymicrobial interaction between the cariogenic bacterium, Streptococcus mutans, and an opportunistic fungal pathogen, Candida albicans. Although cross-sectional studies reveal their important roles in caries development, these exhibit limitations in determining the significance of these microbial interactions in the pathogenesis of the disease. Thus, it remains unclear the mechanism(s) through which the cross-kingdom interaction modulates the composition of the plaque microbiome. Here, we employed a novel ex vivo saliva-derived microcosm biofilm model to assess how exogenous pathogens could impact the structural and functional characteristics of the indigenous native oral microbiota. RESULTS: Through shotgun whole metagenome sequencing, we observed that saliva-derived biofilm has decreased richness and diversity but increased sugar-related metabolism relative to the planktonic phase. Addition of S. mutans and/or C. albicans to the native microbiome drove significant changes in its bacterial composition. In addition, the effect of the exogenous pathogens on microbiome diversity and taxonomic abundances varied depending on the sugar type. While the addition of S. mutans induced a broader effect on Kyoto Encyclopedia of Genes and Genomes (KEGG) ortholog abundances with glucose/fructose, S. mutans-C. albicans combination under sucrose conditions triggered unique and specific changes in microbiota composition/diversity as well as specific effects on KEGG pathways. Finally, we observed the presence of human epithelial cells within the biofilms via confocal microscopy imaging. CONCLUSIONS: Our data revealed that the presence of S. mutans and C. albicans, alone or in combination, as well as the addition of different sugars, induced unique alterations in both the composition and functional attributes of the biofilms. In particular, the combination of S. mutans and C. albicans seemed to drive the development (and perhaps the severity) of a dysbiotic/cariogenic oral microbiome. Our work provides a unique and pragmatic biofilm model for investigating the functional microbiome in health and disease as well as developing strategies to modulate the microbiome. Video Abstract.

Distinct fibroblast progenitor subpopulation expedites regenerative mucosal healing by immunomodulation.

Injuries that heal by fibrosis can compromise organ function and increase patient morbidity. The oral mucosal barrier has a high regenerative capacity with minimal scarring, but the cellular mechanisms remain elusive. Here, we identify distinct postnatal paired-related homeobox-1+ (Prx1+) cells as a critical fibroblast subpopulation that expedites mucosal healing by facilitating early immune response. Using transplantation and genetic ablation model in mice, we show that oral mucosa enriched with Prx1+ cells heals faster than those that lack Prx1+ cells. Lineage tracing and scRNA-seq reveal that Prx1+ fibroblasts exhibit progenitor signatures in physiologic and injured conditions. Mechanistically, Prx1+ progenitors accelerate wound healing by differentiating into immunomodulatory SCA1+ fibroblasts, which prime macrophage recruitment through CCL2 as a key part of pro-wound healing response. Furthermore, human Prx1+ fibroblasts share similar gene and spatial profiles compared to their murine counterpart. Thus, our data suggest that Prx1+ fibroblasts may provide a valuable source in regenerative procedures for the treatment of corneal wounds and enteropathic fibrosis.

Prognostic significance of conventional and volumetric PET parameters with and without partial volume correction in the assessment of head and neck squamous cell carcinoma.

BACKGROUND: The optimal quantification of PET in assessment of head and neck squamous cell carcinoma (HNSCC) is still under development. The effect of partial volume correction (PVC) on the evaluation of survival in the HNSCC patients has not been investigated yet. METHODOLOGY: Pretreatment 18F-FDG-PET/CT scans of a selected group of 57 patients with advanced stage HNSCC were collected. Conventional (SUVmean and SUVmax) and volumetric [total lesion glycolysis (TLG) and metabolic tumor volume (MTV)] PET metrics were calculated. The ROVER software (ABX GmbH, Radeberg, Germany) automatically applied PVC to the PET metrics. Cox proportional hazards regression model calculated hazard ratio (HR) for assessment of predictive parameters of progression-free survival (PFS). RESULTS: In multivariate Cox regression analysis, including age, gender, race, human papillomavirus status, and stage, the only significant predictors of PFS were the volumetric PET parameters (TLG: HR, 1.003; 95% CI, 1.001-1.005; P = 0.02), pvcTLG (HR, 1.002; 95% CI, 1.001-1.004; P = 0.01) and MTV (HR, 1.050; 95% CI, 1.024-1.077; P < 0.01). The partial volume-corrected values were significantly higher than the noncorrected values (Wilcoxon sign test; P < 0.05). However, there was not a statistically significant difference between the nonpartial volume corrected and partial volume-corrected PET metrics for assessment of PFS. CONCLUSION: Volumetric PET metrics were predictors of PFS in Cox regression analysis. Applying PVC could not significantly improve the accuracy of PET metrics for assessment of PFS.

Efficacy of Antibiotics Used as an Adjunct in the Treatment of Peri-implant Mucositis and Peri-implantitis: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review aimed to assess the clinical efficacy of antibiotics when used as an adjunct in treating peri-implant diseases. MATERIALS AND METHODS: A systematic search of papers published between January 1980 and March 2020 was conducted. Randomized clinical trials with at least 10 patients who had peri-implant diseases, treated with or without adjunctive antibiotics in combination with surgical or nonsurgical therapies, and with a minimum of at least 3 months of follow-up were included. Meta-analyses were conducted to analyze weighted mean differences in probing depth reduction, radiographic bone level gain, and odds ratio of treatment success. RESULTS: From the 856 articles identified, 10 articles met the inclusion criteria and were selected. Of these, 7 articles were used for the meta-analysis. The adjunctive use of antibiotics in the treatment of peri-implant diseases yielded significantly greater probing depth reduction (weighted mean differences = 0.56 mm at 3 months, P = .001; 0.77 mm at 6 months, P < .00001; 0.92 mm at 12 months, P < .00001), radiographic bone level gain (weighted mean differences = 0.64 mm, P = .03), and treatment success (odds ratio = 1.74, P = .04) compared to the same treatment without antibiotics. CONCLUSION: Based on the existing evidence, the use of adjunctive antibiotics to treat peri-implant diseases, especially peri-implantitis, provided potential benefits in clinical outcomes for up to 12 months posttherapy.

Ceramic Printing - Comparative Study of the Flexural Strength of 3D Printed and Milled Zirconia.

PURPOSE: To determine and compare the mechanical properties of 3D-printed yttriastabilized zirconia to milled isostatic pressed yttria-stabilized zirconia, with the following hypotheses: (1) The flexural strength of 3D-printed yttria-stabilized zirconia is comparable to milled yttria-stabilized isostatic pressed zirconia; and (2) thermocycling and chewing simulation do not affect the flexural strength of 3D-printed yttria-stabilized zirconia. MATERIALS AND METHODS: A total of 30 bars of an experimental 3D-printed 3 mol% yttriastabilized zirconia (LithaCon 3Y 230, Lithoz) and 10 bars of milled isostatic pressed zirconia (Prettau Zirconia, Zirkonzahn) were utilized. The printed zirconia bars were divided into three groups (n = 10 bars per group): (1) untreated (control); (2) thermocycled; and (3) tested after chewing simulation. A flexural strength test was performed on all samples using a three-point bend test in an Instron Universal testing machine. One-way analysis of variance on ranks was used to compare milled to printed zirconia. The effects of thermocycling and load cycling on 3D-printed zirconia were also determined. RESULTS: The flexural strength values for milled and printed zirconia were 936.3 ± 255.0 MPa and 855.4 ± 112.6 MPa, respectively. There was no statistically significant difference in flexural strength between the milled and printed zirconia (P = .178). No statistically significant differences were observed between the control 3D-printed zirconia group and the thermocycled (888.4 ± 59.3 MPa) or load-cycled printed zirconia (789.6 ± 133.8 MPa; P = .119). CONCLUSION: Printed 3 mol% yttria-stabilized zirconia has comparable flexural strength to milled yttria-stabilized isostatic pressed zirconia. The thermocycling and chewing simulation used in this study did not significantly alter the flexural strength of the printed 3 mol% yttria-stabilized zirconia. These results indicate a promising role for 3D printing in the fabrication of zirconia restorations. Additional studies are needed to explore the full potential of this technology.

Stromal cell-derived DEL-1 inhibits Tfh cell activation and inflammatory arthritis.

The secreted protein developmental endothelial locus 1 (DEL-1) regulates inflammatory cell recruitment and protects against inflammatory pathologies in animal models. Here, we investigated DEL-1 in inflammatory arthritis using collagen-induced arthritis (CIA) and collagen Ab-induced arthritis (CAIA) models. In both models, mice with endothelium-specific overexpression of DEL-1 were protected from arthritis relative to WT controls, whereas arthritis was exacerbated in DEL-1-deficient mice. Compared with WT controls, mice with collagen VI promoter-driven overexpression of DEL-1 in mesenchymal cells were protected against CIA but not CAIA, suggesting a role for DEL-1 in the induction of the arthritogenic Ab response. Indeed, DEL-1 was expressed in perivascular stromal cells of the lymph nodes and inhibited Tfh and germinal center B cell responses. Mechanistically, DEL-1 inhibited DC-dependent induction of Tfh cells by targeting the LFA-1 integrin on T cells. Overall, DEL-1 restrained arthritis through a dual mechanism, one acting locally in the joints and associated with the anti-recruitment function of endothelial cell-derived DEL-1; the other mechanism acting systemically in the lymph nodes and associated with the ability of stromal cell-derived DEL-1 to restrain Tfh responses. DEL-1 may therefore be a promising therapeutic for the treatment of inflammatory arthritis.

A novel digital approach for fixed full-mouth implant-supported rehabilitations: A case report.

Successful rehabilitation of a patient's entire dentition with implant-supported fixed prostheses requires restoration of function, esthetics and comfort. To achieve this goal, the clinician and laboratory technician must work in concert with one another to navigate the multiple steps from the patient's initial evaluation to delivery of the final prostheses. Key to this is the ability of the clinician to provide the technician with detailed information regarding the patient's extra- and intraoral characteristics in a manner that can be easily and accurately transferred to the lab bench where it then serves as the foundation for reconstruction of the dentition. In recent years, the impressive evolution of digital technology in dentistry has dramatically facilitated this complex process. The aim of this case report is to illustrate how digital profiles of a patient's facial and intraoral features can be merged with one another and used to generate artificial teeth and gingival tissue of a full mouth implant supported rehabilitation via computer-aided design and computer-aided manufacturing (CAD/CAM) technology to successfully rehabilitate a patient that initially presented with a terminal dentition. Key words:Facial scan, Zirconia, Implant-supported rehabilitation, Implant-supported prosthesis, Fixed prosthesis, Oral rehabilitation.

Human Oral Motion-Powered Smart Dental Implant (SDI) for In Situ Ambulatory Photo-biomodulation Therapy.

Peri-implant disease is an inflammatory condition affecting the soft and hard tissues surrounding a dental implant. However, current preventative methods are insufficient due to the limited bioactivity on the dental implant and poor patient compliance. Recently, photo-biomodulation (PBM) therapy that can recover and regenerate peri-implant soft tissue has attracted considerable attention in dentistry. In this paper, a seamless human oral motion-powered dental implant system (called Smart Dental Implant or SDI) is presented as an ambulatory PBM therapy modality. SDI allows the in situ light delivery, which is enabled by the energy harvesting from dynamic human oral motions (chewing and brushing) via an engineered piezoelectric dental crown, an associated circuit, and micro light emitting diodes (LEDs). The SDI also offers adequate mechanical strength as the clinical standards. Using primary human gingival keratinocytes (HGKs) as a model host organism and Pseudomonas aeruginosa lipopolysaccharides (LPS) as a model inflammatory stimulus, effective SDI-mediated PBM therapy is demonstrated. A new class of dental implants could be an ambulatory PBM therapy platform for the prevention of peri-implant disease without patient dependency, warranting long-lasting dental implants.

18F-FDG-PET/CT in radiation therapy-induced parotid gland inflammation.

BACKGROUND: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used in the clinical management of oncologic and inflammatory pathologies. It may have utility in detecting radiotherapy (RT)-induced damage of oral tissues. Thus, the aim of the present study was to use FDG-PET/CT to evaluate parotid gland inflammation following RT in patients with head and neck cancer (HNC). METHODS: This retrospective study included patients with HNC treated with photon, proton, or combined photon/proton RT, in addition to chemotherapy. All patients received FDG-PET/CT imaging pre-treatment and 3 months post-treatment. The average mean standardized uptake value (Avg SUVmean) and the average maximum standardized uptake value (Avg SUVmax) of the left and right parotid glands were determined by global assessment of FDG activity using OsiriX MD software. A two-tailed paired t test was used to compare Avg SUVmean and Avg SUVmax pre- and post-RT. RESULTS: Forty-seven HNC patients were included in the study. Parotid gland Avg SUVmean was significantly higher at 3 months post-treatment than pre-treatment (p < 0.05) in patients treated with photon RT, but no significant differences were found between pre- and post-treatment Avg SUVmean in patients treated with proton RT or combined photon/proton RT. CONCLUSION: Our results suggest that photon RT may cause radiation-induced inflammation of the parotid gland, and that proton RT, which distributes less off-target radiation, is a safer treatment alternative.

DEL-1 promotes macrophage efferocytosis and clearance of inflammation.

Resolution of inflammation is essential for tissue homeostasis and represents a promising approach to inflammatory disorders. Here we found that developmental endothelial locus-1 (DEL-1), a secreted protein that inhibits leukocyte-endothelial adhesion and inflammation initiation, also functions as a non-redundant downstream effector in inflammation clearance. In human and mouse periodontitis, waning of inflammation was correlated with DEL-1 upregulation, whereas resolution of experimental periodontitis failed in DEL-1 deficiency. This concept was mechanistically substantiated in acute monosodium-urate-crystal-induced inflammation, where the pro-resolution function of DEL-1 was attributed to effective apoptotic neutrophil clearance (efferocytosis). DEL-1-mediated efferocytosis induced liver X receptor-dependent macrophage reprogramming to a pro-resolving phenotype and was required for optimal production of at least certain specific pro-resolving mediators. Experiments in transgenic mice with cell-specific overexpression of DEL-1 linked its anti-leukocyte-recruitment action to endothelial cell-derived DEL-1 and its efferocytic/pro-resolving action to macrophage-derived DEL-1. Thus, the compartmentalized expression of DEL-1 facilitates distinct homeostatic functions in an appropriate context that can be harnessed therapeutically.

Surgical Alternatives for Treating Peri-implantitis.

The objective of this case series was to describe surgical approaches that can be used to efficiently and effectively treat peri-implantitis as measured by positive changes in clinical parameters. A total of 32 patients with 45 implants were treated surgically to eliminate peri-implantitis. Baseline clinical parameters measured prior to surgery were compared to those made 6 months postsurgery to evaluate the efficacy of each procedure. Implants demonstrating signs of peri-implantitis were treated by one of three approaches: (1) regenerative surgery, (2) osseous resective surgery, or (3) apically repositioned flap surgery. In all instances, the exposed implant surfaces were debrided and decontaminated. Relative to baseline values, regenerative surgery yielded statistically significant changes in probing depth (PD) (7.21 ± 0.27 mm to 4.09 ± 0.14 mm) and percentage of sites exhibiting bleeding on probing (BoP) (100.0% ± 0.0% to 10.6% ± 3.3%) as measured at the 6-month recall visit (P ≤ .05). The decrease in probing depth was not dependent on the type of graft material used (P ≤ .05). Resective surgery yielded statistically significant changes in PD (5.86 ± 0.23 mm to 3.63 ± 0.14 mm) and the percentage of sites exhibiting BoP (100.0% ± 0.0% to none) (P ≤ .05). Finally, the implants treated via apically repositioned flap surgery demonstrated statistically significant decreases (P ≤ .05) in both PD (6.79 ± 0.27 mm to 4.32 ± 0.16 mm) and BOP (100.0% ± 0.0% to 14.3% ± 6.7%) (P ≤ .05). Regenerative, resective, and apically positioned flap surgery can be utilized to successfully treat peri-implantitis.

Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later.

In their classic 1976 paper, Page & Schroeder described the histopathologic events and the types of myeloid cells and lymphocytes involved in the initiation and progression of inflammatory periodontal disease. The staging of periodontal disease pathogenesis as 'initial', 'early', 'established' and 'advanced' lesions productively guided subsequent research in the field and remains fundamentally valid. However, major advances regarding the cellular and molecular mechanisms underlying the induction, regulation and effector functions of immune and inflammatory responses necessitate a reassessment of their work and its integration with emerging new concepts. We now know that each type of leukocyte is actually represented by functionally distinct subsets with different, or even conflicting, roles in immunity and inflammation. Unexpectedly, neutrophils, traditionally regarded as merely antimicrobial effectors in acute conditions and protagonists of the 'initial' lesion, are currently appreciated for their functional versatility and critical roles in chronic inflammation. Moreover, an entirely new field of study, osteoimmunology, has emerged and sheds light on the impact of immunoinflammatory events on the skeletal system. These developments and the molecular dissection of crosstalk interactions between innate and adaptive leukocytes, as well as between the immune system and local homeostatic mechanisms, offer a more nuanced understanding of the host response in periodontitis, with profound implications for treatment. At the same time, deeper insights have generated new questions, many of which remain unanswered. In this review, 40 years after Page & Schroeder proposed their model, we summarize enduring and emerging advances in periodontal disease pathogenesis.

Differential Regulation of Mas-Related G Protein-Coupled Receptor X2-Mediated Mast Cell Degranulation by Antimicrobial Host Defense Peptides and Porphyromonas gingivalis Lipopolysaccharide.

Porphyromonas gingivalis is a keystone pathogen that contributes to periodontal pathogenesis by disrupting host-microbe homeostasis and promoting dysbiosis. The virulence of P. gingivalis likely reflects an alteration in the lipid A composition of its lipopolysaccharide (LPS) from the penta-acylated (PgLPS1690) to the tetra-acylated (PgLPS1435/1449) form. Mast cells play an important role in periodontitis, but the mechanisms of their activation and regulation remain unknown. The expression of epithelium- and neutrophil-derived host defense peptides (HDPs) (LL-37 and human ß-defensin-3), which activate mast cells via Mas-related G protein-coupled receptor X2 (MRGPRX2), is increased in periodontitis. We found that MRGPRX2-expressing mast cells are present in normal gingiva and that their numbers are elevated in patients with chronic periodontitis. Furthermore, HDPs stimulated degranulation in a human mast cell line (LAD2) and in RBL-2H3 cells stably expressing MRGPRX2 (RBL-MRGPRX2). PgLPS1690 caused substantial inhibition of HDP-induced mast cell degranulation, but PgLPS1435/1449 had no effect. A fluorescently labeled HDP (FAM-LL-37) bound to RBL-MRGPRX2 cells, and PgLPS1690 inhibited this binding, but PgLPS1435/1449 had no effect. These findings suggest that low-level inflammation induced by HDP/MRGPRX2-mediated mast cell degranulation contributes to gingival homeostasis but that sustained inflammation due to elevated levels of both HDPs and MRGPRX2-expressing mast cells promotes periodontal disease. Furthermore, differential regulation of HDP-induced mast cell degranulation by PgLPS1690 and PgLPS1435/1449 may contribute to the modulation of disease progression.

Radiologic Assessment of the Periodontal Patient.

Periodontal examination involves evaluation of soft and hard tissue parameters to gauge gingival inflammatory changes and quantify attachment loss. Conventional radiographs are vital components of this process and can be used to assess the presence of calculus and other local factors to establish a diagnosis, prognosis, and periodontal treatment plan. The 2-dimensional nature of these images limits their utility. The advent of high-resolution cone beam computed tomography (CBCT) offers 3-dimensional images that might overcome these limitations. We discuss the use of conventional radiographic techniques as well as CBCT for evaluating, diagnosing, and treatment planning patients presenting for periodontal and/or implant therapy.