Oral Mucosal Barrier Research Articles

Non-canonical IL-22 receptor signaling remodels the mucosal barrier during fungal immunosurveillance.

Mucosal barrier integrity is vital for homeostasis with commensal organisms while preventing pathogen invasion. We unexpectedly found that fungal-induced immunosurveillance enhances resistance to fungal outgrowth and tissue invasion by remodeling the oral mucosal epithelial barrier in mouse models of adult and neonatal Candida albicans colonization. Epithelial subset expansion and tissue remodeling were dependent on interleukin-22 (IL-22) and signal transducer and activator of transcription 3 (STAT3) signaling, through a non-canonical receptor complex composed of glycoprotein 130 (gp130) coupled with IL-22RA1 and IL-10RB. Immunosurveillance-induced epithelial remodeling was restricted to the oral mucosa, whereas barrier architecture was reset once fungal-specific immunity developed. Collectively, these findings identify fungal-induced transient mucosal remodeling as a critical determinant of resistance to mucosal fungal infection during early stages of microbial colonization.

Early intervention with oral mucosal barrier Protective agents in chronic oral graft-versus-host disease: a retrospective cohort study

BackgroundPreventing the progression of chronic oral graft-versus-host disease (cGVHD) is essential for maintaining oral health, improving quality of life, minimizing functional impairment, reducing systemic complications, and addressing treatment challenges.PurposeTo evaluate the effectiveness of early intervention with oral mucosal barrier protective agents in preventing the progression of cGVHD and its impact on oral health, quality of life, and treatment response.MethodsThis retrospective cohort study included 75 participants, with 34 in the non-oral mucosal barrier protective agent group and 41 in the oral mucosal barrier protective agent group. Baseline characteristics, oral mucosal health parameters, quality of life assessments, and curative effect data were collected and compared between the two study groups.ResultsThe group receiving oral mucosal barrier protectants (n = 41) exhibited significantly lower severity of oral mucositis compared to the group without such protectants (n = 34) (2.12 ± 0.48 vs. 2.56 ± 0.63, P = 0.001) and the incidence of complications was significantly lower in the group receiving oral mucosal barrier protectants (P < 0.05). Additionally, the quality of life assessment showed marked improvements in somatization, emotional management, and social reintegration in the oral mucosal barrier protectant group compared to the group without these protectants (P < 0.05). Furthermore, the assessment of treatment efficacy revealed significantly higher rates of both complete and partial responses in the oral mucosal barrier protectant group, along with a notable reduction in disease progression compared to the group without these protectants (P < 0.001).ConclusionEarly intervention with oral mucosal barrier protective agents was associated with improved oral health parameters, enhanced quality of life, and a more favorable treatment response in the context of cGVHD.

Gut microbial dysbiosis and inflammation: Impact on periodontal health.

Periodontitis is widely acknowledged as the most prevalent type of oral inflammation, arising from the dynamic interplay between oral pathogens and the host's immune responses. It is also recognized as a contributing factor to various systemic diseases. Dysbiosis of the oral microbiota can significantly alter the composition and diversity of the gut microbiota. Researchers have delved into the links between periodontitis and systemic diseases through the "oral-gut" axis. However, whether the associations between periodontitis and the gut microbiota are simply correlative or driven by causative mechanistic interactions remains uncertain. This review investigates how dysbiosis of the gut microbiota impacts periodontitis, drawing on existing preclinical and clinical data. This study highlights potential mechanisms of this interaction, including alterations in subgingival microbiota, oral mucosal barrier function, neutrophil activity, and abnormal T-cell recycling, and offers new perspectives for managing periodontitis, especially in cases linked to systemic diseases.

PDE12 disrupts mitochondrial oxidative phosphorylation and mediates mitochondrial dysfunction to induce oral mucosal epithelial barrier damage in oral submucous fibrosis

Oral submucous fibrosis (OSF) is a chronic oral mucosal disease. The pathological changes of OSF include epithelial damage and subepithelial matrix fibrosis. This study aimed to reveal the epithelial injury mechanism of OSF. A histopathological method was used to analyze oral mucosal tissue from OSF patients and OSF rats. The expression of PDE12 in the oral epithelium was analyzed by immunohistochemistry. The epithelial–mesenchymal transition (EMT) and tight junction proteins in arecoline-treated HOKs were explored by western blotting. Epithelial leakage was assessed by transepithelial electrical resistance and lucifer yellow permeability. The expression of PDE12 and the mitochondrial morphology, mitochondrial permeability transition pore opening, mitochondrial membrane potential, and mitochondrial reactive oxygen species (mtROS) were evaluated in arecoline-induced HOKs. Oxidative phosphorylation (OXPHOS) complexes and ATP content were also explored in HOKs. The results showed significant overexpression of PDE12 in oral mucosal tissue from OSF patients and rats. PDE12 was also overexpressed and aggregated in mitochondria in arecoline-induced HOKs, resulting in dysfunction of OXPHOS and impaired mitochondrial function. An EMT, disruption of tight junctions with epithelial leakage, and extracellular matrix remodeling were also observed. PDE12 overexpression induced by PDE12 plasmid transfection enhanced the mtROS level and interfered with occludin protein localization in HOKs. Interestingly, knockdown of PDE12 clearly ameliorated arecoline-induced mitochondrial dysfunction and epithelial barrier dysfunction in HOKs. Therefore, we concluded that overexpression of PDE12 impaired mitochondrial OXPHOS and mitochondrial function and subsequently impaired epithelial barrier function, ultimately leading to OSF. We suggest that PDE12 may be a new potential target against OSF.

Lidocaine-loaded dissolving microneedle for safe local anesthesia on oral mucosa for dental procedure

ABSTRACT Background Lidocaine has been widely used as a short-acting local anesthetic agent to reduce the pain caused by needle insertion. Dissolving microneedles (DMNs), which are minimally invasive, can effectively deliver drugs by overcoming the oral mucosal barrier and relieving patient discomfort. Methods Lidocaine solution prepared by mixing lidocaine-HCl and hyaluronic acid was used to fabricate oral lidocaine HCl-encapsulated DMNs (oral Li-DMNs) via centrifugal lithography. The dissolution, penetration ability, and local transmucosal drug delivery of oral Li-DMNs into the oral mucosa were evaluated in porcine jaws. Pharmacokinetic analysis and safety assessment were performed using rabbits. Results The insertion depth of the oral Li-DMNs satisfies the safety standard. The oral Li-DMNs were completely dissolved after 3 min of application. The local transmucosal drug delivery, pharmacokinetic, and safety evaluations showed that the oral Li-DMNs can obtain a local anesthesia effect at a relatively lower dose, and there was no oral mucosal irritation in rabbits. Conclusions A novel and safe oral Li-DMNs have potential applications in large animals and clinical trials and would possibly enter the anesthesia market.

Research progress on prevention and local intervention of oral mucositis in patients with hematopoietic stem cell transplantation

Oral mucositis (OM) is a common complication during hematopoietic stem cell transplantation. When OM occurs, with the destruction of oral mucosal barrier function, the formation of oral bacterial environment is accelerated, which has a negative impact on the life quality and clinical outcomes of patients. OM can be prevented by keeping the oral cavity clean, using the mouthwash properly, and limiting the delivery of cytotoxic drugs to oral tissues. This review describes the research progress on the prevention and local intervention of OM in patients with hematopoietic stem cell transplantation, in order to provide ideas for the selection of clinical intervention and management strategies on OM, and to provide references for exploring effective management methods for OM.

MUC5B Alters Oral Mucosa of Oral Lichen Planus Patients with Xerostomia

Oral Lichen planus（OLP）is a chronic autoimmune cell-mediated inflammatory disease. Most OLP patients complain of xerostomia/dry mouth due to changes in the oral mucosal protective barrier. Mucin 5B（MUC5B）is the predominate gel-forming mucin in the oral cavity that protects the underlying tissue from mechanical damage, chemical insult, and pathogenic microbes. This study aims to assess MUC5B in OLP subjects and correlate its role in etiopathogenesis. The study included 20 OLP subjects and 10 healthy controls. OLP subjects were divided further into 10 keratotic（reticular）and 10 non-keratotic（atrophic/erythematous）groups based on the clinical criteria. Dryness of mouth was confirmed by the subjective（Xerostomia Inventory, XI; Bother Index, BI）and clinical testing（Clinical Oral Dryness Score, CODS）method. Stimulated, unstimulated saliva and blood samples were collected from subjects. Samples were centrifuged and analysed for MUC5B level using an ELISA kit. The subjective and clinical testing methods which clinically define xerostomia are correlated with the age and sex of the OLP subjects. The stimulated and unstimulated salivary flow rate of OLP subjects was lower（p<0.05）than controls and was associated with the XI, BI, and CODS（p<0.01）. In contrast, the MUC5B level was increased in the serum of OLP subjects compared to controls（p<0.05）. OLP subjects with xerostomia, displayed lower salivary flow, decrease MUC5B in saliva and increase MUC5B in serum. Alteration of MUC5B in the saliva causes oral mucosal alterations affecting the protection of the oral cavity and increase xerostomia in OLP.

Use of Streptococcus salivarius K12 in supporting the mucosal immune function of active young subjects: A randomised double-blind study.

Upper respiratory tract infections (URTI) are the most common illnesses affecting athletes, causing absences from training and competition. Salivary immunoglobulin A (sIgA) is the main immune factor in saliva, and a consistent association between low concentrations of sIgA and an increased incidence of URTIs has been reported. The oral probiotic Streptococcus salivarius K12 has been suggested to have the potential to improve oral diseases and mucosal barrier function. However, the effects of this probiotic on active young subjects performing a high-intensity training (HIT) program have not been investigated. Active young students were randomised into a treated group (S. salivarius K12) and a control (placebo) group and asked to take the product daily for 30 days. After this period, participants performed a graded exercise test and five HIT sessions, all within 3 days. They were also asked to complete the Wisconsin Upper Respiratory Symptom Survey daily to monitor URTI's presence. Before and after the 30 days, and at 0h, 24h and 72h after the last training session, saliva samples were collected to quantify sIgA level, secretion rate, and flow. The effect of S. salivarius K12 intake on these parameters was tested using an ANOVA for repeated measures. Twenty (M = 14, F = 6) young subjects (23.5 ± 2.3 years old) participated in the study. The total accumulated training load (sRPE) in the supplementation period was similar in the two groups (treated: 4345 ± 3441 AU; control: 4969 ± 4165 AU; p > 0.05). Considering both sIgA level and secretion rate, significant time (F(4,15) = 3.38; p = 0.037; F(4,15) = 6.00; p = 0.004) and time×group interactions (F(4,15) = 2.49; p = 0.049; F(4,15) = 5.01; p = 0.009) were reported, with the treated group showing higher sIgA levels at 72h post-exercise and increased secretion rate both at 0h and 72h. The number of URTI episodes was similar in the treated and control groups (χ² = 1.83; p > 0.05). This study demonstrates that relatively short-term S. salivarius K12 supplementation increased sIgA level and secretion in healthy subjects performing a demanding exercise-training programme composed of HIT sessions.

A local dark tea - Liubao tea - extract exhibits remarkable performance in oral tissue regeneration, inflammation relief and oral microbiota reconstruction.

The prevalence of oral health problems is ubiquitous in contemporary society, with particular emphasis placed on the central role of oral flora in mitigating this issue. Both ancient literature and modern research have highlighted the promising application of tea with substantial bioactive properties, particularly dark tea, in preserving and promoting oral health. Liubao tea, a widely consumed dark tea with increasing popularity in recent years, has been reported to possess abundant bioactive constituents, exhibit remarkable antioxidant and anti-inflammatory effects, modulate the flora structure and so on. It may be a promising candidate for addressing oral health problems. In this study, Liubao tea was meticulously extracted, purified and identified, followed by an investigation of its potential to modulate oral microecology by virtue of an acetic acid-induced oral disorder murine model. The results revealed that Liubao tea extract (LTE) application commendably reconstructed the oral mucosal barrier, promoted tissue regeneration and mitigated micro-inflammation. Furthermore, LTE treatment could also ameliorate the oral flora composition by decreasing the abundance of Proteobacteria and increasing the abundance of Firmicutes and Actinobacteria at the phylum level, as well as inhibiting pernicious bacteria such as Streptococcus and Delftia acidovorans. So, it could promote the generation of a beneficial microenvironment and regulate the immune process. Overall, LTE demonstrated remarkable potential in regulating the balance of oral microecology, suggesting that it may represent a promising therapeutic strategy for oral health concerns.

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.

Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier.

Tissue-specific cues are critical for homeostasis at mucosal barriers. Here, we report that the clotting factor fibrin is a critical regulator of neutrophil function at the oral mucosal barrier. We demonstrate that commensal microbiota trigger extravascular fibrin deposition in the oral mucosa. Fibrin engages neutrophils through the αMβ2 integrin receptor and activates effector functions, including the production of reactive oxygen species and neutrophil extracellular trap formation. These immune-protective neutrophil functions become tissue damaging in the context of impaired plasmin-mediated fibrinolysis in mice and humans. Concordantly, genetic polymorphisms in PLG, encoding plasminogen, are associated with common forms of periodontal disease. Thus, fibrin is a critical regulator of neutrophil effector function, and fibrin-neutrophil engagement may be a pathogenic instigator for a prevalent mucosal disease.

ILC1s and ILC3s Exhibit Inflammatory Phenotype in Periodontal Ligament of Periodontitis Patients.

Innate lymphoid cells (ILCs) are emerging as important players in inflammatory diseases. The oral mucosal barrier harbors all ILC subsets, but how these cells regulate the immune responses in periodontal ligament tissue during periodontitis remains undefined. Here, we show that total ILCs are markedly increased in periodontal ligament of periodontitis patients compared with healthy controls. Among them, ILC1s and ILC3s, particularly NKp44+ILC3 subset, are the predominant subsets accumulated in the periodontal ligament. Remarkably, ILC1s and ILC3s from periodontitis patients produce more IL-17A and IFN-γ than that from healthy controls. Collectively, our results highlight the role of ILCs in regulating oral immunity and periodontal ligament inflammation and provide insights into targeting ILCs for the treatment of periodontitis.

Oral mucosal pellicle as an immune protection against micro-organisms in patients with recurrent aphthous stomatitis: A hypothesis

Recurrent Aphthous Stomatitis (RAS) is the most common ulcerative diseases of oral mucosa affecting an estimate of 20% of the world’s population. Majority of the people affected by RAS are under 30 years of age. RAS is located on the lining (non-keratinized) oral mucosa, i.e. buccal mucosa, lateral side of the tongue, soft palate, lip mucosa, or the floor of mouth. An aphthous ulcer develops when lymphocytic cells infiltrate into the epithelium and cause an edema due to transient inflammatory stimuli. Bacteria, viruses and fungi have been suggested to cause aphthous lesions, but findings regarding oral pathogens are conflicting. Prior consensus has been that RAS is a multifactorial condition, with microbes, allergies, nutritional deficiencies, genetic factors, certain illnesses, immunodeficiency, hormonal changes, trauma and stress among others, contributing to the condition. In spite of many suggestions and investigations, the etiology and pathophysiology of RAS remains uncertain.Our hypothesis focuses on mucin proteins that have been shown to play a role in the formation of protective mucosal pellicle, which serves as the first line of defense between oral epithelium and pathogens within the oral cavity. Mucins, including transmembrane mucin 1 (MUC1), and salivary mucins MUC5B and MUC7 form a protein network that is strongly retained to oral epithelium. The role of the mucosal pellicle in pathophysiology of RAS is unknown. Structural variations have been found in the salivary MUC7 terminal end oligosaccharides in RAS patients, rendering the protein unable to agglutinate pathogens. Furthermore, low levels of MUC1 fail to provide a scaffold for assembly of salivary mucins. We introduce a new hypothesis, the alterations in the structure of these glycoproteins could have a profound impact on the oral mucosal barrier function. On the other hand, micro-organisms secreting their mucolytic enzymes destroy the mucosal pellicle causing oral ulcers.

Regulation of host-microbe interactions at oral mucosal barriers by type 17 immunity.

The oral mucosa is a primary barrier site and a portal for entry of microbes, food, and airborne particles into the gastrointestinal tract. Nonetheless, mucosal immunity at this barrier remains understudied compared with other anatomical barrier sites. Here, we review basic aspects of oral mucosal histology, the oral microbiome, and common and clinically significant diseases that present at oral mucosal barriers. We particularly focus on the role of interleukin-17 (IL-17)/T helper 17 (TH17) responses in protective immunity and inflammation in the oral mucosa. IL-17/TH17 responses are highly relevant to maintaining barrier integrity and preventing pathogenic infections by the oral commensal fungus Candida albicans On the other hand, aberrant IL-17/TH17 responses are implicated in driving the pathogenesis of periodontitis and consequent bone and tooth loss. We discuss distinct IL-17-secreting T cell subsets, emphasizing their regulation and function in oropharyngeal candidiasis and periodontitis.

Evaluating the role of local host factors in the candidal colonization of oral cavity: A review update.

Human oral cavity is home to a number of organisms, Candida albicans being one of them. This review article aims at understanding the correlation between the oral candidal colonization and the local host factors that may influence it with special emphasis on congenital craniofacial anomalies such as cleft lip and palate (CLP). Various scientific databases were searched online and relevant articles were selected based on the inclusion criteria. A comparative study was done to understand the interdependence of various factors (including CLP) and oral candidal colonization. The results revealed a strong association of certain local host factors which may influence the oral colonization of Candida species. Factors such as mucosal barrier, salivary constituents and quantity of saliva, congenital deformities like CLP, oral prostheses such as dentures/palatal obturators and fixed orthodontic appliances (FOAs) were identified. All these factors may directly affect the growth of Candida in the oral cavity. Although numerous studies have pointed a positive correlation between Oral Candidal colonization and local host factors such as oral prostheses, FOA, and oral mucosal barrier only one study has been done, in the Indian subcontinent with respect to the correlation of candidal colonization and CLP. After the evaluation of all the factors mentioned in various case studies, it can be concluded that the presence of local host factors such as orofacial clefts, dental prostheses, FOA, xerostomia, and atrophy of the oral mucous membrane lead to significant increase in candidal colonization, but since very few studies in regard to CLP have been done worldwide and in India, in particular, further studies are warranted.

Immune-Related Oral, Otologic, and Ocular Adverse Events.

Emerging immunotherapy agents, such as immune checkpoint inhibitors, have shown remarkable promise in the treatment of various malignancies. These drugs selectively target different steps in the immune response cascade to upregulate the body's normal response to cancer. Due to the novelty of these therapeutic agents, their toxicity profile is less well understood.Meta-analysis results reveal that the overall prevalence of oral mucositis, stomatitis, and xerostomia is lower with checkpoint inhibitors compared to conventional chemotherapy, and head and neck radiation therapy. However, the widespread use of immunotherapy reveals new oral mucosal barrier adverse events, including bullous pemphigoid, mucous membrane pemphigoid, and lichenoid mucositis. Audiovestibular dysfunction can occur from autoimmune-mediated pathways of immunotherapy (adoptive cell) with limited treatment options. Such auditory complications can lead to speech recognition deficits and sensorineural hearing loss. Ocular toxicities are among the most common adverse events resulting from the use of these agents. The majority of ocular immune-related adverse events (irAEs) are mild, low-grade, non-sight threatening, such as blurred vision, conjunctivitis, and ocular surface disease. Serious and sight-threatening events, including corneal perforation, optic neuropathy, and retinal vascular occlusion, can occur but are infrequent. In this chapter, we review the current evidence on the clinical manifestations of oral, audiovestibular, and ocular immune-related adverse events (i.e., irAEs).

Lumbar vertebral osteomyelitis and psoas abscess caused by Actinomyces israelii after an operation under general anesthesia in a patient with end-stage renal disease: a case report

BackgroundActinomycosis is a chronic, slowly progressive infection caused by the Actinomyces species. Lumbar vertebral involvement of Actinomyces israelii is extremely rare; this is the first case report of lumbar vertebral osteomyelitis and psoas abscess caused by Actinomyces israelii after an operation under general anesthesia.Case presentationA 66-year-old Japanese man with end-stage renal disease was admitted to our hospital for an operation for cervical canal stenosis. After the operation under general anesthesia, during which tracheal intubation and nasogastric tube insertion were performed, he developed low back pain. During a second hospitalization, computed tomography revealed osteolysis of the lumbar endplates of L2 and L3, swelling of the intervertebral disk of L2/L3, and swelling of the left psoas major muscle. Percutaneous drainage of the intervertebral disc was performed, and the culture of the aspirate grew Actinomyces israelii. Based on the susceptibility, ampicillin was administered but his condition did not improve. We changed the antibiotics to ampicillin-sulbactam for coverage of unidentified oral commensals, and his symptoms and signs finally improved.ConclusionOur patient’s long-term end-stage renal disease had made the oral and gastrointestinal mucosal barriers very fragile. Under these conditions, even mildly invasive procedures such as tracheal intubation and nasogastric tube insertion could be the cause of infectious complication by oral commensals, including Actinomyces.

Localization of transmembrane mucin MUC1 on the apical surface of oral mucosal cells

ABSTRACTThe purpose of the present study was to demonstrate the localization of transmembrane mucin MUC1 on the outer layer of oral mucosal cells and the involvement of apical cell surface microplicae (MPL) in bioadhesion of MUC1. Tissue samples of six healthy subjects were obtained. First, the presence of MUC1 was examined with an immunohistochemical method using a monoclonal MUC1 antigen called HFMG1. Second, the localization of MUC1 was examined with immuno-scanning electron microscopy. Immunohistochemically, high intense staining for MUC1 (antigen HFMG1) was detected in the epithelial superficial layers. In the superficial layer, intense MUC1 expression was seen predominantly on the apical cell surface. On the apical epithelial cells, MUC1 was associated predominantly with MPL towards the oral cavity. The novelty of the results of the present study is that MPL serves a harbor of MUC1 in superficial epithelial cells towards the oral cavity. It is speculated that the transmembrane MUC1 is one component of the “oral mucosal barrier complex” representing a signaling pathway between saliva and mucosal cells.Abbreviations: MUC1: mucin1; MAM: membrane-anchored mucin; OMBC: oral mucosal barrier complex; LM: light microscopy; TEM: transmission electron microscopy; SEM: scanning electron microscopy; iSEM: immuno-scanning electron microscopy; MPL: microplicae

Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)–induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, β-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

Tissue-resident MAIT cell populations in human oral mucosa exhibit an activated profile and produce IL-17.

Mucosa‐associated invariant T (MAIT) cells are unconventional T lymphocytes defined by their innate‐like characteristics and broad antimicrobial responsiveness. Whether MAIT cells are part of the tissue‐resident defense in the oral mucosal barrier is unknown. Here, we found MAIT cells present in the buccal mucosa, with a tendency to cluster near the basement membrane, and located in both epithelium and the underlying connective tissue. Overall MAIT cell levels were similar in the mucosa compared to peripheral blood, in contrast to conventional T cells that showed an altered representation of CD4+ and CD8+ subsets. The major mucosal MAIT cell subset displayed a tissue‐resident and activated profile with high expression of CD69, CD103, HLA‐DR, and PD‐1, as well as a skewed subset distribution with higher representation of CD4–/CD8– double‐negative cells and CD8αα+ cells. Interestingly, tissue‐resident MAIT cells had a specialized polyfunctional response profile with higher IL‐17 levels, as assessed by polyclonal stimulus and compared to tissue nonresident and circulating populations. Furthermore, resident buccal MAIT cells were low in perforin. Together, these data indicate that MAIT cells form a part of the oral mucosal T cell compartment, where they exhibit a tissue‐resident‐activated profile biased toward IL‐17 production.