Review on predicting pairwise relationships between human microbes, drugs and diseases: from biological data to computational models.

In recent years, with the rapid development of techniques in bioinformatics and life science, a considerable quantity of biomedical data has been accumulated, based on which researchers have developed various computational approaches to discover potential associations between human microbes, drugs and diseases. This paper provides a comprehensive overview of recent advances in prediction of potential correlations between microbes, drugs and diseases from biological data to computational models. Firstly, we introduced the widely used datasets relevant to the identification of potential relationships between microbes, drugs and diseases in detail. And then, we divided a series of a lot of representative computing models into five major categories including network, matrix factorization, matrix completion, regularization and artificial neural network for in-depth discussion and comparison. Finally, we analysed possible challenges and opportunities in this research area, and at the same time we outlined some suggestions for further improvement of predictive performances as well.

γδ T cells in oral diseases.

OBJECTIVE: γδ T cells are a distinct subset of unconventional T cells, which link innate and adaptive immunity by secreting cytokines and interacting with other immune cells, thereby modulating immune responses. As the first line of host defense, γδ T cells are essential for mucosal homeostasis and immune surveillance. When abnormally activated or impaired, γδ T cells can contribute to pathogenic processes. Accumulating evidence has revealed substantial impacts of γδ T cells on the pathogenesis of cancers, infections, and immune-inflammatory diseases. γδ T cells exhibit dual roles in cancers, promoting or inhibiting tumor growth, depending on their phenotypes and the clinical stage of cancers. During infections, γδ T cells exert high cytotoxic activity in infectious diseases, which is essential for combating bacterial and viral infections by recognizing foreign antigens and activating other immune cells. γδ T cells are also implicated in the onset and progression of immune-inflammatory diseases. However, the specific involvement and underlying mechanisms of γδ T cells in oral diseases have not been systematically discussed. METHODS: We conducted a systematic literature review using the PubMed/MEDLINE databases to identify and analyze relevant literature on the roles of γδ T cells in oral diseases. RESULTS: The literature review revealed that γδ T cells play a pivotal role in maintaining oral mucosal homeostasis and are involved in the pathogenesis of oral cancers, periodontal diseases, graft-versus-host disease (GVHD), oral lichen planus (OLP), and oral candidiasis. γδ T cells mainly influence various pathophysiological processes, such as anti-tumor activity, eradication of infection, and immune response regulation. CONCLUSION: This review focuses on the involvement of γδ T cells in oral diseases, with a particular emphasis on the main functions and underlying mechanisms by which γδ T cells influence the pathogenesis and progression of these conditions. This review underscores the potential of γδ T cells as therapeutic targets in managing oral health issues.

GACNNMDA: a computational model for predicting potential human microbe-drug associations based on graph attention network and CNN-based classifier.

As new drug targets, human microbes are proven to be closely related to human health. Effective computational methods for inferring potential microbe-drug associations can provide a useful complement to conventional experimental methods and will facilitate drug research and development. However, it is still a challenging work to predict potential interactions for new microbes or new drugs, since the number of known microbe-drug associations is very limited at present. In this manuscript, we first constructed two heterogeneous microbe-drug networks based on multiple measures of similarity of microbes and drugs, and known microbe-drug associations or known microbe-disease-drug associations, respectively. And then, we established two feature matrices for microbes and drugs through concatenating various attributes of microbes and drugs. Thereafter, after taking these two feature matrices and two heterogeneous microbe-drug networks as inputs of a two-layer graph attention network, we obtained low dimensional feature representations for microbes and drugs separately. Finally, through integrating low dimensional feature representations with two feature matrices to form the inputs of a convolutional neural network respectively, a novel computational model named GACNNMDA was designed to predict possible scores of microbe-drug pairs. Experimental results show that the predictive performance of GACNNMDA is superior to existing advanced methods. Furthermore, case studies on well-known microbes and drugs demonstrate the effectiveness of GACNNMDA as well. Source codes and supplementary materials are available at: https://github.com/tyqGitHub/TYQ/tree/master/GACNNMDA.

Insights into multisource sludge distributed in the Yangtze River basin, China: Characteristics, correlation, treatment and disposal.

Sludge is the by-product of wastewater treatment process. Multisource sludge can be defined as sludge from different sources. Based on the sludge properties of five typical cities in the Yangtze River basin, including Jiujiang, Wuhu, Lu'an, Zhenjiang and Wuhan, this study investigated and summarized the characteristic variations and distribution differences of multiple indicators and substances from municipal sludge, dredged sludge, and river and lake sediments. The results demonstrated pH of multisource sludge was relatively stable in the neutral range. Organic matter and water content among municipal sludge were high and varied considerably between different wastewater treatment plants. Dredged sludge had an obviously higher sand content and wider particle distribution, which could be considered for graded utilization depending on its size. The nutrients composition of river and lake sediments was usually stable and special, with lower nitrogen and phosphorus content but higher potassium levels. The sources of heavy metals and persistent organic pollutants in multisource sludge were correlated, generally much higher among municipal sludge than dredged sludge and river and lake sediments, which were the most important limitation for final land utilization. Despite various properties of multisource sludge, the final fate and destination have some overall similarities, which need to be supplemented and improved by standards and laws. The study provided a preliminary analysis of suitable technical routes for municipal sludge, dredged sludge, river and lake sediments based on their different characteristics respectively, which was of great significance for multisource sludge co-treatment and disposal in the future of China.

GSAMDA: a computational model for predicting potential microbe-drug associations based on graph attention network and sparse autoencoder.

BACKGROUND: Clinical studies show that microorganisms are closely related to human health, and the discovery of potential associations between microbes and drugs will facilitate drug research and development. However, at present, few computational methods for predicting microbe-drug associations have been proposed. RESULTS: In this work, we proposed a novel computational model named GSAMDA based on the graph attention network and sparse autoencoder to infer latent microbe-drug associations. In GSAMDA, we first built a heterogeneous network through integrating known microbe-drug associations, microbe similarities and drug similarities. And then, we adopted a GAT-based autoencoder and a sparse autoencoder module respectively to learn topological representations and attribute representations for nodes in the newly constructed heterogeneous network. Finally, based on these two kinds of node representations, we constructed two kinds of feature matrices for microbes and drugs separately, and then, utilized them to calculate possible association scores for microbe-drug pairs. CONCLUSION: A novel computational model is proposed for predicting potential microbe-drug associations based on graph attention network and sparse autoencoder. Compared with other five state-of-the-art competitive methods, the experimental results illustrated that our model can achieve better performance. Moreover, case studies on two categories of representative drugs and microbes further demonstrated the effectiveness of our model as well.

T cell-derived exosomes containing cytokines induced keratinocytes apoptosis in oral lichen planus.

OBJECTIVE: Oral lichen planus (OLP) is a T cell-mediated inflammatory disease with uncertain etiology. Exosomes are cell-derived vesicles containing biological cargo, being associated with the development of multiple inflammatory diseases. The present study aims to investigate the role of T cell-derived exosomes in the pathogenesis of OLP. METHODS: Exosomal marker CD63 was detected in OLP lesions by immunohistochemistry. Twenty-three cytokines in T cell-derived exosomes were assessed using luminex xMAP-based assay. After co-incubating with exosomes, the apoptosis of keratinocytes and the proliferation of Jurkat cells were assessed via flow cytometry and cell counting kit-8 assay, respectively. RESULTS: CD63 was highly expressed in the lymphocyte infiltrated areas of OLP lesions. OLP T cell-derived exosomes contained upregulated interleukin-7, -10, -12, -17 and downregulated interleukin-1ß, -5, and interferon-γ. Both exosomes from OLP patients and controls induced the apoptosis of keratinocytes and altered their morphology. Moreover, healthy control-derived exosomes markedly inhibited the proliferation of Jurkat cells, whereas OLP-derived exosomes exhibited no inhibitory effect. CONCLUSIONS: OLP T cell-derived exosomes have an aberrant cytokine profile and could trigger the apoptosis of keratinocytes in vitro, which may be involved in the pathogenesis of OLP.

T cell-derived exosomes induced macrophage inflammatory protein-1α/ß drive the trafficking of CD8+ T cells in oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated chronic inflammatory disease with uncertain aetiology. Exosomes are nanosized particles with biological capacities. Here, we aimed to study the effects of T cell-derived exosomes (T-exos) on the pathogenesis of OLP and its mechanism. T-exos were incubated with Jurkat cells for 48 hours, and 26 cytokines in the supernatant were measured by luminex assay. The expression of macrophage inflammatory protein (MIP)-1α/ß was detected using immunohistochemistry and ELISA; that of CCR1/3/5 on peripheral T cells was determined by flow cytometry. Transwell assay was performed to investigate the chemotactic effect of MIP-1α/ß, and cells in the lower chambers were examinated by flow cytometry. As a result, OLP T-exos elevated the production of MIP-1α/ß, which were highly expressed in OLP tissues and plasma. CCR1/5 were markedly expressed on OLP peripheral T cells, and the majority of CCR1/5+ T cells were CD8+ T cells. Besides, MIP-1α/ß promoted the migration of OLP mononuclear cells, while inhibiting CCR1/5 significantly decreased the trafficking of mononuclear cells, especially that of CD8+ T cells. Conclusively, OLP T-exos-induced MIP-1α/ß may drive the trafficking of CD8+ T cells after binding with CCR1/5 in OLP, contributing to the development of OLP.

Omega-3 polyunsaturated fatty acids: a promising approach for the management of oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a T-cell-mediated inflammatory disease with a risk of malignant transformation. Although the etiology of OLP is still uncertain, growing evidence suggests that oral microbiota, antigen-specific, and non-specific mechanisms are involved in the pathogenesis of OLP. Antigen-specific mechanisms include antigen presentation, T-cell activation, nuclear factor-kappa B signaling pathway, and cytokine secretion, while non-specific mechanisms consist of matrix metalloproteinases (MMP)-9 upregulation, psychological pressure, oxidative damage, aberrant expression of microRNAs (miRNAs), and autophagy. Till now, there is no cure for OLP, and the main purpose of OLP therapy is symptomatic control. FINDING: Seafood and its derivative omega-3 polyunsaturated fatty acids (n-3 PUFAs) can suppress antigen presentation, T-cell activation, and nuclear factor-kappa B signaling pathway, modulate the overexpressed inflammatory cytokines, inhibit the expression of MMP-9, as well as regulate the expression of miRNAs and autophagy. And they are possible agents for ameliorating psychological disorder and oxidative damage. Moreover, n-3 PUFAs supplementation has a beneficial effect on preventing tumorigenesis. CONCLUSION: n-3 PUFAs consumption may provide a non-toxic, inexpensive administration for OLP.

Familial oral lichen planus in a 3-year-old boy: a case report with eight years of follow-up.

BACKGROUND: Oral lichen planus (OLP) is a chronic mucocutaneous disease characterized by adult predominance and a prolonged course. However, it is rare in the pediatric population with familial aggregation. CASE PRESENTATION: A 3-year-old boy presented with pain and irritation on the oral mucosa while contacting spicy food for 2 months. Oral examination showed widespread whitish reticular and papular lesions on the lips, the dorsum of the tongue, and bilateral buccal mucosa, with diffuse erosions covered with pseudomembrane on the buccal mucosa. The boy's parents were examined to exhibit white reticular and plaque-like lesions on their oral mucosa. The three patients were clinically diagnosed as affected by OLP and histopathologically confirmed. The boy underwent topical treatment with recombinant bovine basic fibroblast growth factor (rb-bFGF) gel, and oral lesions gradually resolved and healed. Neither of his parents received treatment. During the subsequent follow-ups, none of three patients underwent any medical treatment. Fortunately, their lesions had almost faded over 8 years. CONCLUSIONS: Our case emphasizes that pediatric OLP should be recorded with family history. Besides, long-term periodic follow-up is recommended in pediatric patients with OLP for monitoring any changes in lesions.

Heterogeneity of Outcome Measures Used in Randomized Controlled Trials for the Treatment of Oral Lichen Planus: A Methodological Study.

OBJECTIVE: Oral lichen planus (OLP) is a chronic inflammatory immune disease, recognized as an oral potentially malignant disorder by the World Health Organization. There is considerable controversy over the standardized treatment of OLP, with great diversities in the outcome measures in clinical trials. This methodological study aimed to estimate the degree of consensus on outcome measures in randomized controlled trials (RCTs) for OLP treatment. METHODS: PubMed, Embase, and Cochrane databases were searched to identify RCTs published from 2004 to 2018 about OLP treatment. All the outcome measures and measurement methods mentioned in the trials were extracted and analyzed. RESULTS: After identification of 1087 articles, 88 RCTs were included. A total of 193 single-outcome measures and 119 composite outcome measures were classified into 11 different domains, the chief of which consisted of clinical symptom (78 trials; 88.6%) and clinical score (58 trials; 65.9%). Visual analog scale (65 trials; 73.9%) and Thongprasom scoring system (38 trials; 43.2%) were the predominant measurement methods. Oral health-related quality of life (except for clinical symptoms) accounted for 4.8% of all the outcome measures. CONCLUSIONS: There was high heterogeneity in outcome measures of RCTs for OLP treatment, making it difficult to make valid comparisons between different clinical trials. A core outcome set should be developed and adopted in future trials for OLP treatment.

Artemisinin and its derivatives: a potential therapeutic approach for oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a common T-cell-mediated oral mucosal disease, whose pathogenesis mainly includes antigen-specific and non-specific mechanisms. As a refractory chronic inflammatory disease, there is still no curable management for OLP till now. FINDINGS: Artemisinins are a family of compounds that are widely used as frontline treatment for malaria worldwide. In addition to its well-established antimalarial properties, emerging evidence hints that artemisinin family drugs also possess preferential immunoregulatory and anti-inflammation properties, such as modifying T lymphocytes' activation and cytokines release, modulating Th1/Th2 balance, activating regulatory T cells (Tregs), modulating inflammatory signaling pathways, as well as acting on non-specific mechanisms of OLP. However, there is still no report focused on the influence of artemisinins on OLP. CONCLUSION: This review outlined the data-based immunomodulatory effects of artemisinins on different immune cells in conjunction with their therapeutic prospective with regard to the pathogenesis of OLP, suggesting that artemisinin and its derivatives might be possible candidates for treatment of OLP.

TLR4-induced B7-H1 on keratinocytes negatively regulates CD4+ T cells and CD8+ T cells responses in oral lichen planus.

Oral lichen planus (OLP) is a T-cell-mediated autoimmune mucocutaneous disease affected by the interactions among the keratinocytes, CD4+ T cells and CD8+ T cells. B7-H1 induced by Toll-like receptors (TLRs) can suppress T-cell immune reaction, thereby resulting in immune tolerance. However, the role of TLR-mediated B7-H1 on keratinocytes in the immune response of OLP is still unknown. The present study showed that TLR4 could induce time-coursed B7-H1 expression on oral keratinocytes, and blocking NF-κB or PI3K/mTOR pathway downregulated B7-H1 transcriptional expression. Moreover, TLR4-stimulated oral keratinocytes inhibited the proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and simultaneously prompted their apoptosis. Blockade of keratinocyte-associated B7-H1 restored the declined proliferation of OLP CD4+ T cells and OLP CD8+ T cells, and prevented their increased apoptosis. Therefore, TLR4-upregulated B7-H1 on keratinocytes could decelerate immune responses of CD4+ T cells and CD8+ T cells in OLP.

Increased circulating CXCR5+ CD4+ T follicular helper-like cells in oral lichen planus.

BACKGROUND: CD4+ T-helper cell is crucial for the inflammatory autoimmune condition of oral lichen planus (OLP). Recently, the pathogenetic functions of T follicular helper (Tfh) cells, a subtype of CD4+ T-helper cells, have been revealed in autoimmune diseases for their pivotal regulation on humoral immunity. To explore the potential pathophysiological role of Tfh cells in OLP, the expression of circulating Tfh-like cells and its correlations with IL-21 and B cells were investigated. METHODS: The frequencies of CXCR5+ CD4+ Tfh-like cells and CD19+ B cells were analyzed in peripheral blood of patients with OLP and controls by flow cytometry, respectively. Besides, the serum IL-21 concentration was measured using ELISA technology. Furthermore, the correlations of CXCR5+ CD4+ Tfh-like cells with CD19+ B cells and serum IL-21 expression levels were evaluated. RESULTS: This study showed significant increased circulating Tfh-like cells (P < 0.05) and B cells (P < 0.0001), as well as decreased serum IL-21 expression (P < 0.001) in OLP. Besides, the frequency of Tfh-like cells exhibited negative correlation with B cells in OLP (r = -0.435, P < 0.05). In particular, the proportion of CXCR5+ CD4+ Tfh-like cells in peripheral blood mononuclear cells of erosive OLP was higher than non-erosive OLP and controls (P = 0.012 and 0.021, respectively). CONCLUSIONS: Increased circulating Tfh-like cells may be involved in the pathogenesis of OLP through abnormal modulation on B-cell proliferation and IL-21 production, and associated with different clinical forms of OLP.

Icaritin Reduces Oral Squamous Cell Carcinoma Progression via the Inhibition of STAT3 Signaling.

Icaritin, a traditional Chinese medicine, possesses antitumor activity. The current study aimed to investigate icaritin effect and potential mechanism on oral squamous cell carcinoma (OSCC) development. OSCC cells proliferation, apoptosis, and autophagy were analyzed after incubation with icaritin at different concentrations and incubation times. The expressions of proteins related to proliferation, apoptosis, and autophagy, as well as signal transducer and activator of transcription 3 (STAT3) signal network, were also evaluated by western blot. Furthermore, STAT3 was knocked down by siRNA transfection to determine STAT3 role in OSCC cell proliferation and apoptosis. An oral specific carcinogenesis mouse model was used to explore icaritin effect on OSCC in vivo. Icaritin significantly inhibited OSCC proliferation in vitro and reduced the expression of both the cell-cycle progression proteins cyclin A2 and cyclin D1. Besides, icaritin increased cleaved caspase 3 and cleaved poly-(ADP-ribose) polymerase expression leading to apoptosis, and it activated autophagy. Icaritin significantly inhibited the expression of phospho-STAT3 (p-STAT3) in a dose- and time-dependent manner. In the in vivo experiment, the number of malignant tumors in the icaritin-treated group was significantly lower than the control. Overall, icaritin suppressed proliferation, promoted apoptosis and autophagy, and inhibited STAT3 signaling in OSCC in vitro and in vivo. In conclusion, icaritin might be a potential therapeutic agent against OSCC development.

Altered Autophagy-Associated Genes Expression in T Cells of Oral Lichen Planus Correlated with Clinical Features.

Oral lichen planus (OLP) is a T cell-mediated inflammatory autoimmune disease. Autophagy has emerged as a fundamental trafficking event in mediating T cell response, which plays crucial roles in innate and adaptive immunity. The present study mainly investigated the mRNA expression of autophagy-associated genes in peripheral blood T cells of OLP patients and evaluated correlations between their expression and the clinical features of OLP. Five differentially expressed autophagy-associated genes were identified by autophagy array. Quantitative real-time RT-PCR results confirmed that IGF1 expression in the peripheral blood T cells of OLP patients was significantly higher than that in controls, especially in female and middle-aged (30-50 years old) OLP patients. In addition, ATG9B mRNA levels were significantly lower in nonerosive OLP patients. However, no significant differences were found in the expression of HGS, ESR1, and SNCA between OLP patients and controls. Taken together, dysregulation of T cell autophagy may be involved in immune response of OLP and may be correlated with clinical patterns.

Temperature sensitivity of organic compound destruction in SCWO process.

To study the temperature sensitivity of the destruction of organic compounds in supercritical water oxidation process (SCWO), oxidation effects of twelve chemicals in supercritical water were investigated. The SCWO reaction rates of different compounds improved to varying degrees with the increase of temperature, so the highest slope of the temperature-effect curve (imax) was defined as the maximum ratio of removal ratio to working temperature. It is an important index to stand for the temperature sensitivity effect in SCWO. It was proven that the higher imax is, the more significant the effect of temperature on the SCWO effect is. Since the high-temperature area of SCWO equipment is subject to considerable damage from fatigue, the temperature is of great significance in SCWO equipment operation. Generally, most compounds (imax > 0.25) can be completely oxidized when the reactor temperature reaches 500°C. However, some compounds (imax > 0.25) need a higher temperature for complete oxidation, up to 560°C. To analyze the correlation coefficients between imax and various molecular descriptors, a quantum chemical method was used in this study. The structures of the twelve organic compounds were optimized by the Density Functional Theory B3LYP/6-311G method, as well as their quantum properties. It was shown that six molecular descriptors were negatively correlated to imax while other three descriptors were positively correlated to imax. Among them, dipole moment had the greatest effect on the oxidation thermodynamics of the twelve organic compounds. Once a correlation between molecular descriptors and imax is established, SCWO can be run at an appropriate temperature according to molecular structure.

High-throughput absolute quantification sequencing reveals the adaptive succession and assembly pattern of plastisphere communities in municipal sewer systems: Influence of environmental factors and microplastic polymer types.

Municipal sewer systems have received increasing attention due to the magnitude of the microplastic stock and its potential ecological impacts. However, as a critical aspect of the adverse impacts, little is known about the plastisphere that forms in these engineered environments. Using high-throughput absolute quantification sequencing, we conducted a systemic study combining field survey and laboratory batch test to explain the general plastisphere pattern and the role of environmental and polymeric factors in driving plastisphere succession and assembly there. We demonstrated the capacity of microplastics to support high levels of microbial colonization, increasing by 8.7-56.0 and 1.26-5.62 times at field and laboratory scales, respectively, despite the less diverse communities hosted in the resulting plastisphere. Sediment communities exhibited higher diversity but greater loss of specific operational taxonomic units in their plastisphere than in the wastewater. The former plastisphere had primarily an enhanced methanogenesis-oriented metabolic network linked to hydrolysis fermentation, hydrogen-producing acetogenesis, and denitrification, while the latter had a pronounced niche partitioning and competitive interaction network. Exogenous substrate flux and composition were key in stimulating plastisphere community growth and succession. Furthermore, the high nitrogen baseline facilitated alternative niche formation for plastisphere nitrifiers and denitrifiers, and the plastisphere pathogens associated with denitrification and plastic biodegradation functions increased significantly. The aerobic state also promoted a 1.71 times higher colonizer load and a denser interaction pattern than the anaerobic state. Selective filtering by polymers was evident: polyethylene supported higher plastisphere diversity than polypropylene. This study provides new insights into the mechanisms driving colonizer loads and the adaptive succession and assembly of the plastisphere in such a typically hydrodynamic and highly contaminated environment. The results help to fill the knowledge gap in understanding the potential role of microplastics in shaping the microecology of sewers and increasing health risks and substrate loss during sewer transfer.

Land use, stratified wastewater and sediment, and microplastic attribute factors jointly influence the microplastic prevalence and bacterial colonization patterns in sewer habitats.

The capacity of microplastics to harbor and propagate bacteria has been the focus of attention over the last decade. Such microplastic-supported bacterial colonization behavior in the municipal sewer system could be a critical ecological link influencing the biogeochemical activities and risks in receiving waters in urban areas, given the alarming microplastic loads discharged there. This study conducted a large-scale survey covering a wide range of residential and industrial catchments in Shanghai, China. We aimed to assess the microplastic prevalence and bacterial colonization patterns in different sewer habitats and to explore the role of land use, stratified wastewater and sediment, and microplastic attributes in shaping the patterns. We found that the sewer system formed a temporal but pronounced microplastic pool, with land use playing a significant role in the variability of microplastic prevalence. Industrial sewers contained a high abundance of microplastics with large particle sizes, diverse polymer compositions, and shapes. However, while there was a spatial discrepancy between urban and suburban areas in the abundance of microplastics in residential sewers, their predominant polymer and shape types were simple, i.e., polyethylene terephthalate (PET) and fibers. Sewer habitat characteristics, particularly the stratified wastewater and sediment determined microbial colonization patterns. The latter acted as a long-term sink for microplastics and supported the high growth of colonizers. In contrast, the wastewater plastisphere presented novel niches, hosting communities with a marked proportion of unique bacterial genera after colonization. Besides, statistics showed a highly positive and dense co-occurrence network of the plastisphere communities, especially those from the industrial sewer sediment, with enhanced metabolic activity, cellular processes and systems, and increased human pathogenic potential. Findings indicated a coarse and uncertain effect of the selective pressure of microplastic attributes on plastisphere community structure differentiation.

Autophagy-related 9 homolog B regulates T-cell-mediated immune responses in oral lichen planus.

OBJECTIVES: This study aimed to explore the impacts of autophagy-related 9 homolog B (ATG9B)-mediated autophagy on T-cell immune responses in oral lichen planus. DESIGN: ATG9B expression was detected in lesions and local T cells by immunohistochemical analysis and immunofluorescence assay. The effects of ATG9B-mediated autophagy on T-cell immune responses were explored after ATG9B-overexpression or ATG9B-knockdown lentivirus transfection. A coculture system of activated T cells and lipopolysaccharide-induced keratinocytes was used to simulate the main cell crosstalk in oral lichen planus. RESULTS: The expression of ATG9B upregulated in lesions and local T cells of oral lichen planus, especially in non-erosive oral lichen planus, suggesting that ATG9B may be a diagnostic factor for oral lichen planus. Notably, ATG9B-knockdown T cells of oral lichen planus demonstrated autophagy suppression, enhanced proliferation, and attenuated apoptosis, whereas overexpression of ATG9B showed opposite effects on T cells. In the coculture system of T cells and keratinocytes, ATG9B-knockdown T cells of oral lichen planus, but not ATG9B-overexpression T cells, promoted the proliferation and apoptosis of their cocultured keratinocytes. Additionally, exogenous insulin-like growth factor 1 (IGF1) significantly reversed the apoptosis rates of keratinocytes cocultured with T cells expressing abnormal ATG9B. Furthermore, ATG9B-overexpression T cells showed decreased secretion of interferon-γ and tumor necrosis factor-α in the coculture system. CONCLUSIONS: This study revealed the regulatory roles of ATG9B-mediated T-cell autophagy on T-cell immune responses and crosstalk between T cells and keratinocytes in of oral lichen planus.

Aberrant Activation of the STING-TBK1 Pathway in γδ T Cells Regulates Immune Responses in Oral Lichen Planus.

Oral lichen planus (OLP) is a chronic T cell-mediated inflammatory disease. Interferon (IFN)-γ has been suggested to be vital for the OLP immune responses. A prominent innate-like lymphocyte subset, γδ T cells, span the innate-adaptive continuum and exert immune effector functions by producing a wide spectrum of cytokines, including IFN-γ. The involvement and mechanisms of γδ T cells in the pathogenesis of OLP remain obscure. The expression of γδ T cells in lesion tissues and in the peripheral blood of OLP patients was determined via flow cytometry and immunohistochemistry, respectively. Human leukocyte antigen-DR (HLA-DR), cluster of differentiation (CD) 69, Toll-like receptors (TLRs), natural killer group 2, member D (NKG2D) and IFN-γ were detected in γδ T cells of OLP patients using flow cytometry. Additionally, the involvement of stimulator of the interferon genes (STING)-TANK-binding kinase 1 (TBK1) pathway in γδ T cells was evaluated by multi-color immunofluorescence. Western blotting was employed to investigate the regulatory mechanisms of γδ T cells in OLP. γδ T cells were significantly upregulated in the lesion tissues, whereas their peripheral counterparts were downregulated in OLP patients. Meanwhile, increased frequencies of local CD69+ and NKG2D+ γδ T cells and peripheral HLA-DR+ and TLR4+ γδ T cells were detected in OLP. Furthermore, significant co-localization of STING and TBK1 was observed in the γδ T cells of OLP lesions. In addition, enhanced IFN-γ and interleukin (IL)-17A were positively associated with the activated STING-TBK1 pathway and γδ T cells in OLP. Taken together, the upregulated STING-TBK1 pathway in activated γδ T cells might participate in the regulation of immune responses in OLP.