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Type 2 diabetes (T2D) is a risk factor for mucosal homeostasis and enhances the susceptibility to inflammation, in which neutrophils have been increasingly appreciated for their role. Here, barrier disruption and inflammation are observed at oral mucosa (gingiva) of T2D patients and mice. It is demonstrated that neutrophils infiltrate the gingival mucosa of T2D mice and expel obvious neutrophil extracellular traps (NETs), while removal of NETs alleviates the disruption of mucosal barrier. Mechanistically, gingival neutrophils released NETs are dependent of their metabolic reprogramming. Under hyperglycemic condition, neutrophils elevate both glucose incorporation and glycolysis via increased expression of GLUT1. Moreover, significantly increased levels of NETs are observed in local gingival lesions of patients, which are associated with clinical disease severity. This work elucidates a causative link between hyperglycemia and oral mucosal immunopathology, mediated by the altered immuno‐metabolic axis in neutrophil, thereby suggesting a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Abstract Type 2 diabetes (T2D) is a risk factor for mucosal homeostasis and enhances the susceptibility to inflammation, in which neutrophils have been increasingly appreciated for their role. Here, barrier disruption and inflammation are observed at oral mucosa (gingiva) of T2D patients and mice. It is demonstrated that neutrophils infiltrate the gingival mucosa of T2D mice and expel obvious neutrophil extracellular traps (NETs), while removal of NETs alleviates the disruption of mucosal barrier. Mechanistically, gingival neutrophils released NETs are dependent of their metabolic reprogramming. Under hyperglycemic condition, neutrophils elevate both glucose incorporation and glycolysis via increased expression of GLUT1. Moreover, significantly increased levels of NETs are observed in local gingival lesions of patients, which are associated with clinical disease severity. This work elucidates a causative link between hyperglycemia and oral mucosal immunopathology, mediated by the altered immuno‐metabolic axis in neutrophil, thereby suggesting a potential therapeutic strategy.

Featured Application: Monitoring salivary biomarkers demonstrates a potential application to assess the internal training load and recovery status of elite futsal players during congested competition periods, especially total protein and salivary immunoglobulin A. Tracking biomarker changes provides a practical tool for coaching staff to guide adjustments to training loads, nutrition, and recovery protocols to mitigate risks and optimize athlete performance and health. A congested match and training schedule could alter internal load, and this could be reflected in biomarkers of stress and immunity in elite futsal players. The aim of this study was to analyze the effects of a congested match and training schedule on internal load and levels of total protein, total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index, and the concentrations of salivary immunoglobulin A (SIgA) in 17 professional players from the same Portuguese elite futsal club (age: 23.07 ± 6.76 years old; height: 1.75 ± 0.06 m; body mass: 75.47 ± 7.47 kg; experience in playing in elite: 5.38 ± 2.03 years) who performed 5 matches and 16 training sessions in a period of 27 days. The salivary content of total protein, TOS, TAC, oxidative stress index, and SIgA were calculated before and after the training sessions and the unofficial matches under study. Saliva sampling was conducted 10 min before each match or training session and 40 min after (post-match and post-training). The MANOVA of repeated measures showed a significant difference for total protein and SIgA (p < 0.01). Total protein (sphericity = 0.007; statistical power = 0.818) and SIgA (sphericity = 0.018; statistical power = 0.693) are highly correlated with the time factor. The main findings revealed several key points: (a) There was a significant increase in total protein, SIgA, and TAC during acute load (pre- vs. post-session) in both training and match contexts. Specifically, total protein and SIgA displayed notable increments in both training and match settings, while TAC exhibited significant increases exclusively during matches. (b) No changes in TOS and oxidative stress index were observed during acute load in either training or match contexts. (c) A positive trend was noted between the chronic load during a congested week of the precompetitive season and the decrease in total protein and SIgA levels. (d) Additionally, a positive correlation between internal training loads and oxidative/antioxidant responses was found, as expressed by the oxidative stress index, without significant differences (p-value > 0.05) in acute and chronic loads during congested matches and training schedules. [ABSTRACT FROM AUTHOR]

COVID‐19 as a pan‐epidemic is waning but there it is imperative to understand virus interaction with oral tissues and oral inflammatory diseases. We review periodontal disease (PD), a common inflammatory oral disease, as a driver of COVID‐19 and oral post‐acute‐sequelae conditions (PASC). Oral PASC identifies with PD, loss of teeth, dysgeusia, xerostomia, sialolitis‐sialolith, and mucositis. We contend that PD‐associated oral microbial dysbiosis involving higher burden of periodontopathic bacteria provide an optimal microenvironment for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. These pathogens interact with oral epithelial cells activate molecular or biochemical pathways that promote viral adherence, entry, and persistence in the oral cavity. A repertoire of diverse molecules identifies this relationship including lipids, carbohydrates and enzymes. The S protein of SARS‐CoV‐2 binds to the ACE2 receptor and is activated by protease activity of host furin or TRMPSS2 that cleave S protein subunits to promote viral entry. However, PD pathogens provide additional enzymatic assistance mimicking furin and augment SARS‐CoV‐2 adherence by inducing viral entry receptors ACE2/TRMPSS, which are poorly expressed on oral epithelial cells. We discuss the mechanisms involving periodontopathogens and host factors that facilitate SARS‐CoV‐2 infection and immune resistance resulting in incomplete clearance and risk for 'long‐haul' oral health issues characterising PASC. Finally, we suggest potential diagnostic markers and treatment avenues to mitigate oral PASC. [ABSTRACT FROM AUTHOR]

The mucosal immune response is recognized to be important in the early control of infection sustained by viruses with mucosal tissues as the primary site of entry and replication, such as SARS-CoV-2. Mucosal IgA has been consistently reported in the mouth and eye of SARS-CoV-2 infected subjects, where it correlated inversely with COVID-19 symptom severity. Yet, there is still scarce information on the comparative ability of the diverse SARS-CoV-2 vaccines to induce local IgA responses at the virus entry site. Thus, the aim of this study was to assess the presence of anti-SARS-CoV-2 IgA in the saliva of 95 subjects vaccinated with a booster dose and different combinations of vaccines, including mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Vaxzevria (AstraZeneca). The results showed the presence of a mucosal response in 93.7% of vaccinated subjects, with a mean IgA titer of 351.5 ± 31.77 U/mL, strongly correlating with the serum anti-SARS-CoV-2 IgG titer (p < 0.0001). No statistically significant differences emerged between the vaccine types, although the salivary IgA titer appeared slightly higher after receiving a booster dose of the mRNA-1273 vaccine (Moderna) following two doses of BNT162b2 (Pfizer-BioNTech), compared to the other vaccine combinations. These data confirm what was previously reported at the eye level and suggest that monitoring salivary IgA may be a useful tool for driving forward vaccine design and surveillance strategies, potentially leading to novel routes of vaccine administration and boosting. [ABSTRACT FROM AUTHOR]

A congested match and training schedule could alter internal load, and this could be reflected in biomarkers of stress and immunity in elite futsal players. The aim of this study was to analyze the effects of a congested match and training schedule on internal load and levels of total protein, total oxidant status (TOS), total antioxidant capacity (TAC), oxidative stress index, and the concentrations of salivary immunoglobulin A (SIgA) in 17 professional players from the same Portuguese elite futsal club (age: 23.07 ± 6.76 years old; height: 1.75 ± 0.06 m; body mass: 75.47 ± 7.47 kg; experience in playing in elite: 5.38 ± 2.03 years) who performed 5 matches and 16 training sessions in a period of 27 days. The salivary content of total protein, TOS, TAC, oxidative stress index, and SIgA were calculated before and after the training sessions and the unofficial matches under study. Saliva sampling was conducted 10 min before each match or training session and 40 min after (post-match and post-training). The MANOVA of repeated measures showed a significant difference for total protein and SIgA (p < 0.01). Total protein (sphericity = 0.007; statistical power = 0.818) and SIgA (sphericity = 0.018; statistical power = 0.693) are highly correlated with the time factor. The main findings revealed several key points: (a) There was a significant increase in total protein, SIgA, and TAC during acute load (pre- vs. post-session) in both training and match contexts. Specifically, total protein and SIgA displayed notable increments in both training and match settings, while TAC exhibited significant increases exclusively during matches. (b) No changes in TOS and oxidative stress index were observed during acute load in either training or match contexts. (c) A positive trend was noted between the chronic load during a congested week of the precompetitive season and the decrease in total protein and SIgA levels. (d) Additionally, a positive correlation between internal training loads and oxidative/antioxidant responses was found, as expressed by the oxidative stress index, without significant differences (p-value > 0.05) in acute and chronic loads during congested matches and training schedules.

With the improved quality of life, oral health is under increased pressure. Numerous common oral mucosal diseases, such as oral lichen planus(OLP) and gingivitis, are related to the destruction of the oral immune barrier. The cytokines secreted by T-helper 17 (Th17) cells are essential for maintaining oral immune homeostasis and play essential roles in immune surveillance. When antigens stimulate the epithelium, Th17 cells expand, differentiate, and generate inflammatory factors to recruit other lymphocytes, such as neutrophils, to clear the infection, which helps to maintain the integrity of the epithelial barrier. In contrast, excessive Th17/IL-17 axis reactions may cause autoimmune damage. Therefore, an in-depth understanding of the role of Th17 cells in oral mucosa may provide prospects for treating oral mucosal diseases. We reviewed the role of Th17 cells in various oral and skin mucosal systemic diseases with oral characteristics, and based on the findings of these reports, we emphasize that Th17 cellular response may be a critical factor in inflammatory diseases of the oral mucosa. In addition, we should pay attention to the role and relationship of "pathogenic Th17" and "non-pathogenic Th17" in oral mucosal diseases. We hope to provide a reference for Th17 cells as a potential therapeutic target for treating oral mucosal inflammatory disorders in the future. [ABSTRACT FROM AUTHOR]

The mucosal immune response is recognized to be important in the early control of infection sustained by viruses with mucosal tissues as the primary site of entry and replication, such as SARS-CoV-2. Mucosal IgA has been consistently reported in the mouth and eye of SARS-CoV-2 infected subjects, where it correlated inversely with COVID-19 symptom severity. Yet, there is still scarce information on the comparative ability of the diverse SARS-CoV-2 vaccines to induce local IgA responses at the virus entry site. Thus, the aim of this study was to assess the presence of anti-SARS-CoV-2 IgA in the saliva of 95 subjects vaccinated with a booster dose and different combinations of vaccines, including mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Vaxzevria (AstraZeneca). The results showed the presence of a mucosal response in 93.7% of vaccinated subjects, with a mean IgA titer of 351.5 ± 31.77 U/mL, strongly correlating with the serum anti-SARS-CoV-2 IgG titer (p < 0.0001). No statistically significant differences emerged between the vaccine types, although the salivary IgA titer appeared slightly higher after receiving a booster dose of the mRNA-1273 vaccine (Moderna) following two doses of BNT162b2 (Pfizer-BioNTech), compared to the other vaccine combinations. These data confirm what was previously reported at the eye level and suggest that monitoring salivary IgA may be a useful tool for driving forward vaccine design and surveillance strategies, potentially leading to novel routes of vaccine administration and boosting.

The oral gingival barrier is a constantly stimulated and dynamic environment where homeostasis is often disrupted, resulting in inflammatory periodontal diseases. Type 2 diabetes (T2D) has been reported to be associated with gingival barrier dysfunction, but the effect and underlying mechanism are inconclusive. Herein, we performed single-cell RNA sequencing (scRNA-seq) of gingiva from leptin receptor-deficient mice (db/db) to examine the gingival heterogeneity in the context of T2D. Periodontal health of control mice is characterized by populations of Krt14+-expressing epithelial cells and Col1a1+-fibroblasts mediating immune homeostasis primarily through the enrichment of innate lymphoid cells. The db/db gingiva exhibited decreased epithelial/stromal ratio and dysfunctional barrier. We further observed stromal, particularly fibroblast immune hyperresponsiveness, linked to the recruitment of myeloid-derived cells at the db/db gingiva. Both scRNA-seq and histological analysis suggested the inflammatory signaling between fibroblasts and neutrophils as a potential driver of diabetes-induced periodontal damage. Notably, the "immune-like" stromal cells were wired toward the induction of gingival IL-17A hyperresponsiveness in db/db mice. Our work reveals that the "immune-like" fibroblasts with transcriptional diversity are involved in the innate immune homeostasis at the diabetic gingiva. It highlights a potentially significant role of these cell types in its pathogenesis. [ABSTRACT FROM AUTHOR]

Mortatti, AL, Oliveira, RSCd, Pinto, JCBdL, Galvão-Coelho, NL, Almeida, RN, Aoki, MS, and Moreira, A. A congested match schedule alters internal match load and affects salivary immunoglobulin A concentration in youth soccer players. J Strength Cond Res 36(6): 1655–1659, 2022—The aim of this study was to analyze the effects of a congested match schedule (CMS) undertaken after a tapering week, on internal match load (IML) and salivary immunoglobulin A (SIgA) concentration in 12 youth soccer players (16.6 ± 0.5 years; 175 ± 8 cm; 65 ± 8 kg) who performed 4 official matches within a 4-day period. Internal match load was determined using the session-rating of perceived exertion method and the competitive strain (CS) and monotony index (MI) were also determined. Saliva sampling was conducted, before the last training day of a tapering week (training) preceding the CMS, 60 minutes before the first match (match-1), and 22 hours after match 4 (postmatch 4). Salivary immunoglobulin A was analyzed by ELISA. The results of the analysis of variance with repeated measures showed a significant difference for IML across the matches (p < 0.001). A significant reduction in SIgA was observed from prematch 1 to postmatch 4 (p = 0.019). Regarding the change in SIgA (ΔSIgA), 58.3% of the players presented values equal/higher than the minimal detectable change. A large within-individual correlation was observed between ΔSIgA and MI and CS (r = 0.71 and r = 0.72: p < 0.01, respectively). The current findings suggest that youth players participating in a CMS may present a decrease in mucosal immunity function. In addition, data suggest that the MI and CS may be used as valuable markers for monitoring competition load during CMS in youth soccer players. [ABSTRACT FROM AUTHOR]

The 2nd International Conference on Oral Mucosal Immunity and the Microbiome (OMIM) took place at the Grecotel Kos Imperial Hotel, Kos, Greece, between 25th and 30th September 2021, under the auspices of the Aegean Conferences. This has only been the second Aegean Conference of this thematic, the first one having taken place in 2018 in Crete, during the same period of the year. Given the hardships in travel and heightened infection transmission risks amid the COVID-19 pandemic, the Conference was well attended by 29 international speakers across the world. For many of the participants, this was the first conference travel in the post-pandemic era, and quite significant that it has taken place on the island of Hippocrates. Stringent regional health and safety regulations had to be followed to accomplish for this in-person Conference to take place. Frontiers in Oral Health has hosted papers from presentations of the Conference, whereas the present article serves as the proceedings of the Conference with summaries of the presentations.

In the oral cavity, the immune system is constantly exposed to unique tissue‐specific signals, including a rich community of commensal microbes and their metabolites, continuous tissue damage from mastication, and antigens from food and airborne particles. How this unique combination of signals participates in the training of specialized immunity at this site is not well understood, yet imbalance of local responses is linked to tissue‐specific disease susceptibilities with the prototypic disease being periodontitis. However, the oral mucosa is also well recognized as a site where systemic inflammatory and autoimmune diseases often manifest, indicating that systemic immune deregulation is reflected in the function of the oral immune system. This commentary will discuss both aspects of compartmentalized and systemic immunity at the oral mucosa. [ABSTRACT FROM AUTHOR]

Interleukin-17 ( IL-17) is a multifaceted cytokine with diverse roles in both immune protection and also immunopathology. IL-17 has a well-recognized role in immune surveillance at mucosal and barrier surfaces, but also has been increasingly implicated as a driver of immunopathology in settings of autoimmunity and chronic inflammation. The current review introduces basic aspects of IL-17 biology and examines the protective and pathogenic roles of IL-17 with a focus on oral mucosal immunity and inflammation. Specific emphasis is given to the role of the IL-17 response as a catalyst in 'shaping the microbiome at the oral barrier'. [ABSTRACT FROM AUTHOR]

This study analyzed the effects of carbohydrate and glutamine supplementation on salivary immunity after exercise at a simulated altitude of 4500 m. Fifteen volunteers performed exercise of 70% of VO2peak until exhaustion and were divided into three groups: hypoxia placebo, hypoxia 8% maltodextrin (200 mL/20 min), and hypoxia after six days glutamine (20 g/day) and 8% maltodextrin (200 mL/20 min). All procedures were randomized and double-blind. Saliva was collected at rest (basal), before exercise (pre-exercise), immediately after exercise (post-exercise), and two hours after exercise. Analysis of Variance (ANOVA) for repeated measures and Tukey post hoc test were performed. Statistical significance was set at p < 0.05. SaO2% reduced when comparing baseline vs. pre-exercise, post-exercise, and after recovery for all three groups. There was also a reduction of SaO2% in pre-exercise vs. post-exercise for the hypoxia group and an increase was observed in pre-exercise vs. recovery for both supplementation groups, and between post-exercise and for the three groups studied. There was an increase of salivary flow in post-exercise vs. recovery in Hypoxia + Carbohydrate group. Immunoglobulin A (IgA) decreased from baseline vs. post-exercise for Hypoxia + Glutamine group. Interleukin 10 (IL-10) increased from post-exercise vs. after recovery in Hypoxia + Carbohydrate group. Reduction of tumor necrosis factor alpha (TNF-α) was observed from baseline vs. post-exercise and after recovery for the Hypoxia + Carbohydrate group; a lower concentration was observed in pre-exercise vs. post-exercise and recovery. TNF-α had a reduction from baseline vs. post-exercise for both supplementation groups, and a lower secretion between baseline vs. recovery, and pre-exercise vs. post-exercise for Hypoxia + Carbohydrate group. Five hours of hypoxia and exercise did not change IgA. Carbohydrates, with greater efficiency than glutamine, induced anti-inflammatory responses. [ABSTRACT FROM AUTHOR]

With the improved quality of life, oral health is under increased pressure. Numerous common oral mucosal diseases, such as oral lichen planus(OLP) and gingivitis, are related to the destruction of the oral immune barrier. The cytokines secreted by T-helper 17 (Th17) cells are essential for maintaining oral immune homeostasis and play essential roles in immune surveillance. When antigens stimulate the epithelium, Th17 cells expand, differentiate, and generate inflammatory factors to recruit other lymphocytes, such as neutrophils, to clear the infection, which helps to maintain the integrity of the epithelial barrier. In contrast, excessive Th17/IL-17 axis reactions may cause autoimmune damage. Therefore, an in-depth understanding of the role of Th17 cells in oral mucosa may provide prospects for treating oral mucosal diseases. We reviewed the role of Th17 cells in various oral and skin mucosal systemic diseases with oral characteristics, and based on the findings of these reports, we emphasize that Th17 cellular response may be a critical factor in inflammatory diseases of the oral mucosa. In addition, we should pay attention to the role and relationship of "pathogenic Th17" and "non-pathogenic Th17" in oral mucosal diseases. We hope to provide a reference for Th17 cells as a potential therapeutic target for treating oral mucosal inflammatory disorders in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Xue, Wang, Zeng, Ji and Chen.)

Background There is upregulation of class II molecules of the major histocompatibility complex (MHC) by keratinocytes in oral squamous cell carcinoma (OSCC) and inflammatory diseases such as lichen planus. The significance of this expression, or whether it is accompanied by upregulation of membrane-bound costimulatory molecules, is unknown. Objectives To compare the expression of CD40, CD80, CD86, MHC class II and intercellular adhesion molecule-1 (ICAM-1), and the ability to induce allogeneic T-lymphocyte proliferation in vitro, of a CD40– OSCC cell line, its CD40+ transfected derivative and null transfectants. Methods OSCC cell lines and purified T lymphocytes were cocultured and T cell proliferation recorded. Phenotypes were analysed by flow cytometry. Results After T lymphocyte proliferation, which all OSCC cell lines were able to induce, there was upregulation of MHC class II and ICAM-1. However, the CD40+ transfectants were the most immunologically potent and were the only cells to show increased expression of CD86 (as well as further upregulation of CD40 and a statistically insignificant rise in CD80). The effects of blocking antibodies on T-cell proliferation were only statistically significant with the CD40+ transfectants. Conclusions While not essential, expression of CD40 by OSCC cells is necessary for optimal induction of allogeneic T lymphocytes, possibly because of concurrent upregulation of other membrane-bound costimulatory molecules. [ABSTRACT FROM AUTHOR]

Abstract: Oral mucosal cells such as epithelial cells and fibroblasts are the first cells encountered by bacteria in our body. In addition to acting as a physical barrier, oral mucosal cells appear to express adhesion molecules and secrete many proinflammatory mediators, implying that the cells actively participate in mucosal immunity. Oral epithelial cells express a precursor form of interleukin (IL)-18, an important regulator of innate and acquired immune responses. An active form of IL-18 was secreted from the cells on co-stimulation with neutrophil proteinase 3 (PR3) and lipopolysaccharide after interferon-?-priming. Subsequently, it was evident that neutrophil serine proteases including PR3 activate oral mucosal cells through protease-activated receptor-2 (PAR-2) pathway and play a critical role in IL-18 induction in vivo. These results indicate that induction of IL-18 and PAR-2 activation by neutrophil serine proteases may be critical in regulation of oral mucosal immunity. [Copyright &y& Elsevier]

The 2nd International Conference on Oral Mucosal Immunity and the Microbiome (OMIM) took place at the Grecotel Kos Imperial Hotel, Kos, Greece, between 25th and 30th September 2021, under the auspices of the Aegean Conferences. This has only been the second Aegean Conference of this thematic, the first one having taken place in 2018 in Crete, during the same period of the year. Given the hardships in travel and heightened infection transmission risks amid the COVID-19 pandemic, the Conference was well attended by 29 international speakers across the world. For many of the participants, this was the first conference travel in the post-pandemic era, and quite significant that it has taken place on the island of Hippocrates. Stringent regional health and safety regulations had to be followed to accomplish for this in-person Conference to take place. Frontiers in Oral Health has hosted papers from presentations of the Conference, whereas the present article serves as the proceedings of the Conference with summaries of the presentations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Belibasakis and Hajishengallis.)

The oral mucosa remains an understudied barrier tissue. This is a site of rich exposure to antigens and commensals, and a tissue susceptible to one of the most prevalent human inflammatory diseases, periodontitis. To aid in understanding tissue-specific pathophysiology, we compile a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. We uncover the complex cellular landscape of oral mucosal tissues and identify epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defenses and neutrophil recruitment. Our findings link exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis. Our work provides a resource characterizing the role of tissue stroma in regulating mucosal tissue homeostasis and disease pathogenesis. [Display omitted] • A single-cell atlas of human oral mucosa in individuals with or without periodontitis • Diverse stromal and immune cell populations promote barrier immunity • Stromal cell inflammatory profile is linked to neutrophil recruitment • Identification of cell-specific expression patterns of periodontitis susceptibility genes A single-cell atlas of human oral mucosa connects inflammatory signatures in epithelial and stromal cells with neutrophil infiltration in periodontitis and identifies cell-specific expression patterns of periodontitis susceptibility genes. [ABSTRACT FROM AUTHOR]

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