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The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized bone, but also dentine, cementum and enamel of our teeth. These are exposed to intense mechanical and chemical stress as well as to dense microbiologic colonization. Teeth are susceptible to damage, most commonly to caries, where microorganisms from the oral cavity degrade the mineralized tissues of enamel and dentine and invade the soft connective tissue at the core, the dental pulp. However, the pulp is well-equipped to sense and fend off bacteria and their products and mounts various and intricate defense mechanisms. The front rank is formed by a layer of odontoblasts, which line the pulp chamber towards the dentine. These highly specialized cells not only form mineralized tissue but exert important functions as barrier cells. They recognize pathogens early in the process, secrete antibacterial compounds and neutralize bacterial toxins, initiate the immune response and alert other key players of the host defense. As bacteria get closer to the pulp, additional cell types of the pulp, including fibroblasts, stem and immune cells, but also vascular and neuronal networks, contribute with a variety of distinct defense mechanisms, and inflammatory response mechanisms are critical for tissue homeostasis. Still, without therapeutic intervention, a deep carious lesion may lead to tissue necrosis, which allows bacteria to populate the root canal system and invade the periradicular bone via the apical foramen at the root tip. The periodontal tissues and alveolar bone react to the insult with an inflammatory response, most commonly by the formation of an apical granuloma. Healing can occur after pathogen removal, which is achieved by disinfection and obturation of the pulp space by root canal treatment. This review highlights the various mechanisms of pathogen recognition and defense of dental pulp cells and periradicular tissues, explains the different cell types involved in the immune response and discusses the mechanisms of healing and repair, pointing out the close links between inflammation and regeneration as well as between inflammation and potential malignant transformation.

This study was designed to explore the relative expression of DNA methylation machinery genes in periapical granuloma and to assess longitudinal changes in gene expression within the healing group at 6 and 12 months. A total of twenty-seven patients (13 chronic apical periodontitis and 14 chronic apical abscess) underwent surgical endodontic treatment. During surgical endodontic treatment, periapical lesion tissue was collected and used for relative expression analysis of the following DNA methylation machinery genes: DNMT-1 , TDG , TET-1 , TET-2 , and TET-3 . These patients were subsequently re-appointed after 6 and 12 months for the evaluation of the periapical healing based on the established clinical and radiographic criteria. Quantitative PCR (qPCR) was employed for gene-expression analysis. Statistical analysis was performed using unpaired t-tests and a p- value < 0.05 was considered statistically significant. Post-operative healing was observed in 21 out of 27 patients (77.8%) after 12 months, whereas 6 patients (22.3%) showed no signs of healing at the end of the follow-up period. A statistically significant difference was observed in the expression of the TET-3 genes in chronic apical abscess. Moreover, TDG , TET-2 , and TET-3 exhibited a positive fold change in healed chronic apical abscess samples (H + 12 M and H + 6 M) compared to non-healed (NH) samples. The significant differences in the expression of TET-3 gene, may suggest their potential role as epigenetic markers warranting further validation.

Periapical abscesses, radicular cysts, and periapical granulomas are the most frequently identified pathological lesions in the alveolar bone. While little is known about the initiation and progression of these conditions, the metabolic environment and the related immunological behaviors were examined for the first time to model the development of each pathological condition. Metabolites were extracted from each lesion and profiled using gas chromatography-mass spectrometry in comparison with healthy pulp tissue. The metabolites were clustered and linked to their related immune cell fractions. Clusters I and J in the periapical abscess upregulated the expression of MMP-9, IL-8, CYP4F3, and VEGF, while clusters L and M were related to lipophagy and apoptosis in radicular cyst, and cluster P in periapical granuloma, which contains L-(+)-lactic acid and ethylene glycol, was related to granuloma formation. Oleic acid, 17-octadecynoic acid, 1-nonadecene, and L-(+)-lactic acid were significantly the highest unique metabolites in healthy pulp tissue, periapical abscess, radicular cyst, and periapical granuloma, respectively. The correlated enriched metabolic pathways were identified, and the related active genes were predicted. Glutamatergic synapse (16–20),-hydroxyeicosatetraenoic acids, lipophagy, and retinoid X receptor coupled with vitamin D receptor were the most significantly enriched pathways in healthy control, abscess, cyst, and granuloma, respectively. Compared with the healthy control, significant upregulation in the gene expression of CYP4F3 , VEGF , IL-8 , TLR2 ( P  < 0.0001), and MMP-9 ( P  < 0.001) was found in the abscesses. While IL-12A was significantly upregulated in cysts ( P  < 0.01), IL-17A represents the highest significantly upregulated gene in granulomas ( P  < 0.0001). From the predicted active genes, CIBERSORT suggested the presence of natural killer cells, dendritic cells, pro-inflammatory M1 macrophages, and anti-inflammatory M2 macrophages in different proportions. In addition, the single nucleotide polymorphisms related to IL-10 , IL-12A , and IL-17D genes were shown to be associated with periapical lesions and other oral lesions. Collectively, the unique metabolism and related immune response shape up an environment that initiates and maintains the existence and progression of these oral lesions, suggesting an important role in diagnosis and effective targeted therapy.

Periapical granulomas are lesions around the apex of a tooth caused by a polymicrobial infection. Treatment with antibacterial agents is normally performed to eliminate bacteria from root canals; however, loss of the supporting alveolar bone is typically observed, and tooth extraction is often selected if root canal treatment does not work well. Therefore, bacteria and other microorganisms could be involved in this disease. To understand the pathogenesis of periapical granulomas more precisely, we focused on the association with Epstein-Barr virus (EBV) using surgically removed periapical granulomas (n = 32). EBV DNA was detected in 25 of 32 periapical granulomas (78.1%) by real-time PCR, and the median number of EBV DNA copies was approximately 8,688.01/μg total DNA. In contrast, EBV DNA was not detected in healthy gingival tissues (n = 10); the difference was statistically significant according to the Mann-Whitney U test (p = 0.0001). Paraffin sections were also analyzed by in situ hybridization to detect EBV-encoded small RNA (EBER)-expressing cells. EBER was detected in the cytoplasm and nuclei of B cells and plasma cells in six of nine periapical granulomas, but not in healthy gingival tissues. In addition, immunohistochemical analysis for latent membrane protein 1 (LMP-1) of EBV using serial tissue sections showed that LMP-1-expressing cells were localized to the same areas as EBER-expressing cells. These data suggest that B cells and plasma cells in inflamed granulomas are a major source of EBV infection, and that EBV could play a pivotal role in controlling immune cell responses in periapical granulomas.

Background Various inflammatory and anti-inflammatory mediators, along with diverse cell types, are implicated in the development and progression of periapical lesions. This work aimed to assess the immuno-expression of transforming growth factor-beta 1 (TGF-β1) and CD68 (a macrophage marker), elucidating their roles and potential correlations. Additionally, histological analysis was conducted to evaluate the intensity of inflammatory infiltrates in chronic periapical lesion samples. Methods Tissue samples from fifty individuals with chronic periapical lesions [25 radicular cysts (RCs) and 25 periapical granulomas (PGs)] were obtained, along with control samples from four healthy third molars’ dental pulp. Histological examination and inflammatory infiltrate categorization were performed. Immunohistochemical analysis of TGF-β1 and CD68 markers, along with morphometric assessment, were conducted. Results The control group displayed normal, inflammation-free pulp tissues, while intense inflammation was observed in PGs and RCs (Score 4 and 3, respectively) dominated by macrophages, plasma cells, and lymphocytes. Immunohistochemistry showed higher TGF-β1 and CD68 expression in PGs and RCs versus control ( P  < 0.001). Moreover, PGs exhibited greater TGF-β1 and CD68 expression than RCs ( P  < 0.001). However, a negative relationship was detected between the 2 markers ( P  < 0.05). Conclusions This study highlighted varying expressions of TGF-β1 and CD68 in PGs and RCs, indicating their potential roles in lesion pathology. However, a negative correlation between these markers was observed. Accordingly, their precise role in periapical lesion progression and repair requires further investigation.

Inflammatory radicular cysts (IRCs) are chronic lesions that follow the development of periapical granulomas (PGs). IRCs result from multiple inflammatory reactions led initially by several pro-inflammatory interleukins and growth factors that provoke the proliferation of epithelial cells derived from epithelial cell rests of Malassez present in the granulomatous tissue, followed by cyst formation and growth processes. Multipletheories have been proposed to help explain the molecular process involved in the development of the IRC from a PG. However, although multiple studies have demonstrated the presence of epithelial cells in most PGs, it is still not fully understood why not all PGs turn into IRCs, even though both are stages of the same inflammatory phenomenon and receive the same antigenic stimulus. Histopathological examination is currently the diagnostic gold standard for differentiating IRCs from PGs. Although multiple studies have evaluated the accuracy of non-invasive or minimally invasive methods in assessing the histopathological nature of the AP before the intervention, these studies' results are still controversial. This narrative review addresses the biological insights into the complex molecular mechanisms of IRC formation and its histopathological features. In addition, the relevant inflammatory molecular mediators for IRC development and the accuracy of non-invasive or minimally invasive diagnostic approaches are summarised. (EEJ-2022-03-041)

Objectives T lymphocytes (T cells) are crucial important types of immune cells which are responsible for adaptive immune response during the progression of bacterial infectious diseases. Different subtypes of T cells can participate in regulating the progress of human periapical lesions. This study investigates the co-localization of different types of T cells by multiplex immunofluorescence staining (mIHC) from different types of human periapical lesions (PLs) which might elucidate the potential clinical relevance of T cell infiltration with PLs. Materials and methods 20 PLs tissues and 6 healthy samples from healthy periodontal ligament tissues were collected for subsequent experiments. Histological examination and immunohistochemical analysis were performed using hematoxylin-eosin (H&E) staining, immunohistochemical staining (IHC) and mIHC. Data analysis involved quantifying the number of positive cells of CD3, CD4, GATA3, Tbet and Foxp3 using QuPath software. In addition, the co-localization of CD4, GATA3, Tbet and Foxp3 was also assessed. Results Radicular cysts (RCs) ( n  = 10) and periapical granulomas (PGs) ( n  = 10) were identified by histological evaluation. The number of CD3 + cells in RCs was significantly higher compared to PGs and healthy controls. Additionally, the infiltration numbers of CD3, CD4, GATA3, T-bet and Foxp3 cells were greater in RCs than in PGs. Conclusions This study demonstrates the different expression levels of T cells in PLs and indicates the distinct inflammatory states between the two types of PLs.

S100A4 expression is associated with the pathology of chronic inflammatory diseases. In this study, we investigated the role of S100A4 and four inflammatory mediators (IL-1β, IκB, IL-10, and TNF-α) in human periapical granulomas (PGs). S100A4 expression in PGs obtained by apicoectomy was examined by immunohistochemistry. Further, the expression of S100A4 and four inflammatory mediators was compared between PGs and healthy gingival tissues (HGTs) using real-time PCR. In the PGs, S100A4 was found to be expressed in endothelial cells and fibroblasts. Furthermore, real-time PCR revealed that the expression of S100A4 and IL-1β in PGs was significantly higher than that in HGTs. Although a correlation between the expression of S100A4 and IκB or IL-10 was not detected, a positive correlation between the expression of S100A4 and IL-1β or TNF-α was observed. The expression of S100A4 correlates with the pathogenesis of PGs.

Background Matrix metalloproteinases (MMPs) catalyzes the degradation of the extracellular matrix components and have a major role in many physiological processes including wound healing. In the current study, we examined the correlation of baseline MMPs 1, 2, 7, and 9 expressions with periapical wound healing after surgical endodontic treatment. Methods 27 patients aged between 15 and 57 years presenting with chronic apical periodontitis or chronic apical abscess of an anterior tooth with previously attempted or failed root canal treatment were included in this study. During surgical endodontic treatment, tissue from the periapical lesion sample was collected and used for gross histopathological analysis as well as mRNA expression analysis of MMPs 1, 2, 7, and 9. Patients were recalled for follow-up after 6  months to evaluate the healing status both clinically and radiographically and healing was correlated with baseline MMP expression. Results Out of 27 patients, healing was observed in 15 patients at the end of 6 months, and in 21 patients after 12 months.. Six patients showed no healing even after 12 months. Analysis of baseline MMP 1, 2, 7, and 9 expression levels with healing status showed the mean relative expression of MMP2 and MMP9 to be considerably increased in the non-healing group as compared to the healing group. Conclusion Overexpression of MMP2 and MMP9 may be considered as a potential prognostic biomarker for periapical wound healing after surgical endodontic treatment. However, further studies are desirable to establish its precise relationship with periapical wound healing.

Background ZEB1, a zinc-finger E homeobox-binding transcription factor most frequently associated with developmental programs linked to epithelial-mesenchymal transition, has been demonstrated to regulate immune cell function. The study aimed to investigate the expression pattern of ZEB1 in Th17 cells and its colocalization with p-STAT3 in human apical periodontitis lesions. Methods Thirty-nine human periapical tissues were collected for ex vivo study, including periapical granulomas (PGs, n  = 14), radicular cysts (RCs, n  = 12), and healthy control tissues (control group, n  = 13). Inflammatory infiltration of the lesions was assessed using hematoxylin-eosin staining. The expression of ZEB1 was detected and analyzed by immunohistochemistry. The localization of ZEB1 in Th17 cells and its colocalization with p-STAT3 were assessed using fluorescence colocalization. Results ZEB1 expression was significantly higher in PGs and RCs than in the healthy control group; however no significant difference between the two groups was observed. Immunofluorescence analysis revealed that ZEB1 expression was correlated with IL17 and CD4 double-positive cells in human periapical lesions. ZEB1/ p-STAT3 double-positive cells were predominant in RCs and PGs than in the healthy control group. Conclusions The expression of ZEB1 was significantly elevated in PGs and RCs, and correlated with Th17 cells and p-STAT3 expression. This study revealed that ZEB1 is a potential player correlated with STAT3 activation and Th17 cells in apical periodontitis pathogenesis.