An update on periodontal inflammation and bone loss.

Periodontal disease is a chronic inflammatory condition that affects the supporting structures of the teeth, including the periodontal ligament and alveolar bone. Periodontal disease is due to an immune response that stimulates gingivitis and periodontitis, and its systemic consequences. This immune response is triggered by bacteria and may be modulated by environmental conditions such as smoking or systemic disease. Recent advances in single cell RNA-seq (scRNA-seq) and in vivo animal studies have provided new insight into the immune response triggered by bacteria that causes periodontitis and gingivitis. Dysbiosis, which constitutes a change in the bacterial composition of the microbiome, is a key factor in the initiation and progression of periodontitis. The host immune response to dysbiosis involves the activation of various cell types, including keratinocytes, stromal cells, neutrophils, monocytes/macrophages, dendritic cells and several lymphocyte subsets, which release pro-inflammatory cytokines and chemokines. Periodontal disease has been implicated in contributing to the pathogenesis of several systemic conditions, including diabetes, rheumatoid arthritis, cardiovascular disease and Alzheimer's disease. Understanding the complex interplay between the oral microbiome and the host immune response is critical for the development of new therapeutic strategies for the prevention and treatment of periodontitis and its systemic consequences.

Toll-like receptor 4 deficiency affects the balance of osteoclastogenesis and osteoblastogenesis in periodontitis.

Toll-like receptor 4 (TLR4) acts as a double-edged sword in the occurrence and development of periodontitis. While the activation of TLR4 in macrophages aids in clearing local pathogens, it can also disrupt innate immune responses, upsetting microecological balance and accelerating the destruction of periodontal bone tissues. To date, the effects of TLR4 on osteogenesis and osteoclastogenesis in periodontitis have not been comprehensively studied. In this study, we investigated the development of periodontitis in the Tlr4-/- mice by ligating their second molars with silk threads. Compared to wild-type (WT) mice, Tlr4-/- mice demonstrated increased resistance to periodontitis-associated bone destruction, as evidenced by decreased bone resorption and enhanced bone regeneration. Mechanistically, the deletion of Tlr4 not only inhibited osteoclast formation by reducing the expression of NFATc1, CTSK and TRAP, but also enhanced osteogenic abilities through increased expression of OCN, OPN and RUNX2. In conclusion, TLR4 tips the balance of osteoclastogenesis and osteogenesis, thereby promoting periodontal bone destruction in periodontitis.

Type 17 immune response promotes oral epithelial cell proliferation in periodontitis.

OBJECTIVES: This study aims to investigate the effects of type 17 immune response on the proliferation of oral epithelial cells in periodontitis. DESIGN: A time-dependent ligature induced periodontitis mouse model was utilized to explore gingival hyperplasia and the infiltration of interleukin 17A (IL-17A) positive cells. Immunohistochemistry and flow cytometry were employed to determine the localization and expression of IL-17A in the ligature induced periodontitis model. A pre-existing single-cell RNA sequencing dataset, comparing individuals affected by periodontitis with healthy counterparts, was reanalyzed to evaluate IL-17A expression levels. We examined proliferation markers, including proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription (STAT3), Yes-associated protein (YAP), and c-JUN, in the gingival and tongue epithelium of the periodontitis model. An anti-IL-17A agent was administered daily to observe proliferative changes in the oral mucosa within the periodontitis model. Cell number quantification, immunofluorescence, and western blot analyses were performed to assess the proliferative responses of human normal oral keratinocytes to IL-17A treatment in vitro. RESULTS: The ligature induced periodontitis model exhibited a marked infiltration of IL-17A-positive cells, alongside significant increase in thickness of the gingival and tongue epithelium. IL-17A triggers the proliferation of human normal oral keratinocytes, accompanied by upregulation of PCNA, STAT3, YAP, and c-JUN. The administration of an anti-IL-17A agent attenuated the proliferation in oral mucosa. CONCLUSIONS: These findings indicate that type 17 immune response, in response to periodontitis, facilitates the proliferation of oral epithelial cells, thus highlighting its crucial role in maintaining the oral epithelial barrier.

Th17-to-Tfh plasticity during periodontitis limits disease pathology.

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.

IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

Nlrp3 inflammasome drives regulatory T cell depletion to accelerate periapical bone erosion.

AIM: Apical periodontitis is an inflammatory disorder triggered by an immune response to bacterial infection, leading to the periapical tissue damage and alveolar resorption. However, the underlying mechanisms driving this process remain elusive, due to the complex and interconnected immune microenvironment within the local lesion site. In this study, the influence of Nlrp3 inflammasome-mediated immune response on the apical periodontitis was investigated. METHODOLOGY: RNA sequencing, immunohistochemistry and ELISA assay were performed to investigate the activation of Nlrp3 inflammasome signalling pathways in the human periapical tissues, including radicular cysts, periapical granulomas and healthy oral mucosa. A mouse model of apical periodontitis was established to study the role of Nlrp3 knockout in periapical bone resorption and Treg cell stability, and the underlying mechanism was explored through in vitro experiments. In vivo Treg cell adoptive transfer was performed to investigate the effects of Treg cells on the progression of apical periodontitis. RESULTS: Our findings find that the hyperactivated Nlrp3 inflammasome is present in human periapical lesions and plays a vital role in the immune-related periapical bone loss. Using a mouse model of apical periodontitis, we observe that Nlrp3 deficiency is resistant to bone resorption. This protection was accompanied by elevated generation and infiltration of local Treg cells that displayed a notable ability to suppress RANKL-dependent osteoclast differentiation. In terms of the mechanism of action, Nlrp3 deficiency directly inhibits the osteoclast differentiation and bone loss through JNK/MAPK and NF-κB pathways. In addition, Nlrp3 induces pyroptosis in the stem cells from apical papilla (SCAPs), and the subsequent release of cytokines affects the stability of Treg cell in periapical lesions, leading indirectly to enhanced bone resorption. In turn, adoptive transfer of both Nlrp3-deficient and wild-type Treg cells effectively prevent the bone erosion during apical periodontitis. CONCLUSIONS: Together, our data identify that the Nlrp3 inflammasome modulates the Treg cell stability and osteoclastogenesis in the periapical inflammatory microenvironment, thus determining the progression of bone erosion.

MyD88 exacerbates inflammation-induced bone loss by modulating dynamic equilibrium between Th17/Treg cells and subgingival microbiota dysbiosis.

BACKGROUND: This study aimed to investigate the contribution of myeloid differentiation primary-response gene 88 (MyD88) on the differentiation of T helper type 17 (Th17) and regulatory T (Treg) cells and the emerging subgingival microbiota dysbiosis in Porphyromonas gingivalis-induced experimental periodontitis. METHODS: Alveolar bone loss, infiltrated inflammatory cells, immunostained cells for tartrate-resistant acid phosphatase (TRAP), the receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) were quantified by microcomputerized tomography and histological staining between age- and sex-matched homozygous littermates (wild-type [WT, Myd88+/+] and Myd88-/- on C57BL/6 background). The frequencies of Th17 and Treg cells in cervical lymph nodes (CLNs) and spleen were determined by flow cytometry. Cytokine expression in gingival tissues, CLNs, and spleens were studied by quantitative polymerase chain reaction (qPCR). Analysis of the composition of the subgingival microbiome and functional annotation of prokaryotic taxa (FAPROTAX) analysis were performed. RESULTS: P. gingivalis-infected Myd88-/- mice showed alleviated bone loss, TRAP+ osteoclasts, and RANKL/OPG ratio compared to WT mice. A significantly higher percentage of Foxp3+CD4+ T cells in infected Myd88-/- CLNs and a higher frequency of RORγt+CD4+ T cells in infected WT mice was noted. Increased IL-10 and IL-17a expressions in gingival tissue at D14-D28 then declined in WT mice, whereas an opposite pattern was observed in Myd88-/- mice. The Myd88-/- mice exhibited characteristic increases in gram-positive species and species having probiotic properties, while gram-negative, anaerobic species were noted in WT mice. FAPROTAX analysis revealed increased aerobic chemoheterotrophy in Myd88-/- mice, whereas anaerobic chemoheterotrophy was noted in WT mice after P. gingivalis infection. CONCLUSIONS: MyD88 plays an important role in inflammation-induced bone loss by modulating the dynamic equilibrium between Th17/Treg cells and dysbiosis in P. gingivalis-induced experimental periodontitis.

The Role of Cytokines Produced via the NLRP3 Inflammasome in Mouse Macrophages Stimulated with Dental Calculus in Osteoclastogenesis.

Dental calculus (DC) is a common deposit in periodontitis patients. We have previously shown that DC contains both microbial components and calcium phosphate crystals that induce an osteoclastogenic cytokine IL-1ß via the NLRP3 inflammasome in macrophages. In this study, we examined the effects of cytokines produced by mouse macrophages stimulated with DC on osteoclastogenesis. The culture supernatants from wild-type (WT) mouse macrophages stimulated with DC accelerated osteoclastogenesis in RANKL-primed mouse bone marrow macrophages (BMMs), but inhibited osteoclastogenesis in RANKL-primed RAW-D cells. WT, but not NLRP3-deficient, mouse macrophages stimulated with DC produced IL-1ß and IL-18 in a dose-dependent manner, indicating the NLRP3 inflammasome-dependent production of IL-1ß and IL-18. Both WT and NLRP3-deficient mouse macrophages stimulated with DC produced IL-10, indicating the NLRP3 inflammasome-independent production of IL-10. Recombinant IL-1ß accelerated osteoclastogenesis in both RANKL-primed BMMs and RAW-D cells, whereas recombinant IL-18 and IL-10 inhibited osteoclastogenesis. These results indicate that DC induces osteoclastogenic IL-1ß in an NLRP3 inflammasome-dependent manner and anti-osteogenic IL-18 and IL-10 dependently and independently of the NLRP3 inflammasome, respectively. DC may promote alveolar bone resorption via IL-1ß induction in periodontitis patients, but suppress resorption via IL-18 and IL-10 induction in some circumstances.

VISTA Blockade Aggravates Bone Loss in Experimental Murine Apical Periodontitis.

V-domain Ig suppressor of T cell activation (VISTA) is a novel coinhibitory immune checkpoint molecule that maintains immune homeostasis. The present study explored the role of VISTA in human and murine inflammatory tissues of apical periodontitis (AP). VISTA was upregulated in inflammatory tissues of human AP. In mice, the expression of VISTA gradually increased with the development of mouse experimental apical periodontitis (MAP), the CD3+ T cells, CD11b+ myeloid cells, and FOXP3+ regulatory T cells also gradually accumulated. Moreover, a blockade of VISTA using a mouse in vivo anti-VISTA antibody aggravated periapical bone loss and enhanced the infiltration of immune cells in an experimental mouse periapical periodontitis model. The collective results suggest that VISTA serves as a negative regulator of the development and bone loss of apical periodontitis.

HIF-1α activator DMOG inhibits alveolar bone resorption in murine periodontitis by regulating macrophage polarization.

Periodontitis is initiated by serious and sustained bacterial infection and ultimately results in chronic immune-mediated inflammation, tissue destruction, and bone loss. The pathogenesis of periodontitis remains unclear. Host immunological responses to periodontal bacteria ultimately determine the severity and mechanisms governing periodontitis progression. This study aimed to clarify the effect of the hypoxia-inducible factor-1α (HIF-1α) activator dimethyloxalylglycine (DMOG) on a mouse periodontitis model and its underlying role in macrophage polarization. qRT-PCR analysis showed that DMOG inhibited the M1-like polarization of both RAW264.7 macrophages and murine bone marrow macrophages (BMMs) and downregulated TNF-α, IL-6, CD86, and MCP-1 expression in vitro. Immunofluorescence staining and flow cytometry also confirmed the less percentage of F4/80 + CD86 + cells after DMOG treatment. The phosphorylation of NF-κB pathway was also inhibited by DMOG with higher level of HIF-1α expression. Furthermore, mice treated with DMOG showed decreased alveolar bone resorption in the experimental periodontitis model, with significant increases in alveolar bone volume/tissue volume (BV/TV) and bone mineral density (BMD). DMOG treatment of mice decreased the ratio of M1/M2 (CD86+/CD206+) macrophages in periodontal tissues, resulting in the downregulation of proinflammatory cytokines such as TNF-α and IL-6 and increased levels of anti-inflammatory factors such as IL-4 and IL-10. DMOG treatment promoted the number of HIF-1α-positive cells in periodontal tissues. This study demonstrated the cell-specific roles of DMOG in macrophage polarization in vitro and provided insight into the mechanism underlying the protective effect of DMOG in a model of periodontitis.

Calprotectin (S100A8/A9) Is an Innate Immune Effector in Experimental Periodontitis.

Upregulated in inflammation, calprotectin (complexed S100A8 and S100A9; S100A8/A9) functions as an innate immune effector molecule, promoting inflammation, and also as an antimicrobial protein. We hypothesized that antimicrobial S100A8/A9 would mitigate change to the local microbial community and promote resistance to experimental periodontitis in vivo. To test this hypothesis, S100A9-/- and wild-type (WT; S100A9+/+) C57BL/6 mice were compared using a model of ligature-induced periodontitis. On day 2, WT mice showed fewer infiltrating innate immune cells than S100A9-/- mice; by day 5, the immune cell numbers were similar. At 5 days post ligature placement, oral microbial communities sampled with swabs differed significantly in beta diversity between the mouse genotypes. Ligatures recovered from molar teeth of S100A9-/- and WT mice contained significantly dissimilar microbial genera from each other and the overall oral communities from swabs. Concomitantly, the S100A9-/- mice had significantly greater alveolar bone loss than WT mice around molar teeth in ligated sites. When the oral microflora was ablated by antibiotic pretreatment, differences disappeared between WT and S100A9-/- mice in their immune cell infiltrates and alveolar bone loss. Calprotectin, therefore, suppresses emergence of a dysbiotic, proinflammatory oral microbial community, which reduces innate immune effector activity, including early recruitment of innate immune cells, mitigating subsequent alveolar bone loss and protecting against experimental periodontitis.

Inflammasomes in Alveolar Bone Loss.

Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast-osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

Local Sustained Delivery of Anti-IL-17A Antibodies Limits Inflammatory Bone Loss in Murine Experimental Periodontitis.

Periodontal disease (PD) is a chronic destructive inflammatory disease of the tooth-supporting structures that leads to tooth loss at its advanced stages. Although the disease is initiated by a complex organization of oral microorganisms in the form of a plaque biofilm, it is the uncontrolled immune response to periodontal pathogens that fuels periodontal tissue destruction. IL-17A has been identified as a key cytokine in the pathogenesis of PD. Despite its well documented role in host defense against invading pathogens at oral barrier sites, IL-17A-mediated signaling can also lead to a detrimental inflammatory response, causing periodontal bone destruction. In this study, we developed a local sustained delivery system that restrains IL-17A hyperactivity in periodontal tissues by incorporating neutralizing anti-IL-17A Abs in poly(lactic-coglycolic) acid microparticles (MP). This formulation allowed for controlled release of anti-IL-17A in the periodontium of mice with ligature-induced PD. Local delivery of anti-IL-17A MP after murine PD induction inhibited alveolar bone loss and osteoclastic activity. The anti-IL-17A MP formulation also decreased expression of IL-6, an IL-17A target gene known to induce bone resorption in periodontal tissues. This study demonstrates proof of concept that local and sustained release of IL-17A Abs constitutes a promising therapeutic strategy for PD and may be applicable to other osteolytic bone diseases mediated by IL-17A-driven inflammation.

Influence of the shared epitope on the elicitation of experimental autoimmune arthritis biomarkers.

Our previous studies have shown that inoculation of the oral cavity of "humanized" B6.DR1/4 mice with the periodontal pathogen Porphyromonas gingivalis results in an increase in the percentage of circulating Th17 cells, loss of bone and an exacerbation of experimental autoimmune arthritis. The aim of this study was to assess the role played by the human HLA-DRß molecule containing the shared epitope supplied as a transgene to I-A˚ (murine class II null) C57BL/6 (B6) mice in driving these findings. We compared various immune response parameters as well as alveolar and peri-articular bone loss between humanized B6.DR1 (or B6.DR4) mice and their WT (B6) counterparts. We found that the presence of the shared epitope in the context of inoculation with P. gingivalis enhanced the percentage of Th17 cells generated, dramatically enhanced bone loss and importantly allowed for the generation of CCP2⁺ ACPAs that are not found in C57BL/6 or DBA/1 arthritic mouse serum. Due to the exceedingly complex nature of environmental factors impacting on genetic elements, it has been difficult to unravel mechanisms that drive autoimmune arthritis in susceptible individuals. The findings in this study may provide one small piece of this puzzle that can help us to better understand part of this complexity.

Impaired salivary SIgA antibodies elicit oral dysbiosis and subsequent induction of alveolar bone loss.

OBJECTIVE: Secreted IgA (SIgA) plays a central role in preventing bacterial and viral infections on mucosal surfaces by neutralizing toxins and viruses and inhibiting bacterial attachment to epithelial cells. However, the role of salivary SIgA antibodies (Abs) in regulating oral flora is still unknown. This study aimed to evaluate the association among oral bacteria, their metabolites and periodontitis in IgA-deficient (IgA KO) and wild-type (WT) control mice. METHODS: Microcomputed tomography (micro-CT) analysis was used to assess alveolar bone resorption as a development of periodontitis. The bacterial profiles of saliva were determined using the next-generation sequencing assays. Furthermore, the metabolites in saliva were measured and compared using CE-TOFMS. RESULTS: Salivary microbiota of IgA KO mice revealed a remarkably decreased frequency of Streptococcus, and increased percentages of Aggregatibacer, Actinobacillus, and Prevotella at the genus level when compared with those of WT. Compared to WT control mice of the same age, the level of alveolar bone loss was significantly increased in IgA KO mice, and infiltration of osteoclasts was found on the surface of the alveolar bone. The metabolome profile indicated that the metabolites of IgA KO mice had greater variability in carbon metabolic, urea cycle, and lipid pathways than WT mice. CONCLUSION: These results suggest that salivary SIgA plays an important role in regulating and maintaining normal oral microflora to prevent the development of periodontal disease.

Reliability assessment between clinical attachment loss and alveolar bone level in dental radiographs.

BACKGROUND: The clinical attachment level (CAL) and radiographically assessed bone levels are used to assess the loss of periodontal tissue support in periodontitis, a chronic, multifactorial inflammatory disease of the periodontium. However, few studies have been done to study the relationship between these two parameters. According to our knowledge, this is the first study investigating the relationship between the two measurements using intraclass correlation analysis. AIM: The aim of the study is to investigate the relationship between CAL and radiographically assessed bone level in teeth affected with periodontitis. METHODS: A retrospective cross-sectional study was conducted by selecting a sample of 880 periodontal sites in 104 periodontitis patients, aged 25-60 years. CAL and peri-apical radiographs of the selected sites were obtained from the computerized patient records. The distance from the cemento-enamel junction (CEJ) to the base of the alveolar bone level (ABL) was measured. The data was analyzed using SPSS. RESULTS: Intraclass correlation analysis (ICC) revealed a moderate degree of reliability between CAL and CEJ to ABL measurements. The average ICC was 0.68 with a 95% confidence interval of 0.53-0.77 (p < .001) indicating moderate to good reliability. Comparing the types of teeth, the central incisors, particularly the lower central incisors showed the highest ICC values (ICC: 0.822, CI: 0.77-0.86) indicating good reliability while the premolar and molars showed poor to moderate agreement (Maxillary premolars ICC: 0.464, CI: -0.18-0.74; maxillary first molar ICC: 0.516, CI: -0.154-0.772; mandibular first premolar ICC: 0.662, CI: 0.269-0.782; mandibular first molar ICC: 0.625, CI: 0.31-0.82). A moderate correlation existed between the radiographic and the clinical assessments (r = 0.5, p < .001). CONCLUSION: Despite the fact that significant varying levels of reliability has been found between CAL and radiographic bone level, both the clinical and radiographic examinations should be performed for the accuracy of diagnosis.

Toll-Like Receptor Signaling and Immune Regulatory Lymphocytes in Periodontal Disease.

Periodontitis is known to be initiated by periodontal microbiota derived from biofilm formation. The microbial dysbiotic changes in the biofilm trigger the host immune and inflammatory responses that can be both beneficial for the protection of the host from infection, and detrimental to the host, causing tissue destruction. During this process, recognition of Pathogen-Associated Molecular Patterns (PAMPs) by the host Pattern Recognition Receptors (PRRs) such as Toll-like receptors (TLRs) play an essential role in the host-microbe interaction and the subsequent innate as well as adaptive responses. If persistent, the adverse interaction triggered by the host immune response to the microorganisms associated with periodontal biofilms is a direct cause of periodontal inflammation and bone loss. A large number of T and B lymphocytes are infiltrated in the diseased gingival tissues, which can secrete inflammatory mediators and activate the osteolytic pathways, promoting periodontal inflammation and bone resorption. On the other hand, there is evidence showing that immune regulatory T and B cells are present in the diseased tissue and can be induced for the enhancement of their anti-inflammatory effects. Changes and distribution of the T/B lymphocytes phenotype seem to be a key determinant of the periodontal disease outcome, as the functional activities of these cells not only shape up the overall immune response pattern, but may directly regulate the osteoimmunological balance. Therefore, interventional strategies targeting TLR signaling and immune regulatory T/B cells may be a promising approach to rebalance the immune response and alleviate bone loss in periodontal disease. In this review, we will examine the etiological role of TLR signaling and immune cell osteoclastogenic activity in the pathogenesis of periodontitis. More importantly, the protective effects of immune regulatory lymphocytes, particularly the activation and functional role of IL-10 expressing regulatory B cells, will be discussed.

The Interrelationship Between Diabetes, IL-17 and Bone Loss.

PURPOSE OF REVIEW: Diabetes has a detrimental effect on bone, increasing the risk of fracture and formation of osteolytic lesions such as those seen in periodontitis. Several diabetic complications are caused by diabetes-enhanced inflammation. This review examines mechanisms by which IL-17 contributes to diabetes-enhanced periodontitis and other effects of IL-17 on bone. RECENT FINDINGS: IL-17 upregulates anti-bacterial defenses, yet its expression is also linked to a destructive host response in the periodontium. Periodontal disease is caused by bacteria that stimulate an inflammatory response. Diabetes-enhanced IL-17 increases gingival inflammation, which alters the composition of the oral microbiota to increase its pathogenicity. In addition, IL-17 can induce osteoclastogenesis by upregulation of TNF and RANKL in a number of cell types, and IL-17 has differential effects on osteoblasts and their progenitors. Increased IL-17 production caused by diabetes alters the pathogenicity of the oral microbiota and can promote periodontal bone resorption.

Distal Consequences of Oral Inflammation.

Periodontitis is an incredibly prevalent chronic inflammatory disease, which results in the destruction of tooth supporting structures. However, in addition to causing tooth and alveolar bone loss, this oral inflammatory disease has been shown to contribute to disease states and inflammatory pathology at sites distant from the oral cavity. Epidemiological and experimental studies have linked periodontitis to the development and/or exacerbation of a plethora of other chronic diseases ranging from rheumatoid arthritis to Alzheimer's disease. Such studies highlight how the inflammatory status of the oral cavity can have a profound impact on systemic health. In this review we discuss the disease states impacted by periodontitis and explore potential mechanisms whereby oral inflammation could promote loss of homeostasis at distant sites.

[Research progress in secreting sytokines interferon-gamma and interleukin-17 of T helper 1 and 17 cells on periodontitis].

Periodontal disease (PD) is an infection-driven chronic inflammatory disease characterized by the inflammation of tooth-supporting tissues and the destruction of the associated alveolar bone. The immune response of the host to periodontal pathogens infection determines the course and progress of the disease. The effects of secreting cytokines interferon-gamma (IFN-γ) and interleukin-17 (IL-17) of T helper 1 cells (Th1) and T helper 17 cells (Th17) on the development of periodontitis has attracted much attention. IFN-γ is a potential immune-modulatory cytokine and can mediate cellular immune responses by activating various immune cells of the host such as macrophages. As one of the most potential bone physiological regulation mediators, IL-17 is closely related with alveolar bone resorption in periodontitis. This review elaborated the relationship between IFN-γ and IL-17 in the progress of periodontitis, providing new explanations into the development of periodontitis and alveolar bone destruction caused by the host immune response.